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Respiratory studies right approach in designs dia 11 april 2019 r

This presentation guides ANDA preparation for Orally Inhaled and Nasal Drug Products. It gives a few in vitro models mimicking inhalation.

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Respiratory studies right approach in designs dia 11 april 2019 r

  1. 1. Prof. (Dr.) Bhaswat S. Chakraborty Emeritus Professor, Institute of Pharmacy, Nirma University Former Sr.VP &Chair, R&D, Cadila Pharmaceuticals Former Director, Biopharmaceutics, Biovail, Toronto Former Sr. Efficacy & Safety Reviewer, TPD (Canadian FDA), Ottawa Respiratory Studies: right approach in designs
  2. 2. Orally Inhaled And Nasal Drug Products (OINDPs) Performance of orally inhaled and nasal drug products (OINDPs) is governed by complex interactions between device, formulation, and patient factors Because existing in vitro methods have limited predictability of these interactions, both development and BE demonstration of generic OINDPs is For this reason, even though there is a current, clear regulatory pathway utilizing the weight-of-evidence approach for BE assessment of OINDPs, the OGD is exploring new methods to make development and BE assessment of OINDPs more cost and time-effective in the future: © 2019 Prof. Bhaswat Chakraborty 2
  3. 3. Research for BE of OINDPs 1) Identification of formulation and device variables which are important for successful development of generic OINDPs 2) Development of clinically relevant in vitro tools for prediction of in vivo regional drug deposition and dissolution from OINDPs 3) Development of computational fluid dynamic (CFD) and physiology-based pharmacokinetic (PBPK) models for prediction of the fate of drugs delivered through OINDPs and to assess their applicability in generic OINDP development programs 4) Identification, validation and standardization of novel techniques that may have the potential to reduce the burden of current BE requirements for generic OINDPs © 2019 Prof. Bhaswat Chakraborty 3
  4. 4. Research for BE of OINDPs.. Advanced in vitro/in silico methods such as CFD modelling and clinically relevant in vitro dissolution and deposition tests are being used to understand and predict performance of OIDNPs in a realistic way These clinically relevant in vitro methods have shown good in vivo predictability of regional nasal and lung drug deposition and dissolution AND Local and systemic drug bioavailability of OIDNPs See next slides © 2019 Prof. Bhaswat Chakraborty 4
  5. 5. Model Simulations Model simulations gives insight to the understanding of the absorption of inhaled corticosteroids (ICS) and will support and facilitate development of PSGs for generic drug development In support of these objectives, droplet size distributions (DSDs) from three commercial nasal sprays were determined at three different actuation pressures using laser diffraction Computational fluid dynamics (CFD) models of the nasal passages of healthy and rhinitic subjects were developed to simulate the transport and deposition of droplets © 2019 Prof. Bhaswat Chakraborty 5
  6. 6. Model Simulations.. CFD simulation results for the three nasal sprays were used as model inputs to simulate absorption of the corticosteroids fluticasone propionate and budesonide The PBPK models included the effects of mucociliary clearance, drug dissolution, diffusion through nasal epithelial layers, binding kinetics to the glucocorticoid receptor, liver metabolism, and systemic clearance The PBPK models can be used to determine which physicochemical properties of the ICS affect the absorption and systemic bioavailability Also data from a CFD model of a human nasal cavity also indicated that local delivery of several ICSs may not be sensitive to actuation force when assessed across the range normally seen within a clinical setting © 2019 Prof. Bhaswat Chakraborty 6
  7. 7. Computational fluid dynamics (CFD) model © 2019 Prof. Bhaswat Chakraborty A B (A) CFD predictions of the droplet deposition pattern of fluticasone propionate nasal spray at a typical actuation pressure in a healthy adult nasal model. (B): PBPK model simulations of the dissolution and absorption of fluticasone propionate (FP) and budesonide (BUD) in the nasal mucosa [Figures are courtesy of Applied Research Associates]. 7
