Academic-industrial collaborations in  respiratory drug delivery & developmentDr. Sally-Ann Cryan, School of Pharmacy, RCS...
Pharmaceutical Development                 Drug Compound                (Discovery Phase)                 Pharmaceutical...
Translational pharmaceutics for respiratory therapeutics• Basic biomedical research   – Molecular pharmaceutics   – In vit...
Inhaled medicines•   Ancient civilisations, current smokers    and drug abusers know the efficacy of    inhaled drugs•   R...
Currently inhaled medicines•   Beta-2 agonists e.g. salbutamol, terbutaline•   Corticosteroids e.g. budesonide, beclometha...
Respiratory drug delivery market• Worldwide market for prescription respiratory medicines is now more  than $64B• Predicte...
Challenges from Delivery & Development Perspective• Pharmaceutical & Regulatory issues   – Inefficient delivery   – Expens...
Meeting the Challenges & Harnessing Opportunities:              academic-industrial collaborationDrivers/Needs:•Therapeuti...
Example 1: Therapeutic BiomoleculeSecretory Leukocyte Protease Inhibitor (rSLPI) therapyrSLPI therapeutic properties:•   E...
Particle Engineering for Respiratory Drug Delivery
Particle Engineering for Respiratory Drug Delivery:          Approved Biomaterials/Excipients
Improving rSLPI pharmacokinetics                                                                   Intracellular rSLPIrSLP...
Effect of liposome encapsulation of rSLPI on targeting   DOPC Liposomes   DOPS Liposomes    Gibbons et al Pharm Res 2011
Development of a liposome-rSLPI dry powder for inhalation Manufacturing an inhalable powder of DOPS-rSLPIGibbons et al    ...
Meeting the Challenges & Harnessing Opportunities:              academic-industrial collaborationDrivers/Needs:•Therapeuti...
Aerogen™-IDDN collaborations  Projects Focus:  • Project 1 Optimising performance:  Investigation of fluid physicochemical...
Project 1 Optimising performanceInvestigation of fluid physicochemical properties on Aeroneb® performance
Project 2 Expanding applications:Effect of nebulisation on the stability of a range of therapeutic biomolecule RP-HPLC of ...
Project 3: Added ValueNebulised Nanoparticles forPulmonary siRNA Deliveryconvergent device-nanoparticlesystem             ...
Development of Nebulised Nanoparticles forPulmonary siRNA Delivery                         Undifferentiated Calu-3        ...
Meeting the Challenges & Harnessing Opportunities:              academic-industrial collaborationDrivers/Needs:•Therapeuti...
Example 3: Pre-clinical testing                Screening of Nanomedicines in Respiratory CellsOglesby et al. Respiratory R...
Example 3: Pre-clinical testing                             B      Screening of Nanomedicines in Respiratory CellsControl ...
Secreening of “Smart” Biomaterials/ExcipientsExample: Star-shaped polypeptide carriers       Heise Group, DCU
Advanced tools for Respiratory Drug Development:                                 3D Modelling of the Airway               ...
Opportunities in the Irish Context• Interdisciplinary research to maximise impact: clinical, biomedical,  pharmaceutical, ...
AcknowledgementsResearch Team:        Respiratory Collaborators:•Dr. Aileen Gibbons   •Dr. Marc Devocelle & Dr. James Barl...
