Carrier Permeability and Performance of Dry Powder Inhalation Mixtures: A Step Towards Universal Performance Prediction Model

Transcription

1 Carrier Permeability and Performance of Dry Powder Inhalation Mixtures: A Step Towards Universal Performance Prediction Model Prepared by Ahmed O. Shalash B.S. M.S. Supervised by Professor Dr. Nawal M. Khalafallah Professor Dr. Abdullah M. Molokhia Dr. Mustafa M.A. Elsayed Edinburgh, 8th December, 2016

2 Introduction: Carrier-Based DPI Formulations Coarse carrier Ternary fine additive Drug Inhalation mixture Ternary mixture components micronized drug, Ternary fines, and the coarse carrier Inhaler devices passive or active

3 Introduction: Force Balance Separation forces (Inertial, shear, lift and drag) 1.Device geometry and ΔP 2.Flow rate 3.Carrier-drug properties Adhesion forces (Van der Waals, capillary forces, and mechanical interlocking)

4 Introduction: Recent Multivariate Models Author Thalberg K., et al Total fines concept Kinnuen H., et al ANN Muddle J., et al ANN Elia A., et al MLR Xu Z., et al Langmuir analogue Carrier, Fine and Drug grades 3C+1F+2D 3C+3F+1D 3C+1F+2D 1C+1F+1D (22Cx1D Samples) 1C+1F+2D/4SETs Device R 2 Drawbacks Single custom 0.97 Performance-based model parameters Limited by fines > 15%w/w, and carrier surface texture, single Device at a single flow rate CH 90 L.min -1 - Based on strengths of linear relationships only limited significance given to device or carrier surface texture. The highest linear relationship had R 2 of 0.85 RH,CH,HH Single Flow rate/device 0.92 Based on strengths of linear relationships and on 2-level variation (Taguchi), gave only limited significance to device, carrier surface texture & packing but accounted for drug using (CPP) -- Poor Relying solely on rheological parameters CH,RH, SETs 60 L.min -1 >0.95 Each drug-carrier combination had a separate fit τ s may only describe simple device geometries MLR is multiple linear regression, C is coarse carrier grade, F is carrier fines grade, D is drug types or grade, CH is Cyclohaler, RH is Rotahaler, HH is Handihaler, CPP critical pressure (intrinsic dispersibility) and τ s is turbulent shear stress

5 Limitations of Bulk Porosimetry Techniques Mercury porosimetry Gas adsorption Permeametry Powder rheometry Nanoporosity Microporosity Macroporosity Porosity scale

6 Carrier Porosity Distribution Nanoporosity Microporosity Macroporosity Cumulative pore volume of each region similar impact on performance is expected throughout a region s pore diameter range Drug agglomerates

7 Inhalation Performance Determinants

8 Materials and Methods: Optical Microscopy Images Eleven different carrier grades including six lactose grades were employed as carriers Resulting in fifteen adhesive mixtures, each was different in size and contained 1% w/w Fluticasone Propionate Produced from spray dried lactose monohydrate dispersion

9 Characterization Methods Crystallinity Moisture content Particle shape Particle size distribution Porosity distribution and permeability Differential scanning calorimetry Loss on drying Optical microscopy image analysis Laser diffraction analysis Mercury porosimetry Inhalation performance was assessed using Aerolizer at 60 L.min -1.

10 Results Fifteen uniform mixtures (1% w/w FP). Carrier grades modal diameter ranged from 33.8 to 88.9 µm. Carriers fines contents (D<15μm) varied from 0.46 to 20.1 % v/v. Carrier air permeability varied from 0.4 to14.6 Darcy.

11 Carrier Permeability

12 Similar Carrier Size Influence Reported Reproduced from Louey M., et al., 2003

13 Carrier Microporosity Macroscale rough DCL-14

14 Carrier Nanoroughness Nanorough CD carriers

15 Carrier Classical Size Parameters However,

16 Establishing A Simple Multivariate Model (MLR) From previous performance-determinant relationships. Determinants were Linearized via using the functions themselves. All mixtures were included Then fitting residuals were fitted against nanoroughness.

17 Fine Fraction Performance Prediction

18 Respirable Fraction Performance Prediction

19 Conclusions Permeability is an outstanding performance descriptor for all regularly shaped crystalline carriers. Taking porosity scales into account in a simple multivariate model, resulted in a performance predictive relationship with adj. R 2 > These relationships are also related to inhaler device properties (Aerolizer ) at flow rate of 60 L.min -1. Carrier chemical entity or crystal form seems to have a minor effect on the performance. Out of the carriers investigated, nanorough carriers (e.g. CD) are suggested as excellent carriers with superior performance.

20 Acknowledgements The study was funded by a Global Fellowship Award from the United States Pharmacopeial Convention (USP).

21 References K. Thalberg, E. Berg, M. Fransson, Modeling dispersion of dry powders for inhalation. The concepts of total fines, cohesive energy and interaction parameters, International journal of pharmaceutics, 427 (2012) H. Kinnunen, G. Hebbink, H. Peters, J. Shur, R. Price, Defining the critical material attributes of lactose monohydrate in carrier based dry powder inhaler formulations using artificial neural networks, AAPS PharmSciTech, 15 (2014) J. Muddle, S.B. Kirton, I. Parisini, A. Muddle, D. Murnane, J. Ali, M. Brown, C. Page, B. Forbes, Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks, Journal of pharmaceutical sciences, (2016). A. Elia, M. Cocchi, C. Cottini, D. Riolo, C. Cafiero, R. Bosi, E. Lutero, Multivariate data analysis to assess dry powder inhalers performance from powder properties, Powder Technology, 301 (2016) Z. Xu, H.M. Mansour, T. Mulder, R. McLean, J. Langridge, A.J. Hickey, Heterogeneous particle deaggregation and its implication for therapeutic aerosol performance, Journal of pharmaceutical sciences, 99 (2010) M.D. Louey, M. Van Oort, A.J. Hickey, Standardized entrainment tubes for the evaluation of pharmaceutical dry powder dispersion, Journal of Aerosol Science, 37 (2006) P.J. Mendes, J.F. Pinto, J.M.M. Sousa, A non-dimensional functional relationship for the fine particle fraction produced by dry powder inhalers, Journal of Aerosol Science, 38 (2007)

22 References W. Wong, D.F. Fletcher, D. Traini, H.K. Chan, J. Crapper, P.M. Young, Particle aerosolisation and break-up in dry powder inhalers: evaluation and modelling of impaction effects for agglomerated systems, Journal of pharmaceutical sciences, 100 (2011) Z. Tong, H. Kamiya, A. Yu, H.K. Chan, R. Yang, Multi-scale modelling of powder dispersion in a carrierbased inhalation system, Pharmaceutical research, 32 (2015) J. Shur, H. Harris, M.D. Jones, J.S. Kaerger, R. Price, The Role of Fines in the Modification of the Fluidization and Dispersion Mechanism Within Dry Powder Inhaler Formulations, Pharmaceutical research, 25 (2008) A.O. Shalash, A.M. Molokhia, M.M. Elsayed, Insights into the roles of carrier microstructure in adhesive/carrier-based dry powder inhalation mixtures: Carrier porosity and fine particle content, European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.v, 96 (2015) M.D. Louey, S. Razia, P.J. Stewart, Influence of physico-chemical carrier properties on the in vitro aerosol deposition from interactive mixtures, International journal of pharmaceutics, 252 (2003) B.F. Swanson, A Simple Correlation between Permeabilities and Mercury Capillary Pressures, J Petrol Technol, 33 (1981) A.E. Scheidegger, The Physics of Flow Through Porous Media, University of Toronto Press, 1974.

23 Thank you

24 Q & A