Development of in vitro dissolution tests for orally inhaled products

Abstract

Background: Dissolution testing has been proposed as a sensitive and discriminatory in vitro test for evaluating the quality or similarity of inhaled pharmaceuticals. This has led to a number of bespoke respirable particle collection and dissolution techniques being developed by academic and industrial pharmaceutical scientists. However, each comes with limitations and there is no standard or universal dissolution system for orally inhaled products. A dissolution test system would ideally reproduce conditions that represent the in vivo lung environment and would have the potential to be used for both quality control purposes and as a predictive in vitro-in vivo correlation tool. However, test systems proposed to date do not meet these criteria fully, for example many have not utilised media designed to simulate respiratory tract lung fluid (RTLF). Dissolution methodology should fulfil requirements such as simplicity, reproducibility, ease of handling, robustness and be able to discriminate differences between inhaler batch, product and formulation types. Aim: The aim of this thesis was to develop dissolution methods for OIPs by identifying the critical attributes and shortcomings of current systems and designing and evaluating improved systems using fluticasone propionate (FP) as the model drug. Methods: Two dissolution systems were evaluated: a Next Generation Impactor/Rotating paddle system and a Twin stage Impinger/Transwell® system. A novel simulated lung fluid (SLF) based on the major components of human RTLF was manufactured and characterised in terms of its physicochemical properties and stability in solution and after freeze-drying. The solubility and dissolution of inhaled drugs, including FP, were evaluated in the SLF and compared to other media. The impact of using SLF as a dissolution media was evaluated in a biorelevant dissolution system, the novel DissolvIt® system, and an in-silico PBPK model was developed and applied to evaluate the impact of in vitro data on drug pharmacokinetics and enable comparison with in vivo data. To develop the TSI/Transwell system as a biorelevant system, a Design of Experiments (DOE) approach was used to identify the influence of temperature, stirring and the solubilising capacity of dissolution media on dissolution profiles of FP. Finally, a biorelevant methodology was used to compare the dissolution of nebulised suspension and microemulsion formulations to other inhaled formulations. Results: Both dissolution systems were simple and easy to handle, producing reproducible data. Although the novel NGI/rotating paddle system was a convenient starting point for quality control purposes, the TSI/Transwell system was more amenable to development as a biorelevant technique as it was able to mimic the low fluid volume of RTLF and could be used with lung fluid simulants that are expensive and only available in limited volume. A SLF of biorelevant composition, consisting of proteins (albumin, transferrin and IgG), lipids (DPPC, DPPG and cholesterol) and antioxidants, was characterised. It was shown to possess physiochemical properties comparable to those of RTLF, such as being an isotonic solution with a physiological pH of 7.2, viscosity of 1.138 x 10-3 Pa s, conductivity of 14.5 mS/m, surface tension of 54.9 mN/m and density of 0.999 g/cm3.The simulant was stable for 24 and 48 h at 37 and 20°C and for 14 days at 4°C and when freeze-dried. A novel and sensitive solid phase extraction and LC-MS/MS technique for the assay of FP was established and validated successfully to quantify the drug in low concentrations in biological matrices, in picogram concentrations. In the DissolvIt system the use of SLF as a dissolution medium did not impact on dissolution profiles compared to the standard polymer solution (P>0.05), but DOE using the TSI/Transwell system found solubilising capacity of the medium to be a major factor. Biorelevant conditions assigned as a dissolution medium of 0.1% w/v SDS in PBS (providing the same solubilising capacity as SLF), temperature 37°C and stirring rate 15 rpm. These biorelevant dissolution test conditions indicated that the dissolution of FP from a novel microemulsion formulation reached approximately 70% (almost double) over the 8 h experiment, compared to the dissolution of FP from the Flixotide suspension formulation (P< 0.05). Conclusion: A simulated lung fluid has been developed for use in a dissolution system tailored to orally inhaled products. The dissolution technique is sensitive to temperature, stirring and the solubilising capacity of the dissolution medium and in preliminary tests has shown promise in discriminating between different fluticasone inhaler products and formulations.

Date of Award	2019
Original language	English
Awarding Institution	King's College London
Supervisor	Ben Forbes (Supervisor) & Paul Royall (Supervisor)