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Dr Sally-Ann Cryan, Senior Lecturer in Pharmaceuticals, RCSI
1. Academic-industrial collaborations in
respiratory drug delivery & development
Dr. Sally-Ann Cryan, School of Pharmacy, RCSI
Gobal BioPharma Summit, Dublin Oct 31st 2012
1
2. Pharmaceutical Development
Drug Compound
(Discovery Phase)
Pharmaceutical
Development
Medicinal product
(patient-end user)
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. 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. 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. 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. 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. Meeting the Challenges & Harnessing Opportunities:
academic-industrial collaboration
Drivers/Needs:
•Therapeutic biomolecules
•Device applications
•Pre-clinical testing
•Personnel training
9. Example 1: Therapeutic Biomolecule
Secretory 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 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 Irritation
Collaborators: Prof. Gerry McElvaney & Dr. Catherine Greene (Beaumont & RCSI), Prof. Clifford
Taggart (QUB), Amgen
12. Improving rSLPI pharmacokinetics
Intracellular rSLPI
rSLPI Transport in vitro: Calu-3 monolayer
rSLPI transport in vivo: guinea pig asthma model
Gibbons et al., Pharm Res 2011
13. Effect of liposome encapsulation of rSLPI on targeting
DOPC Liposomes DOPS Liposomes Gibbons et al Pharm Res 2011
14. Development of a liposome-rSLPI dry powder for inhalation
Manufacturing an inhalable
powder of DOPS-rSLPI
Gibbons et al
Stability of liquid & dry powder formulations of rSLPI-DOPS
AAPSPharmSciTech 2010
15. Meeting the Challenges & Harnessing Opportunities:
academic-industrial collaboration
Drivers/Needs:
•Therapeutic biomolecules
•Device applications
•Pre-clinical testing
•Personnel training
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. Project 1 Optimising performance
Investigation of fluid physicochemical properties on Aeroneb® performance
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. Project 3: Added Value
Nebulised Nanoparticles for
Pulmonary siRNA Delivery
convergent device-nanoparticle
system
Kelly et al 2012 RNAi for
Respiratory disease
20. Development of Nebulised Nanoparticles for
Pulmonary 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. Meeting the Challenges & Harnessing Opportunities:
academic-industrial collaboration
Drivers/Needs:
•Therapeutic biomolecules
•Device applications
•Pre-clinical testing
•Personnel training
22. Example 3: Pre-clinical testing
Screening of Nanomedicines in Respiratory Cells
Oglesby et al. Respiratory Research 2010,
11:148
Collaborators: Prof. Gerry McElvaney & Dr. Catherine Greene (Beaumont & RCSI)
23. Example 3: Pre-clinical testing
B
Screening of Nanomedicines in Respiratory Cells
Control PEI-miRNA, N:P 10:1 Blue=nucleus
Green=cytoskeleton
Red=nanomedicines
Chitosan-miRNA, N:P 50:1 Chitosan-TPP-miRNA, N:P
200:1
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. 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. Acknowledgements
Research 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)