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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0 10 20 30 40 50 60 70 80

(DensityxSurface Tension)/ Viscosity

Ou

tpu

t R

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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)