3/11/2017

Novel Drug Delivery and Precision Pulmonary Medicine by Inhalation Therapy in Children and Adults with PH Disclosures

Dr. Heidi M. Mansour, Ph.D., R.Ph. I have nothing to disclose. The University of Arizona Colleges of Pharmacy & Medicine

Current Support: NIH, NSF, Tech Launch Arizona, The UA BIO5 Institute

A Brief History of Inhaled Medicines

GLOBAL IMPACT & FORECAST • What was the first asthma treatment? • Local & Systemic •In 2013, the global pulmonary drug delivery market reached $32.4 billion and is expected to reach $43.9 billion in 2018.

•Several top selling inhalation products are dual-drug combination products : DuoNeb®, Advair®, Spiriva®, Dulera®, and Symbicort®.

•In 2010, the DPI market was $6.6 billion, reached $17.5 billion in 2013, and is forecasted to reach $31.5 billion in 2018.

BCC market research report. http://www.marketwatch.com/story/pulmonary-drug-delivery-systems- technologies-and-global-markets-2014-06-10 (accessed July 1,2014). Patton and Bryon, Nature Reviews:Drug Discovery (2007); pp. 67-74.

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Targeted Lung Delivery for Pulmonary Disease Aerosol Particle Deposition for Targeted Pulmonary Treatment & Prevention Delivery

Local delivery to site of action –Asthma, COPD (COPD is currently the third leading cause of death in the US. predicted to become the third leading cause for death worldwide by 2030.), EIB, CF, pulmonary infections, pulmonary fibrosis, pulmonary hypertension –Targeted to the site of the diseased lung region=enhanced therapeutic efficacy – Successful pharmaceutical products –Lower dose (a few micrograms exert the therapeutic effect) – Minimizes systemic effects (corticosteroids) and resistance – Rapid onset (beta‐adrenergic agonists in rescue treatment in acute asthma attacks) –low metabolic organ with fewer metabolic enzymes with slower kinetics –No interactions with food –no first‐pass metabolism in the liver (PH Rxs) – Superior pulmonary disease state management and prevention –High patient acceptability –Lowers the overall healthcare costs for pulmonary treatment

Hickey and Mansour, Book Chapter 43 in Modified‐Release Drug Delivery Technology, 2nd Ed., 2008 Hickey and Mansour, Book Chapter 5 in Modern Pharmaceutics, 5th Ed., (2009)

Inhaled Particle Deposition Deposition & Inhaler Device Patient Instruction

• Oropharnyx junction and inertial impaction (coughing side effect) – head‐down position makes situation worse – Patient instructed to “hold head upright”

• Breath hold Instruction: gravitation settling deposition mechanism

• If Velocity is too high, more drug deposits in the throat by inertial impaction – Patient instructed to “breathe normally”

large surface area of 100 – 150 m2 (~tennis court)

• Asthma & COPD: target bronchi & bronchioles • Mucociliary escalator: conducting zone • Systemic delivery: alveolar region

• All below 10 microns • Shoot for 5 microns • Shape factor=1

Hickey, A.J. and Mansour, H.M. Book Chapter 5: Modern Pharmaceutics (2009): 191‐219. Suarez and Hickey. Respir Care 2000;45(6):652– 666

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Lung Anatomy Important Points of Lung Anatomy & Inhalation Drug Therapy • Pathway is tortuous with many bifurcations

• Major airways covered with mucus and ciliated cells‐conducting zone, higher air velocity, low surface area, thicker fluid lining, thicker cells – Drug dissolves in mucus

•Airways become progressively narrower with many bifurcations providing large surface area and decreasing air velocity

• Deep lung (alveolar region) covered with very thin lung surfactant lining; thinner cells, large surface area; no air velocity to facilitate gas exchange; no cilia; has pulmonary immune cells; respiratory zone –Drug dissolves in lung surfactant & aqueous layer

Patton and Bryon, Nature Reviews:Drug Discovery (2007); pp. 67-74.

