dr sally-ann cryan, senior lecturer in pharmaceuticals, rcsi
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Academic-industrial collaboration in respiratory drug delivery & developmentTRANSCRIPT
Academic-industrial collaborations in respiratory drug delivery & development
Dr. Sally-Ann Cryan, School of Pharmacy, RCSI
Gobal BioPharma Summit, Dublin Oct 31st 2012
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Pharmaceutical Development
Drug Compound (Discovery Phase)
Pharmaceutical Development
Medicinal product (patient-end user)
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
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
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
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-, Cyclosporin A, Gene
therapies (pDNA, siRNA/shRNA, miRNA)
• Examples of systemically acting molecules for inhaled delivery– Insulin, FSH, Calcitonin, hGH, Interferon-, Heparin
Challenges from Delivery & Development Perspective
• Pharmaceutical & Regulatory issues– Inefficient delivery– Expense of biomolecules
– Instability– Lack of licensed excipients– Inadequate screening tools– Multi-drug regimens
• Biopharmaceutical issues– Instability & rapid clearance in vivo– Poor site-specific targeting– Cell-type specific targeting– Poor intracellular delivery– Toxicology and immunogenicity– Poor IVIVIC
Meeting the Challenges & Harnessing Opportunities:academic-industrial collaboration
Drivers/Needs:•Therapeutic biomolecules•Device applications•Pre-clinical testing•Personnel training
Example 1: Therapeutic BiomoleculeSecretory Leukocyte Protease Inhibitor (rSLPI) therapy
rSLPI therapeutic properties:• Endogenous cationic protein with antiprotease activity• Anti-oxidant; Anti-bacterial; Anti-viral activity; Anti-inflammatory
Barriers to inhaled rSLPI therapy:• Delivery
– Degradation during aerosolisation & processing
– Poor lung distribution• Pharmacokinetic: short half-life
– Proteolytic: degradation by cathepsins
• Toxicological
– High doses may cause lung IrritationEpithelial cells
Strategy: rSLPI-loaded liposomesEnhance in vivo stabilityImprove lung retention & sustained releaseDecrease toxicityProtect during aerosolisation
Collaborators: Prof. Gerry McElvaney & Dr. Catherine Greene (Beaumont & RCSI), Prof. Clifford Taggart (QUB), Amgen
Particle Engineering for Respiratory Drug Delivery
Particle Engineering for Respiratory Drug Delivery:Approved Biomaterials/Excipients
Improving rSLPI pharmacokinetics
rSLPI Transport in vitro: Calu-3 monolayer
rSLPI transport in vivo: guinea pig asthma model
Gibbons et al., Pharm Res 2011
Intracellular rSLPI
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
Stability of liquid & dry powder formulations of rSLPI-DOPS
Manufacturing an inhalable powder of DOPS-rSLPI
Gibbons et al AAPSPharmSciTech 2010
Meeting the Challenges & Harnessing Opportunities:academic-industrial collaboration
Drivers/Needs:•Therapeutic biomolecules•Device applications•Pre-clinical testing•Personnel training
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
Project 1 Optimising performanceInvestigation of fluid physicochemical properties on Aeroneb® performance
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(DensityxSurface Tension)/ Viscosity
Ou
tpu
t R
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g/m
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Ethylene Glycol
Et. Gl+0.9%NaCl
Prop. Glycol
Pr.Gl+0.9%NaCl
Glycerol
Glycerol+0.9%NaCl
Butanediol
But+0.9%NaCl
Project 2 Expanding applications: Effect of nebulisation on the stability of a range of therapeutic biomolecule
SEC of calcitonin pre- and post-nebulisation
RP-HPLC of calcitonin pre- and post nebulisation
Project 3: Added ValueNebulised Nanoparticles for Pulmonary siRNA Delivery convergent device-nanoparticle system
Kelly et al 2012 RNAi for Respiratory disease
Development of Nebulised Nanoparticles for Pulmonary siRNA Delivery
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80Pre-neb %KDPost-neb %KD
% K
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Pre-neb %KDPost-Neb %KD
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Undifferentiated Calu-3 Differentiated Calu-3
Hibbitts et al unpublished
Meeting the Challenges & Harnessing Opportunities:academic-industrial collaboration
Drivers/Needs:•Therapeutic biomolecules•Device applications•Pre-clinical testing•Personnel training
Example 3: Pre-clinical testingScreening of Nanomedicines in Respiratory Cells
Oglesby et al. Respiratory Research 2010, 11:148
Collaborators: Prof. Gerry McElvaney & Dr. Catherine Greene (Beaumont & RCSI)
Example 3: Pre-clinical testingScreening of Nanomedicines in Respiratory Cells
Chitosan-miRNA, N:P 50:1 Chitosan-TPP-miRNA, N:P 200:1
Control
B
PEI-miRNA, N:P 10:1 Blue=nucleus
Green=cytoskeleton
Red=nanomedicines
Secreening of “Smart” Biomaterials/Excipients
Example: Star-shaped polypeptide carriers
Heise Group, DCU
Potential Applications:– Co-culture models
– Toxicity & immunogenciity (including nanotoxicology)
– Disease models
– Regeneration
Advanced tools for Respiratory Drug Development:3D Modelling of the Airway
Collaborators: RCSI TERG & Dr. Shirley O’Dea & Prof. Noel G McElvaney
Taken from Klein et al., Toxicol in Vitro, 2011
Collagen-Gag Scaffold (O’Brien lab)Calu-3 cultures after 14 days
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
Acknowledgements
Research Team:Research Team:•Dr. Aileen Gibbons•Dr. Awadh Yadav•Dr. Ciaran Lawlor•Dr. Ciara Kelly•Dr. Joanne Ramsey•Alan Hibbitts•Cian O’Leary•Paul McKiernan
Respiratory Respiratory Collaborators:Collaborators:•Dr. Marc Devocelle & Dr. James Barlow (RCSI)•Prof. NG McElvaney & Dr. Catherine Greene (Beaumont& RCSI)•Prof. Joe Keane & Dr. Mary O’Sullivan (SJH)•Dr. Brian Robertson & Dr. Robert Endres (Imperial College London)•Dr. Shirley O’Dea (NUIM)•Prof. Clifford Taggart (QUB)•Prof. Anthony Hickey (UNC-Chapel Hil)•Dr Ronan MacLoughlin (Aerogen)•Prof. Fergal O’Brien (RCSI)