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The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.4, 3.9 and 6.3 mu m) were analysed after aerosolization in a modified Andersen Cascade Impactor. Systematic control of the release rate of drug loaded into the particles was demonstrated in simulated lung fluid by variation of the mean particle diameter, as well as an enhanced release compared to a commercial micronized formulation. The mesoporous silica formulations all demonstrated an increased release rate of the loaded drug and moreover, under aerosolization from a commercial, low-cost dry powder inhaler (DPI) device, the formulations showed excellent performance, with low retainment and commercially viable fine particle fractions (FPFs). In addition, the measured median mass aerodynamic diameter (MMAD) of the different formulations (2.8, 4.1 and 6.2 mu m) was shown to be tuneable with particle size, which can be helpful for targeting different regions in the lung. Together these results demonstrate that mesoporous silica formulations offer a promising novel alternative to current dry powder formulations for pulmonary drug delivery.

In this study, the effect of pressure drop (Delta P) on the in vitro dispersion of a series of carrier-based adhesive mixtures of different fines-to-carrier proportions, corresponding to the four different blend states of the blend state model, i.e. S1 to S3, was investigated. Four binary and one ternary adhesive mixture consisting of lactose carrier and budesonide fines and lactose fines were prepared. The dispersion was assessed using a next generation impactor (NGI) at Delta P of 0.5, 2 and 4 kPa. For the S1 mixture, where the fines were located in surface cavities of the carrier, the fine particle fraction (FPF) increased nearly linearly with Delta P. For S2 and S3 mixtures, with adhesion layers on the enveloped carrier surface, the FPF-Delta P relationships were bended and approached a plateau. Examination of powder captured in the pre-separator of the NGI led to the conclusion that the dispersion of these adhesive mixtures occurred by erosion of the adhesion layer, i.e. budesonide was liberated as single particles or micro-agglomerates. It is concluded that the FPF-Delta P relationships were dependent on the blend state and for the S2 and S3 mixtures, a critical pressure drop was identified above which the pressure drop had a limited effect on the FPF.

Dissolution rate impacts the absorption rate of poorly soluble inhaled drugs. In vitro dissolution tests that can capture the impact of changes in critical quality attributes of the drug product on in vivo dissolution are important for the development of products containing poorly soluble drugs, as well as modified release formulations. In this study, an extended mathematical model allowing for dissolution of polydisperse powders and subsequent diffusion of dissolved drug across a membrane is described. In vitro dissolution profiles of budesonide, fluticasone propionate, and beclomethasone dipropionate delivered from three commercial drug products were determined using a membrane-type Transwell dissolution test, which consists of a donor and an acceptor compartment separated by a membrane. Subsequently, the profiles were analyzed using the developed mechanistic model and a semi-empirical model based on the Weibull distribution. The two mathematical models provided the same rank order of the performance of the three drug products in terms of dissolution rates, but the rates were significantly different. The faster rate extracted from the mechanistic model is expected to reflect the true dissolution rate of the drug; the Weibull model provides an effective and slower rate that represents not only drug dissolution but also diffusion across the Transwell membrane. In conclusion, the developed extended model provides superior understanding of the dissolution mechanisms in membrane-type (Transwell) dissolution tests.

The aim of this study was to determine the thickness of the hydrodynamic diffusion layer (h(HDL)) of three poor water-soluble compounds under laminar fluid flow using a single particle dissolution technique. The single particle dissolution experiments were performed in a flowing aqueous medium using four different fluid velocities (v), ranging from 46 to 103 mm/s. The particles used had an initial radius (r) of 18.8 to 52.3 mu m. The determined h(HDL) values were calculated from both dissolution experiments and computational fluid dynamics (CFD) simulation. In this study, single particle dissolution experiments gave, with one exception, h(HDL) values in the range of 2.09 to 8.85 mu m and corresponding simulations gave h(HDL) values in the range of 2.53 to 4.38 mu m. Hence, we found a semi-quantitative concordance between experimental and simulated determined h(HDL) values. Also, a theoretical relation between the dependence of hHDL on particle radius and flow velocity of the medium was established by a series of CFD simulations in a fluid velocity range of 10-100 mm/s and particle size (radius) range of 5-40 mu m. The outcome suggests a power law relation of the form h(HDL)alpha r(3/5)v(-2/5). In addition, the h(HDL) seems to be independent of the solubility, while it has a diffusion coefficient dependence. In conclusion, the hHDL values were determined under well-defined conditions; hence, this approach can be used to estimate the h(HDL) under different conditions to increase the understanding of the mass transfer mechanisms during the dissolution process.