Same lung deposited dose in dog dosing a fine and coarse aerosol indicates no difference in intranasal filtration.

A novel inhalation exposure system was developed with the aim to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog. It enables collecting PK data for multiple drug candidates in a single experiment by simultaneous administration of the drugs to the same animal. This facilitates a direct PK comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective.

Hyaluronic Acid Hydrogels for Controlled Pulmonary Drug Delivery-A Particle Engineering Approach.

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.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients.

Milling of poorly soluble crystalline drug compounds to generate appropriate particle sizes for inhaled sustained drug delivery.

One of the simplest design concepts of inhaled sustained drug delivery to the lung is to utilize the slow dissolution of drug crystals with poor aqueous solubility. An optimum dissolution rate, and thereby a delivery profile locally in the lung tissue, can be achieved in a reliable way by selecting a compound with an appropriate combination of solubility and particle size. It is in our experience relatively straightforward to manufacture monomodal particle size distributions of poorly soluble drug crystals in the mass median diameter range of either a few micrometers or a few hundred nanometers, but very challenging to manufacture a monomodal distribution in the range intermediate to these two.

Nanoscale characterization of PEGylated phospholipid coatings formed by spray drying on silica microparticles.

Phospholipids constitute biocompatible and safe excipients for pulmonary drug delivery. They can retard the drug release and, when PEGylated, also prolong the residence time in the lung. The aim of this work was to assess the structure and coherence of phospholipid coatings formed by spray drying on hydrophilic surfaces (silica microparticles) on the nanoscale and, in particular, the effect of addition of PEGylated lipids thereon.

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging.

For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI).

Applying spectral peak area analysis in near-infrared spectroscopy moisture assays.

Spectral peak area analysis has in this study been shown to be a viable method in near-infrared spectroscopy (NIRS) moisture assays. The study also shows that the required number of calibration samples can be minimized, and the method is, therefore, especially suitable for moisture assays in early formulation development and in-situ process monitoring. Diffuse NIRS was utilized in the development of moisture assays for the model compounds polyvinylpyrrolidone and hydroxypropyl-beta-cyclodextrin and also for a lyophilized formulation.

In-situ near-infrared spectroscopy monitoring of the lyophilization process.

Purpose: The purpose of this work was to demonstrate the feasibility of using near-infrared spectroscopy (NIRS) to monitor the freeze-drying process in-situ.

Methods: The experiment was performed in a pilot-scale freeze-dryer, in which the NIRS probe was interfaced using a lead-through to the lyophilizer. Special equipment for the sample presentation was developed.