Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health burdens on the global population. To treat diseases of the lung, topical therapies using dry powder inhalers (DPIs) have been employed. However, a relatively small amount of dose (5.5 - 28 %) reaches the lung during DPI therapy leading to high inter-patient variability in therapy response and oropharyngeal deposition. Strategies were assessed to take patient variability in inhalation performance into account when developing devices to reduce throat deposition and to mitigate flow rate dependency of the emitted aerosol. A cyclone-spacer was manufactured and evaluated with marketed and in-house manufactured formulations. An in vivo study showed that a high resistance inhaler would produce longer inhalation times in lung disease patients and that a spacer with high resistance may prove a suitable approach to address inter-patient variability. Two spacer prototypes were evaluated with cohesively- and adhesively-balanced particle blends. The data suggested that the throat deposition dramatically decreased for the emitted particles when the spacers were used with the inhalers (e.g. 18.44 ± 2.79% for salbutamol sulphate, SS 4 kPa) due to high retention of the formulation within the spacer (87.61 ± 2.96%). Moreover, variation in fine particle fraction and dose was mitigated when increasing the flow rate (82.75 ± 7.34 %, 92.2 ± 7.7 % % and 77.0 ± 10.1 % at 30, 45 and 60 Lmin-1, respectively). The latter was an improvement over previous proposed DPI spacers, where variability in emitted dose due to airflow rate was a major issue. Due to the different physicochemical properties of the active pharmaceutical ingredients used in the formulation, throat deposition and respirable fraction for adhesively-balanced particles (e.g. SS) were double that of the cohesively- balanced particles (salmeterol xinafoate, SX) (e.g. 65.83 ± 8.99 % vs. 45.83 ± 5.04 % for SS:Coarse Lactose (CL) and SX:CL, respectively). Scanning electron microscopy revealed that surface-bound agglomerates were more freely removed from the carrier, but subject to decreased impaction-type deagglomeration forces in the spacer than for carrier-bound drug. An ex vivo study using breath profiles from healthy volunteers identified the minimization of differences between adhesively- and cohesively-balanced blends when full breath profiles were studied compared to square-wave airflow. Therefore the use of constant flow for in vitro testing should not be the sole flow regime to study aerosolization when developing new inhalation devices and formulations.

Class of 2015 Abstract / Objectives: To evaluate the in vitro performance of various pressurized metered dose inhaler (pMDI) formulations by cascade impaction primarily focusing on throat deposition, fine particle fraction (FPF), and mass-median aerodynamic diameter (MMADR) measurements Methods: Ten solution pMDIs were prepared with varying cosolvent species in either low (8% w/w) or high (20% w/w) concentration. The chosen cosolvents were either alcohol (ethanol, n-propanol) or acetate (methyl-, ethyl-, and butyl acetate) in chemical nature. All formulations used HFA-134a propellant and 0.3% drug. The pMDIs were tested by cascade impaction with three different inlets to determine the aerodynamic particle size distribution (APSD), throat deposition, and FPF of each formulation. Theoretical droplet evaporation time (DET), a measure of volatility, for each formulation was calculated using the MMADR. Results: Highly volatile formulations with short DET showed consistently lower throat deposition and higher FPF than their lower volatility counterparts when using volume-constrained inlets. However, FPF values were not significantly different for pMDI testing with a non-constrained inlet. The MMADR values generated with volume-constrained inlets did not show any discernible trends, but MMADR values from the non-constrained inlet correlated with DET. Conclusions: Formulations with shorter DET exhibit lower throat deposition and higher FPF, indicating potentially better inhalational performance over formulations with longer DET. There appear to be predictable trends relating both throat deposition and FPF to DET. The shift in MMADR values for volume-constrained inlets suggests that large diameter drug particles are preferentially collected in these inlets.

Surface energetics play a key role in the delivery of a dry powder inhaler formulation into the lungs, as there must be a sufficient balance of adhesive and cohesive forces to allow optimal lung delivery. In this study, measuring the surface energies of a set of single drug and carrier (budesonide or theophylline with either mannitol or lactose) with different levels of surfactant using Inverse Gas Chromatography, and comparing them to their lung deposition performance using a Next Generation Impactor established a relationship between the two. A 1:10 mixing ratio of budesonide with either carrier was found to have the highest FPF. Coating the carriers with 0.05% sodium lauryl sulphate resulted in a further increase in the FPF when using either budesonide or theophylline as the API, and the same results were seen when a sonocrystallised version of the API was substituted for the micronised form. The calculated IGC values then showed that the highest performing formulations had the lowest dispersive energy and total free surface energy. Furthermore, a trend was observed in the work of adhesion (Wa) and work of cohesion (Wc) for each set of formulations depending on which API was chosen, where for the less polar drug (budesonide) a higher Wa/Wc ratio was associated with the highest formulation performance, and for the more polar drug (theophylline) a smaller Wa/Wc ratio was associated with the highest formulation performance, enabling the estimation of lung performance for a set of single drug and carrier using their surface energy data. / Kuwait’s government and the Ministry of Health of Kuwait