Inhaled Nitric Oxide Gas for Pulmonary Hypertension MARKETED INHALER DEVICES

pMDI (pressurized Metered Dry Powder Inhalers (DPIs) Nitric Oxide Gas for Inhalation (dissolves and passive diffusion across membranes) Nebulizer Dose Inhaler) eg. single drug or in preterm and near-term ventilated babies with PH NICU (neonatal intensive care unit) combination drugs

Multi-Unit Dose DPI eg. Single drug or combination drugs

Respimat SMI® (Soft-Mist Inhaler) Unit Dose DPI for drugs

Multi-Unit Dose Anti-Viral DPI Vaccine DPI

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Types of Nebulizer Devices NEBULIZERS

•First developed in the late 1820s •These successful inhalation aerosol products are used clinically to treat patients with various pulmonary diseases: ‐asthma ‐CF (cystic fibrosis) ‐COPD (chronic obstructive pulmonary disease) • Air‐Jet (Compressor) Nebulizer: standard (“sidestream”)vs. breath‐enhanced (more output during ‐pulmonary bacterial infections that occur secondary to CF inhalation, blue expiratory valve) vs. breath‐activated (output only during inhalation) ‐pulmonary viral infections due to RSV (respiratory syncytial virus)  e.g. Pari LC Sprint, Pari LC Plus for TOBI®, Philips Respironics ‐pulmonary hypertension • Ultrasonic nebulizer (i.e. electronic): electricity vibrates a piezoelectric crystal at high frequency that sends vibrations through the liquid creating waves to droplets, heat generation/protein denaturation •Great in more severe stages of lung disease risk e.g Omron •Great in patients having difficulty taking deep breaths, as these are active devices • Vibrating mesh/oscillating membrane nebulizer (i.e. electronic): silent, lightweight, portable, battery‐ operated, still bigger than pMDIs, DPIs, and SMIs, faster treatment times, less loss/residual •Used in animals with respiratory disease – Can be breath‐enhanced or breath‐activated – e.g. Altera eFlow rapid nebulizer by Pari for Cayston® inhaled aztreonam – e.g. by Aerogen Ultra, Omron MicroAir, Philips Respironics I‐Neb AAD, Pari eFlow, • Several current nebulizers can deliver 1 mL within 2.5‐3 minutes • Droplet size 2.5 microns and higher depending on the model, typically in the range of 3‐4 microns • 5‐10 mL max cup capacity

Mansour, H.M., Myrdal, P.B., et al. Book Chapter 11: Pulmonary Drug Delivery. Drug Delivery & Targeting Second Edition, CRC Press/Taylor & Francis, Inc., (2016): 249-277.

Types of Nebulizer Devices: Vibrating Mesh Vibrating Mesh: I‐Nebulizer AAD (Adaptive Aerosol Delivery)

• Iloprost is a synthetic analog of prostacyclin (oily drug, triple bond, racemic mixture: R- breath-enhanced breath-activated isomer more potent than the S-isomer) causing vasodilation and affects platelet aggregation • 1 mL of sterile aqueous solution in single-use glass ampule per dose: 0.01 mg iloprost, 0.81 mg EtOH, 0.121 mg tromethamine, 9.0 mg NaCl and ~0.51 mg HCl (for pH adjustment=8.1) in WFI (water for injection); all inhaled • Vibrating mesh/oscillating membrane nebulizer (i.e. electronic): silent, lightweight, • Breath-activated vibrating mesh nebulizer device that delivers precise individualized dosing handheld, portable, battery‐operated, still relatively bigger than pMDIs, DPIs, and SMIs, only during personal inspiratory phase with continuous monitoring and adjustment faster treatment times, less loss/less residual volume • 2.5-5 micrograms iloprost emitted out of mouthpiece – Can be breath‐enhanced or breath‐activated • Short administration treatment time with more inhaled drug and little drug loss – e.g. Altera eFlow rapid nebulizer by Pari for Cayston® inhaled aztreonam • High frequency of administration of 6-9 times a day needed (short plasma t1/2 as within 30 – Aerogen Pro, Aerogen Ultra, Omron MicroAir, Philips Respironics I‐Neb ADD, Pari eFlow minutes to 1 hr drug is no longer detected in the plasma after inhalation tx) • Small, hand-held, portable, battery-operated inhaler device

Mansour, H.M., Myrdal, P.B., et al. Book Chapter 11: Pulmonary Drug Delivery. Drug • Aerosolized droplets have aerodynamic size under 3 microns Delivery & Targeting Second Edition, CRC Press/Taylor & Francis, Inc., (2016): 249-277. • Clean in distilled water with liquid detergent (no dishwasher nor microwave)