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Dr Sally-Ann Cryan, Senior Lecturer in Pharmaceuticals, RCSI

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Academic-industrial collaboration in respiratory drug delivery & development

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Dr Sally-Ann Cryan, Senior Lecturer in Pharmaceuticals, RCSI

  1. 1. Academic-industrial collaborations in respiratory drug delivery & developmentDr. Sally-Ann Cryan, School of Pharmacy, RCSIGobal BioPharma Summit, Dublin Oct 31st 2012 1
  2. 2. Pharmaceutical Development  Drug Compound (Discovery Phase)  Pharmaceutical Development Medicinal product (patient-end user)
  3. 3. Translational pharmaceutics for respiratory therapeutics• Basic biomedical research – Molecular pharmaceutics – In vitro cell culture studies – HTS for respiratory cells• Applied clinical research – Translational pharmaceutics • formulation of “therapeutic” cargoes – In vivo pre-clinical studies • delivery, toxicology, pharmacokinetics• Industrial research/commercialisation – Product development – Device development – Particle delivery platforms
  4. 4. Inhaled medicines• Ancient civilisations, current smokers and drug abusers know the efficacy of inhaled drugs• Route harnessed by scientists and physicians for therapeutic drug delivery• Convenient and targeted drug delivery directly to site of action for respiratory conditions• Growing interest in its use for systemic delivery and delivery of biopharmaceuticals
  5. 5. Currently inhaled medicines• Beta-2 agonists e.g. salbutamol, terbutaline• Corticosteroids e.g. budesonide, beclomethasone• Anti-cholinergics e.g ipratropium bromide• Anti-inflammatory e.g. comoglycate• Mucolytics e.g. DNase, N-acetylcysteine• Antibiotics e.g. tobramycin, pentamidine• Anti-proteases e.g. Alpha-1-antitrypsin – Applications • Asthma • COPD • Cystic fibrosis
  6. 6. Respiratory drug delivery market• Worldwide market for prescription respiratory medicines is now more than $64B• Predicted global pulmonary drug delivery technologies market of up to $44B by 2016 – significant portion of growth supported by technological advances in biomaterials-based delivery systems• Eamples of locally acting molecules for inhaled delivery: – Secretory leukocyte inhibitor (rSLPI), Interferon-γ, Cyclosporin A, Gene therapies (pDNA, siRNA/shRNA, miRNA)• Examples of systemically acting molecules for inhaled delivery – Insulin, FSH, Calcitonin, hGH, Interferon-α, Heparin
  7. 7. Challenges from Delivery & Development Perspective• Pharmaceutical & Regulatory issues – Inefficient delivery – Expense of biomolecules– Instability – Lack of licensed excipients • Biopharmaceutical issues – Inadequate screening tools – Instability & rapid clearance in vivo – Multi-drug regimens – Poor site-specific targeting – Cell-type specific targeting – Poor intracellular delivery – Toxicology and immunogenicity – Poor IVIVIC
  8. 8. Meeting the Challenges & Harnessing Opportunities: academic-industrial collaborationDrivers/Needs:•Therapeutic biomolecules•Device applications•Pre-clinical testing•Personnel training
  9. 9. Example 1: Therapeutic BiomoleculeSecretory Leukocyte Protease Inhibitor (rSLPI) therapyrSLPI therapeutic properties:• Endogenous cationic protein with antiprotease activity• Anti-oxidant; Anti-bacterial; Anti-viral activity; Anti-inflammatoryBarriers to inhaled rSLPI therapy:• Delivery Strategy: rSLPI-loaded liposomes – Degradation during aerosolisation & processing Enhance in vivo stability – Poor lung distribution Improve lung retention & sustained release• Pharmacokinetic: short half-life Decrease toxicity – Proteolytic: degradation by cathepsins Protect during aerosolisation• Toxicological Epithelial cells – High doses may cause lung IrritationCollaborators: Prof. Gerry McElvaney & Dr. Catherine Greene (Beaumont & RCSI), Prof. CliffordTaggart (QUB), Amgen
  10. 10. Particle Engineering for Respiratory Drug Delivery
  11. 11. Particle Engineering for Respiratory Drug Delivery: Approved Biomaterials/Excipients
