Respiratory. Martin Jetzer DDL27 Edinburgh December 2016

Transcription

1 Respiratory Investigating the Effect of the Force Control Agent Magnesium Stearate in Fluticasone Propionate Dry Powder Inhaled Formulations with Single Particle Aerosol Mass Spectrometry Martin Jetzer DDL27 Edinburgh December 216

2 Agenda 1. Introduction and Aims of the Study 2. Single Particle Aerosol Mass Spectrometry (SPAMS) 3. Results 4. Conclusions 2

3 Background Blending lactose together with a Force Control Agent (FCA) can modify the aerosol performance of inhaled pharmaceutical products Choice of blending technique can be used to influence the aerosol performance e. g. mechanofusion, particle smoothing and others Particle interactions were investigated with AFM (CAB), IGC and cascade impactors (ACI, NGI) 3

4 Introduction and Aims of the Study Mechanistic understanding of how FCAs alter the aerosol performance Active blends with Fluticasone Propionate manufactured with MgStcontent between.1 and.5% (w/w) FP Lactose (untreated, % MgSt) as reference FP Lactose.1% MgSt FP Lactose.5% MgSt FP Lactose.1% MgSt FP Lactose.5% MgSt High-shear mixing Low-shear mixing Aerosol performance determined with SPAMS and NGI Formulation systems were investigated with additional analytical techniques including SPAMS and Tof-SIMS 4

5 SPAMS 3. DPI setup Sizing by light scattering Dae Mass spectrum by desorption/ionization chemical identity 5 Calibration of the instrument with particles of known size (transit time) Convert Dae into mass

6 Why SPAMS? Aerodynamic diameters and chemical compositions of individual aerosol particles in real-time APSD of the API and excipient is determined simultaneously. Mass spectra give additional information on co-associations of APIs and excipients Identify differences between formulations at least as well as cascade impaction (NGI) APSD data obtained by SPAMS correlate with NGI data 6

7 Particle interface in action SPAMS 3. basic principle of operation Aerodynamic lenses Oscilloscope trace Scattering laser D/I laser Mass spectrum by desorption/ionization 7

8 SPAMS Data Fluticasone Propionate Dae 2.3 μm -19 λ=248nm Excipient Lactose and MgSt Dae 4.1 μm 8

9 Number of Particles Number of particles SPAMS Aerodynamic Particle Size Distribution FP Lactose untreated FP Lactose untreated FP Lactose.1% MgSt (high-shear) FP Lactose.1% MgSt (low-shear) FP Lactose.5% MgSt (high-shear) FP Lactose.5% MgSt (low-shear) High-shear 12 Low-shear Aerodynamic diameter [μm] Aerodynamic diameter [μm] 9

10 Amount FP [mcg] Amount FP [mcg] NGI Aerodynamic Particle Size Distribution FP Lactose untreated FP Lactose untreated FP Lactose.5% MgSt (high-shear) FP Lactose.5% MgSt (low-shear) High-shear 6 5 Low-shear

11 Fine Particle Fraction obtained by NGI (% of Declared Content) Results collected by SPAMS can be correlated to NGI results. NGI shows an increase in FPF for the high-shear manufactured blend Both techniques showed a similar increase in NGI Cup4 - Cup8 (cutoff μm) Formulation FPF [%] ± SD Δ [%] FP Lactose untreated 24.4 ± FP Lactose.1% MgSt (high-shear) 26.3 ± FP Lactose.5% MgSt (high-shear) 32.2 ± FP Lactose.1% MgSt (low-shear) 22. ± FP Lactose.5% MgSt (low-shear) 22.3 ±

12 Surface Imaging Distribution of MgSt Time-of-flight Secondary Ion Mass Spectrometry (ToF-SIMS) High-shear blend μm Mg+ MC: 2 42; TC: 5.939e+5 4 μm 2 C3H5O2+ MC: 43; TC: 3.561e+5 4 μm 2 Overlay of Mg+, C3H5O2+, Low-shear blend μm Mg+ MC: 2 19; TC: 1.226e+4 4 μm 2 C3H5O2+ MC: 5; TC: 1.521e+6 4 μm 2 Overlay of Mg+, C3H5O2+, 4 Red: Ion signal for Mg + (from MgSt) Green: Ion signal for lactose (C 3 H 5 O 2+ ) Overlay of MgSt and lactose 12

13 Conclusions Pre-blending process applied to excipients strongly impacts the APSD and FPF of FP MgSt coating of the lactose surface in the high-shear process changes the interaction forces between FP and lactose carrier High-shear blending lead to a shift of APSD profile of FP and increase in the total number of small (<2 μm) particles. This is observed in both SPAMS and NGI High-shear process resulted in better detachment of small particles overall and possibly co-associations of FP with fine MgSt or very fine lactose formed during actuation of capsule Low-shear mixing of the excipient-blend did not significantly increase the performance of FP in our formulations at the MgSt concentrations evaluated 13

14 14 Acknowledgements Bradley Morrical Marcel Schneider Thomas Storm Nuno Silva Barbara Häberlin Prof. Georgios Imanidis (University of Basel) David Fergenson (Livermore Instruments Inc.) Rowena Crockett (EMPA)

15 Thank you