  8. 8. Lung Models Combining CFD with PBPK Modelling © 2019 Prof. Bhaswat Chakraborty A B Integrated computational framework for pulmonary drug delivery and PBPK- PD simulation. [Figures are courtesy of CFD Research Corporation] 8
  9. 9. Predicted Inhaled Plasma Concentrations © 2019 Prof. Bhaswat Chakraborty The predicted inhaled plasma PK values for momentasone furoate (left), budesonide (center) and fluticasone propionate (right) simulations is shown in comparison with experimental data [Figures are courtesy of CFD Research Corporation] 9
  10. 10. Predicted Inhaled Plasma Concentrations © 2019 Prof. Bhaswat Chakraborty The FDA explored various realistic mouth throat models that are currently used by industry and academia to compare their in vivo predictability The experimental setup and inhalation profiles for a test dry powder inhaler are shown in next two slides The test dry powder inhaler’s in vitro performance may be dependent on both the mouth-throat geometric size and the inhalation profile The studies have also evaluated the developed method using a metered dose inhaler and a soft mist inhaler This method, by incorporating both airway geometry and inhalation profiles, allows assessment of aerodynamic particle size distribution in a clinically relevant manner 10
  11. 11. Predicted Inhaled Profiles © 2019 Prof. Bhaswat Chakraborty Left (a): Experimental setup to measure total lung dose in vitro and its aerodynamic particle size distributions for drug aerosols delivered from an inhaler. The side inlet of the Nephele Mixing Inlet (NMI) is also connected to a breath simulator and compressed air source. Right (b): Inhalation profiles for the test inhaler representative of subjects trained at fast inhalation condition [Figures are courtesy of Dr. Michael Hindle, Virginia Commonwealth University] 11
  12. 12. Dissolution Method 1 © 2019 Prof. Bhaswat Chakraborty Left Selected Transwell® system for the evaluation of the dissolution rate of inhalation drugs. Right Differences in the dissolution rate of three model corticosteroids (Bud: budesonide DPI; CIC: ciclesonide MDI; FP: fluticasone propionate DPI) as assessed by the Transwell® system [Figures are courtesy of Dr. Guenther Hochhaus, University of Florida]. 12
  13. 13. Dissolution Method 2 © 2019 Prof. Bhaswat Chakraborty Left Modified stage assemblies of the Andersen cascade impactor (ACI) operated at 28.3, 60 and 90 L/min of the airflow rate to collect ≤ 5.8, ≤ 6.5 and ≤ 6.5 µm ‘respirable’ drug aerosols from inhaler products onto the 70 mm filter membrane placed under Stage 7, 6 and 5, respectively. Right Dissolution and permeation of the ‘respirable’ aerosol drug particles in the Transwell® dish system. The filter membrane was placed, with the deposited drug face down, onto the donor compartment, followed by addition of 10 mL aqueous fluid to initiate aerosol drug dissolution and permeation into the receptor fluid at 37oC and near 100% relative humidity [Figures are courtesy of Dr. Mashahiro Sakagami, Virginia Commonwealth University]. 13
  14. 14. © 2019 Prof. Bhaswat Chakraborty Superimposed data and statistical models for three MDI formulations manufactured according to a design of experiments (DoE) approach for delivered dose (DD) at beginning of canister life and fine particle dose < 5µm (FPD<5). The models were determined based on the formulation parameters that were found to significantly impact the given performance metric [Figures are courtesy of Dr. Poonam Aliyah Sheth, Recipharm Laboratories Inc.]. 14
  15. 15. © 2019 Prof. Bhaswat Chakraborty Hochhaus et al. AAPS J. 2015 Sep; 17(5): 1305–1311. 15
  16. 16. References https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/u cm549167.htm Santos et al. AAPS PharmSciTech. 2018 Oct;19(7):3134-3140. doi: 10.1208/s12249-018-1154-5. Epub 2018 Aug 20. https://www.ncbi.nlm.nih.gov/pubmed/26033698 © 2019 Prof. Bhaswat Chakraborty 16
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