Novel Deposition and In Vitro Dissolution Model for Orally Inhaled Drug Products

Purpose Administration of aerosolised drugs to the lungs represents an effective route for local and systemic drug administration, with advantages such as large surface area, good permeability, optimum blood perfusion and avoidance of the first pass effect. However, the fate of an inhaled particle upon deposition remains unclear. Factors such as aerodynamic particles size, surface area of inhaled particulates and site of delivery may directly affect dissolution rates and thus pharmacological effects for dissolution limited drugs (Davies and Feddah, 2003). For solid oral dosage forms, pharmacopoeias describe standard tests for the dissolution of solid and semisolid formulations for in-vitro quality control, as well as comparisons between pharmaceutical dosage forms and predictive estimates of in-vivo behaviour. There is not, however, a standardized method for dissolution studies of inhaled products. Several previous studies have focused on dissolution for aerosols, but appear to be limited by experimental difficulties related to aerosol dose collection (Niemiec et al 2014; Son and McConville 2009). This study attempts to address these issues and understand the fate of inhaled particles within the respiratory tract. A specific dissolution test for aerosols, which integrates particles deposition and dissolution studies in sink conditions, was developed. In our study an in-vitro dissolution method that can be applied for discrimination as well as bio relevant studies and having a novel membrane holder was developed and validated for inhalation products. Methods From a Dry Powder Inhaler (DPI) containing Fluticasone Propionate (FP) as active ingredient (Flixotide 250ìg), aerosolized particles were collected on a glass fibre filter (i.e. GF/D 25 mm diameter Whatman®) using a NGI apparatus modified on stage 2 with a novel sample holder and vacuum pump set at 60 L/min for 4s. This novel modification of the stage 2 allowed collection of particles under a uniform air stream, resulting in even distribution of aerosolised particles on the filters surface. Increased doses (1, 2, 5 and 10 doses) from DPI were loaded upon GF/D filters using the novel membrane holder on NGI stage 2. Each filter was then placed in a flow through cell and dissolution testing was performed with USP IV apparatus (Erweka DFZ 720) operating as an open system. During dissolution a constant flow of fresh solvent through the cells at a flow rate of 2 or 4 ml/min was set at 37°C. The media used was phosphate buffer saline solution (Tomaszewska et al., 2013) with 0.2% w/w SLS. Samples were collected every 15 minutes for 240 minutes. After dissolution the total recovery was also measured by washing filters in defined quantities of mobile phase and sonicating. All quantification measurements were carried out by HPLC-UV (Agilent Technologies, 1200 Series). All experiments were run in triplicate. Results The flow through cell dissolution apparatus (USP IV) provides sink conditions, during the whole test period being particularly suitable for poorly soluble drugs such as FP. Powder dissolution profiles of Flixotide 250ìg at 2 mL/min loaded with 1 dose released >90% within the first 60 minutes and reached 100% release after 120 minutes. Whereas at the same flow rate (2 mL/min) samples loaded with higher doses (2, 5, 10 doses) showed a similar dissolution performance but slower compared to the performance of the lower dose under these conditions and the % dissolved reached >90% in 240 minutes of dissolution. This dissolution conditions used were able to estimate dissolution rates of this inhalation product and to provide discrimination between the different doses. Using a higher flow rate (4mL/min) all samples (1, 2, 5 and 10 doses) reached 100% dissolution after 60 minutes, with negligible differences between the loaded doses providing the biorelevance of the selected conditions. Conclusion A novel deposition model has been developed for the evaluation of in-vitro dissolution behaviour of an aerosol formulation and the dissolution performance of a commercial product with an open flow through cell system was successfully estimated. The method developed would be suitable for quality control studies of DPIs and for prediction of their in vivo performance.