  12. 12. Improving rSLPI pharmacokinetics Intracellular rSLPIrSLPI Transport in vitro: Calu-3 monolayer rSLPI transport in vivo: guinea pig asthma model Gibbons et al., Pharm Res 2011
  13. 13. Effect of liposome encapsulation of rSLPI on targeting DOPC Liposomes DOPS Liposomes Gibbons et al Pharm Res 2011
  14. 14. Development of a liposome-rSLPI dry powder for inhalation Manufacturing an inhalable powder of DOPS-rSLPIGibbons et al Stability of liquid & dry powder formulations of rSLPI-DOPSAAPSPharmSciTech 2010
  15. 15. Meeting the Challenges & Harnessing Opportunities: academic-industrial collaborationDrivers/Needs:•Therapeutic biomolecules•Device applications•Pre-clinical testing•Personnel training
  16. 16. Aerogen™-IDDN collaborations Projects Focus: • Project 1 Optimising performance: Investigation of fluid physicochemical properties on Aerogen™ performance • Project 2 Expanding applications: Effect of nebulisation on the stability of a range of therapeutic biomolecule • Project 3 Added value: Development of convergent device-drug particle platforms
  17. 17. Project 1 Optimising performanceInvestigation of fluid physicochemical properties on Aeroneb® performance
  18. 18. Project 2 Expanding applications:Effect of nebulisation on the stability of a range of therapeutic biomolecule RP-HPLC of calcitonin pre- and post nebulisation SEC of calcitonin pre- and post-nebulisation
  19. 19. Project 3: Added ValueNebulised Nanoparticles forPulmonary siRNA Deliveryconvergent device-nanoparticlesystem Kelly et al 2012 RNAi for Respiratory disease
  20. 20. Development of Nebulised Nanoparticles forPulmonary siRNA Delivery Undifferentiated Calu-3 Differentiated Calu-3 Pre-neb %KD 80 Post-neb %KD % Knockdown 60 40 20 0 5 1 5 = 1 Pre-neb %KD /P = /P N Post-Neb %KD N 60 G I % Knockdown E E P P I- E P 40 20 0 5 1 5 = 1 /P = /P N N G I E E P P I- E P Hibbitts et al unpublished
  21. 21. Meeting the Challenges & Harnessing Opportunities: academic-industrial collaborationDrivers/Needs:•Therapeutic biomolecules•Device applications•Pre-clinical testing•Personnel training
  22. 22. Example 3: Pre-clinical testing Screening of Nanomedicines in Respiratory CellsOglesby et al. Respiratory Research 2010, 11:148 Collaborators: Prof. Gerry McElvaney & Dr. Catherine Greene (Beaumont & RCSI)
  23. 23. Example 3: Pre-clinical testing B Screening of Nanomedicines in Respiratory CellsControl PEI-miRNA, N:P 10:1 Blue=nucleus Green=cytoskeleton Red=nanomedicinesChitosan-miRNA, N:P 50:1 Chitosan-TPP-miRNA, N:P 200:1
  24. 24. Secreening of “Smart” Biomaterials/ExcipientsExample: Star-shaped polypeptide carriers Heise Group, DCU
  25. 25. Advanced tools for Respiratory Drug Development: 3D Modelling of the Airway Potential Applications: – Co-culture models – Toxicity & immunogenciity (including nanotoxicology) – Disease models Taken from Klein et al., Toxicol in Vitro, 2011 – Regeneration Calu-3 cultures after 14 days Collagen-Gag Scaffold (O’Brien lab)Collaborators: RCSI TERG & Dr. Shirley O’Dea & Prof. Noel G McElvaney
  26. 26. Opportunities in the Irish Context• Interdisciplinary research to maximise impact: clinical, biomedical, pharmaceutical, engineering• Academic-industrial partnership: convergent technologies• Biomedical respiratory research – In vitro and in vivo studies – Range of therapeutic cargoes emerging • Small molecules and biomolecules• Indigenous translational & commercial respiratory research platforms & know-how – To realise full clinical & commercial potential of basic research – Drug product development & IP – Biomaterials – Device – Screening tools
  27. 27. AcknowledgementsResearch Team: Respiratory Collaborators:•Dr. Aileen Gibbons •Dr. Marc Devocelle & Dr. James Barlow (RCSI)•Dr. Awadh Yadav •Prof. NG McElvaney & Dr. Catherine Greene (Beaumont& RCSI)•Dr. Ciaran Lawlor •Prof. Joe Keane & Dr. Mary O’Sullivan (SJH)•Dr. Ciara Kelly •Dr. Brian Robertson & Dr. Robert Endres (Imperial College London)•Dr. Joanne Ramsey •Dr. Shirley O’Dea (NUIM)•Alan Hibbitts •Prof. Clifford Taggart (QUB)•Cian O’Leary •Prof. Anthony Hickey (UNC-Chapel Hil)•Paul McKiernan •Dr Ronan MacLoughlin (Aerogen) •Prof. Fergal O’Brien (RCSI)
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