Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs

University of Technology Sydney. Graduate School of Health.The nose, is a promising site to deliver drugs with low oral bioavailability and for treatment of conditions that require a rapid onset of action. It is the first option to treat localized diseases such as rhinitis but also it can be used as site to deliver drug systemically. In the future, the number of product administered through the nose it is expected to increase, as more drugs will require an effective route for drug absorption. Hence, while the current characterization of nasal product focus mainly on the physicochemical properties of spray formulations, the biopharmaceutical evaluation of new nasal drug delivery products and formulations will require robust and reliable pre-clinical in vitro models. The first aim of this study was to develop an apparatus able to perform deposition and permeation of nasal formulation at the same time, mimicking so the in vivo process of drug administration. The second aim was the application of this model to the characterization of commercial products and the development of novel formulations. In particular, to provide a physiologically relevant surface and barrier for the deposition and permeation studies, the cell line RPMI 2650 was chosen in order to establish a model of the nasal mucosa. The model was obtained using the air-liquid interface culturing method, in which the upper surface of the cell is exposed to air after the seeding on cell culture insert. The model developed showed production of mucus, expression of xenobiotic transporters similar to primary nasal cells and barrier properties matching those reported in literature for excised human nasal mucosa. The deposition apparatus was produced via 3D printing starting from an expansion chamber proposed by FDA for the determination the aerodynamic particle size of nasal sprays with cascade impactors. The apparatus developed consists of a plastic chamber able to accommodate cell culture inserts on its internal surface. This allows the deposition of aerosolised particles directly onto the surface of the RPMI 2650 cells previously cultured on inserts. The apparatus was validated against FDA glass expansion chamber using three different commercial products: two suspensions and one powder. The powder has shown faster permeation rate across RPMI 2650 cells nasal mucosa model. In conclusion, this work has developed, validated and tested an in vitro method to assess particles deposition and drug permeation in conditions similar to those occurring in vivo and which will be useful for the characterization and development of future nasal products

Mitral valve repair [version 1; referees: 3 approved]

Mitral regurgitation (MR) is the most common valvular heart disease in the Western world. The MR can be either organic (mainly degenerative in Western countries) or functional (secondary to left ventricular remodeling in the context of ischemic or idiopathic dilated cardiomyopathy). Degenerative and functional MR are completely different disease entities that pose specific decision-making problems and require different management. The natural history of severe degenerative MR is clearly unfavorable. However, timely and effective correction of degenerative MR is associated with a normalization of life expectancy. By contrast, the prognostic impact of the correction of functional MR is still debated and controversial. In this review, we discuss the optimal treatment of both degenerative and functional MR, taking into account current surgical and percutaneous options. In addition, since a clear understanding of the etiology and mechanisms of valvular dysfunction is important to guide the timing and choice of treatment, the role of the heart team and of echo imaging in the management of MR is addressed as well

Combination of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate for the treatment of inflammatory lung diseases: An in vitro study

This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL – SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL – SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) – SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL – SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA – SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent

Nanoemulsion-Enabled Oral Delivery of Novel Anticancer ω-3 Fatty Acid Derivatives

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathways linked to their proliferation and invasiveness. In particular, ω-3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study, 16-(4'-chloro-3'-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω-3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI < 0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug

Co-Spray-Dried Urea Cross-Linked Hyaluronic Acid and Sodium Ascorbyl Phosphate as Novel Inhalable Dry Powder Formulation

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL-SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA-SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 +/- 4.8% and 75.5 +/- 7.2% for SD HA-SAP, 70.0 +/- 1.5% and 66.5 +/- 5.7% for SD HA-CL-SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter similar to 3.4 mm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 +/- 0.7% for SD HA-SAP and 35.3 +/- 0.3% for SD HA-CL-SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (&gt;90% of SAP transported within 4 h). The innovative SD HA-CL-SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved