Modeling Deposition in the Respiratory Tract: What Can We Learn That Impactors Don’t Tell Us

http://www.copleyscientific.com/images/ww/side/_resized/Pic-9_288_0_0_0_362_223.jpg http://www.labautomate.net/images/next-generation-impactor.jpg http://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0118454.g001 https://image.issuu.com/161128184357-57dbb0207b084e3f1d118b2742dbe378/jpg/page_1.jpg https://www.omicsonline.org/articles-images/pulmonary-respiratory-medicine-larger-bore-prong-6-376-g002.png

vs.

Computational Fluid Dynamics

https://en.wikipedia.org/wiki/Computational_fluid_dynamics https://commons.wikimedia.org/wiki/File:CFD_Shuttle.jpg http://mdx.plm.automation.siemens.com/marine http://fluidsengineering.asmedigitalcollection.asme.org/data/journals/jfega4/930613/fe_136_10_101101_f015.png

“Computational fluid dynamics (CFD) is a branch of fluid mechanics that uses numerical analysis and data structures to solve and analyze problems that involve fluid flows. Computers are used to perform the calculations required to simulate the interaction of liquids and gases with surfaces defined by boundary conditions.”

Comparison of Monodisperse Particle Deposition in the Pulmonary System: Experimental vs. CFD

Stahlhofen W, Rudolf G, James AC. J Aerosol Med 2, 285-308, 1989 Tian G, Hindle M, Lee S, Longest PW. Pharm Res 32, 3170-3187, 2015

Comparison of CFD Predicted Deposition Patterns and Deposition Measured via Imaging

Novolizer DPI Respimat Soft Mist Inhaler

MP = mouthpiece C= central pulmonary compartment MT = mouth + trachea I = intermediate pulmonary compartment P = peripheral pulmonary compartment

Tian G, Hindle M, Lee S, Longest PW. Pharm Res 32, 3170-3187, 2015; Newman Respir J 16, 178-183, 2000; Newman Chest 113, 957-963, 1998

What About Deposition in the Upper Respiratory Tract?

Ghahramani E, Abouali O, Emdad H, Ahmadi G. J Aerosol Sci 67, 188-206, 2014.

The Challenge of CFD Model Development Specifying the Mesh

Engelhardt L, Rohm M, Mavoungou C, Schindowski K, Schafmeister A, Simon U. Pharm Res 33, 1337-1350. 2016.

Modeling Airflow Velocities in the Nasal Cavity

Model Measured

Engelhardt L, Rohm M, Mavoungou C, Schindowski K, Schafmeister A, Simon U. Pharm Res 33, 1337-1350. 2016

What Do Typical Nasal Deposition Patterns Look Like?

Foo, MY., PhD Thesis, University of Iowa 2007

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What Do CFD Nasal Models Predict?

Dastan A, Abouali O, Ahmadi G. J Aerosol Sci 69, 132-149, 2014

CFD Predictions of Deposition Patterns

Ghahramani E, Abouali O, Emdad H, Ahmadi G. J Aerosol Sci 67, 188-206, 2014

Linking CFD and PK Models

Rygg A, Hindle M, Longest PW J Pharm Sci 105, 1995-2004, 2016

But Noses Come in All Shapes and Sizes….

Zhu J, Lee H, Lim K, Lee S, Wang, D Respiratory Physiology & Neurobiology 175, 62-69, 2011

But Noses Come in All Shapes and Sizes….

Engelhardt L, Rohm M, Mavoungou C, Schindowski K, Schafmeister A, Simon U. Pharm Res 33, 1337-1350, 2016

But Noses Come in All Shapes and Sizes….

• “Current Study” 9 Taiwanese adults

• Particle loss protocol ∆ particles inspired-expired • Taiwanese showed lower

particle deposition efficiency than Caucasians

But Noses Come in All Shapes and Sizes….

Carrigy NB, Rzycki CA, Golshahi L, Finlay WH J Aerosol Med 27, 149-169, 2014

But Noses Come in All Shapes and Sizes….

Conclusions and Recommendations • Computational fluid dynamic models are powerful tools to address

questions regarding particle deposition and spray performance in the respiratory tract.

• Good correlation between CFD and experimental respiratory deposition patterns have been observed.

• While the exact anatomical measurements of the respiratory tract will vary, similar deposition patterns are observed.

• CFD modeling will improve the opportunity to evaluate population-based differences (age, race, disease state) in respiratory delivery system efficacy without the need to conduct human trials.

• Be cautious in data interpretation – models will show differences! It is important to understand when those differences are clinically relevant or able to demonstrate product quality and when they do not!

Acknowledgements

Arthur Foo (University of Iowa, Novartis Pharmaceuticals) Yung-Sung Cheng (Lovelace Respiratory Research Institute) Wei-Chung Su (Lovelace Respiratory Research Institute) Namita Sawant (University of Iowa) The pediatric nasal deposition studies were funded by FDA U01 5U01FD004275 "The Critical Path Manufacturing Sector Research Initiative” to NIPTE.