Impactor-type
dose deposition is a common prerequisite for dissolution
testing of inhaled medicines, and drug release typically takes place
through a membrane. The purpose of this work is to develop a mechanistic
model for such combined dissolution and release processes, focusing
on a drug that initially is present in solid form. Our starting points
are the Noyes–Whitney (or Nernst–Brunner) equation and
Fick’s law. A detailed mechanistic analysis of the drug release
process is provided, and approximate closed-form expressions for the
amount of the drug that remains in solid form and the amount of the
drug that has been released are derived. Comparisons with numerical
data demonstrated the accuracy of the approximate expressions. Comparisons
with experimental release data from literature demonstrated that the
model can be used to establish rate-controlling release mechanisms.
In conclusion, the model constitutes a valuable tool for the analysis
of in vitro dissolution data for inhaled drugs.
Hydrogels warrant attention as a potential material for use in sustained pulmonary drug delivery due to their swelling and mucoadhesive features. Herein, hyaluronic acid (HA) is considered a promising material due to its therapeutic potential, the effect on lung inflammation, and possible utility as an excipient or drug carrier. In this study, the feasibility of using HA hydrogels (without a model drug) to engineer inhalation powders for controlled pulmonary drug delivery was assessed. A combination of chemical crosslinking and spray-drying was proposed as a novel methodology for the preparation of inhalation powders. Different crosslinkers (urea; UR and glutaraldehyde; GA) were exploited in the hydrogel formulation and the obtained powders were subjected to extensive characterization. Compositional analysis of the powders indicated a crosslinked structure of the hydrogels with sufficient thermal stability to withstand spray drying. The obtained microparticles presented a spherical shape with mean diameter particle sizes from 2.3 ± 1.1 to 3.2 ± 2.9 μm. Microparticles formed from HA crosslinked with GA exhibited a reasonable aerosolization performance (fine particle fraction estimated as 28 ± 2%), whereas lower values were obtained for the UR-based formulation. Likewise, swelling and stability in water were larger for GA than for UR, for which the results were very similar to those obtained for native (not crosslinked) HA. In conclusion, microparticles could successfully be produced from crosslinked HA, and the ones crosslinked by GA exhibited superior performance in terms of aerosolization and swelling.
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.
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