Inhaled JAK Inhibitor GDC-0214 Nanoaggregate Powder Exhibits Improved Pharmacokinetic Profile in Rats Compared to the Micronized Form: Benefits of Thin Film Freezing.

Asthma is a common chronic disease affecting the airways in the lungs. The receptors of allergic cytokines, including interleukin (IL)-4, IL-5, and IL-13, trigger the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which involves the pathogenesis of asthma. GDC-0214 is a JAK inhibitor that was developed as a potent and selective target for the treatment of asthma, specifically targeting the lungs. While inhaled GDC-0214 is a promising novel treatment option against asthma, improvement is still needed to achieve increased potency of the powder formulation and a reduced number of capsules containing powder to be inhaled. In this study, high-potency amorphous powder formulations containing GDC-0214 nanoaggregates for dry powder inhalation were developed using particle engineering technology, thin film freezing (TFF). A high dose per capsule was successfully achieved by enhancing the solubility of GDC-0214 and powder conditioning. Lactose and/or leucine as excipients exhibited optimum stability and aerosolization of GDC-0214 nanoaggregates, and aerosolization of the dose was independent of air flow through the device between 2 and 6 kPa pressure drops. In the rat PK study, formulation F20, which contains 80% GDC-0214 and 20% lactose, resulted in the highest AUC0-24h in the lungs with the lowest AUC0-24h in the plasma that corresponds to a 4.8-fold higher ratio of the lung-to-plasma exposures compared to micronized crystalline GDC-0214 powder administered by dry powder inhalation. Therefore, GDC-0214 nanoaggregates produced by TFF provided an improved dry powder for inhalation that can lead to enhanced therapeutic efficacy with a lower risk of systemic toxicity.

Pharmaceutical dry powders of small molecules prepared by thin-film freezing and their applications - A focus on the physical and aerosol properties of the powders.

Thin-film freeze-drying is a dry powder engineering technology that involves in a rapid thin-film freezing (TFF) process followed by lyophilization to remove solvent. TFF process has been successfully used to produce pharmaceutical powders of the small and large molecule drugs as well as live organisms. This paper provides a comprehensive review of the pharmaceutical applications of TFF powders of small molecule drugs intended for pulmonary delivery or oral administration. The powders produced by the TFF process often exhibited unique physical properties such as amorphous morphology, high porosity, brittle matrix structure, and high specific surface area, and the powders also often contain loosely connected micron or submicron particles or aggregates. The TFF process parameters and formulation compositions directly affect the physical properties of the powders. These physical properties render TFF powders desirable aerodynamic properties for efficient pulmonary delivery by oral inhalation and help enhance the dissolution of poorly water-soluble small molecule drugs in the powders and thus improve their bioavailability after oral administration.

Inhaled nanoparticles-An updated review.

We are providing an update to our previously published review paper on inhaled nanoparticles, thus updating with the most recent reports in the literature. The field of nanotechnology may hold the promise of significant improvements in the health and well-being of patients, as well as in manufacturing technologies. The knowledge of the impact of nanomaterials on public health is limited so far. This paper reviews the unique size-controlled properties of nanomaterials, their disposition in the body after inhalation, and the factors influencing the fate of inhaled nanomaterials. The physiology of the lungs makes it an ideal target organ for non-invasive local and systemic drug delivery, especially for protein and poorly water-soluble drugs that have low oral bioavailability via oral administration. More recently, inhaled nanoparticles have been reported to improve therapeutic efficacies and decrease undesirable side effects via pulmonary delivery. The potential application of pulmonary drug delivery of nanoparticles to the lungs, specifically in context of published results reported on nanomaterials in environmental epidemiology and toxicology is reviewed in this paper. This article presents updated delivery systems, process technologies, and potential of inhaled nanoparticles for local and systemic therapies administered to the lungs. The authors acknowledge the contributions of Wei Yang in our 2008 paper published in this journal.