(W0930-08-52) Method Development for the Evaluation of Orally Inhaled Drug Products (OIDPs) containing Spray-Dried Phospholipid Porous Particles (PPPs)

Purpose: Spray-dried phospholipid porous particles (PPPs) are increasingly used in orally inhaled drug products (OIDPs) such as dry powder inhalers (DPIs) and meter-dosed inhalers (MDIs). PPPs enable higher drug loading, improved dose uniformity and lung deposition as compared to OIDPs formulated with traditional drug-excipient (e.g., lactose). The PPPs' distinctive nano-sized (200–500 nm) pore structure creates an ultra-low density that minimizes particle aggregation and allows for lung penetration. Identifying suitable techniques for the characterization of PPP-containing OIDPs is important for understanding how differences in PPPs may affect an OIDP’s product quality and performance that may impact bioequivalence (BE). This study aims to develop techniques for morphological and physicochemical characterization of OIDPs containing spray-dried PPPs, which may aid the assessment of product quality and performance for these OIDPs.

Methods: One DPI and two MDIs (MDI-1 and MDI-2) containing spray-dried PPPs, were used as model drug products. The active pharmaceutical ingredient (API) for DPI is tobramycin; APIs in MDI-1 are glycopyrrolate and formoterol fumarate and APIs in MDI-2 are budesonide, glycopyrrolate and formoterol fumarate. A dry powder dispersion unit on Morphologically Directed Raman Spectroscopy (MDRS) was used for sample collection from DPI. A dosage unit sampling apparatus (DUSA) was used for sample collection from the MDIs. Different types of filter membranes (i.e., polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), and glass fiber) and various air flow rates (i.e., 8-28 L/min) were tested in the DUSA. Scanning electron microscopy (SEM) was carried out for morphological studies of the PPPs. The physicochemical characterization of these formulations, including particle size distribution, thermal analysis, water content, and water activities, were evaluated with MDRS, Differential Scanning Calorimeters (DSC), Thermogravimetric Analysis (TGA), and Dynamic Vapor Sorption analyzer (DVS), respectively.

Results: The SEM results in Figure 1A demonstrate that the DPI formulation contained highly porous spherical particles. These particles ranged in size from hundreds of nanometers to five micrometers. The particles in MDI formulations were found to have a similar size distribution but tended to aggregate when transferred from the filter membrane to the carbon tape for SEM imaging (Figures 1B and 1C). MDI particles were better dispersed on the PTFE and PVDF filter membranes without transferring to the carbon tape for imaging (Figures 1D and 1E). MDRS examination of the particle size reported the mean circle equivalent (CE) diameter (number distribution) for the DPI, MDI-1 and MDI-2 as 3.7 µm, 3.4 µm and 5.2 µm, respectively. DSC analyses revealed that all APIs and excipients in both DPI and MDIs showed crystalline thermographs. The TGA results revealed that the DPI had 9.3% of water whereas MDI-1 and MDI-2 had 5.5% and 6.5% of water, respectively. DVS results of the DPI, MDI-1 and MDI-2 revealed 15.4%, 8.1% and 4.4% of moisture absorption, respectively, when samples were exposed to 60% of relative humidity (RH) at room temperature, which agreed with the TGA results.

Conclusion: The sample preparation technique and several physicochemical characterization methods were successfully developed to evaluate different OIDPs containing spray-dried PPPs. In addition, sample preparation technique was shown to be critical for minimizing particle aggregation when evaluating the PPP morphology from MDI products.

References: 1. Amber Doty, et. al., "Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability" AAPS PharmSciTech, Vol. 19, No. 2, February 2018 (# 2017) DOI: 10.1208/s12249-017-0891-1.

Acknowledgements: Disclaimer: This poster reflects the views of the authors and should not be construed to represent the views or policies of the Food and Drug Administration. Funding Support: FDA intramural research fund (CORES Fund)

Figure 1: SEM images of PPP particles from a DPI (A); MDI-1 (B) and MDI-2 (C); MDI-1 on PTFE 0.45 µm membrane (D) and MDI-1 on PVDF 0.45 µm membrane (E) (all images at 10 kx magnification)