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Ultrasonic Nebulizer: Optineb

• Treprostinil is a synthetic analog of prostacyclin: add-on to oral tx from a different drug class • Patients use 1 ampule of sterile soln per day, QID at least four hours apart, longer plasma t1/2, 54 ug per treatment PDE-5 inhibitor=phosphodiesterase type 5 inhibitor • Chronic use affects blood clotting (check drug ixs with warfarin/anticoags). sGC stimulator=soluble guanylate cyclase stimulator • Optineb ultrasonic device, treatment time 2-3 minutes per neb treatment plus prep plus ERA=endothelin receptor antagonist cleaning • Tyvaso has been shown to help patients already taking oral therapy (bosentan, an endothelin receptor antagonist [ERA], or sildenafil, a phosphodiesterase-5 [PDE-5] inhibitor) • Inhaled Excipients: sodium chloride, sodium citrate, sodium hydroxide, hydrochloric acid, and water for injection. pH 6.0-7.2 • Photosensitive drug (foil pouch storage)

Face masks for neonates, infants, and small children (up to 3 y.o.) Face masks for neonates, infants, and toddlers • Face masks can be attached to most nebulizers and valved holding chambers (VHCs) with pMDIs • Face masks available in various sizes based on age (i.e. baby-neonate, infant, toddler, child, adult) Pari Baby Face Masks • A good seal is crucial (4 sizes) • A small leak can make a big difference in delivered lung dose • During crying, dose reaching the lungs is minimal.

Pari Baby Aerosol Masks (4 sizes)

• Non‐latex polymer (silicone) • Must be cleaned regularly to prevent drug buildup, bacterial/fungal growth, • dishwasher‐safe and can be boiled • Rotatable elbow adapter=“baby bend” • Baby bend + baby mask=stress‐free inhaln while sitting or lying

• Baby Face Masks come in 4 sizes: • Size 0=premature babies • Baby bend + baby mask=stress‐ • Size 1=age 0‐1 year i.e. neonate/newborn (age 0‐1 month) and infants (age 1 month‐1 y.o.) free inhaln while sitting or lying • Size 2=age 1‐3 y.o (toddler) • Size 3=age 3 y.o and 3+ US Pediatric Aerosol Formulation Working Group, NIH NICHD (Mansour H.M., Fink, J.) US Pediatric Aerosol Formulation Working Group, NIH NICHD (Mansour H.M., Fink, J.)

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Pacifier Aerosol Device for Infants Peds Neb Facemasks (ages 3 and older)

“Spiggy” Soft face mask with blue expiratory valve (Pari) i.e. breath-enhanced nebulizer

Bubbles the Fish

Sami the Seal Tucker the Turtle Spot the Dog • A pacifier aerosolized medication device for infants “PediNeb™ Pacifier” • Non‐latex polymer (silicone) • Must be cleaned regularly to prevent drug buildup and bacterial/fungal growth • dishwasher‐safe and can be boiled • Medication inhaled through nose

Eden (Ellie) the Elephant US Pediatric Aerosol Formulation Working Group, NIH NICHD (Mansour H.M., Fink, J.) Spike the Dog Nick the Dragon

Peds Air Compressors-5 mL max cup, continuous standard Adults

Penguin air compressor

Adult face mask with air ports (Philips Respironics, Pari) Adult soft face mask with blue expiratory valve (Pari) i.e. standard continuous “sidestream” neb i.e. breath-enhanced nebulizer Beagle air compressor

Panda air compressor

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Respimat ® Soft Mist Inhaler (SMI)

Combivent® Respimat ® SMI (ipratropium bromide/albuterol)

•Ventavis™ (iloprost) for PH Spiriva® Handihaler ® DPI vs •Tyvaso™ (treprostinil) for PH Spiriva® Respimat ® SMI •Arikace™ (nanoliposomal amikacin in CF) Mansour, H.M., Myrdal, P.B., et al. Book Chapter 11: Pulmonary Drug Delivery. Drug (tiotropium) Delivery & Targeting Second Edition, CRC Press/Taylor & Francis, Inc., (2016): 249-277.

Dry Powder Inhalers (DPIs): Drug‐Device General Types of DPI Devices

Combination Products with Increasing Growth Unit‐dose Multi‐unit‐dose Multidose (capsule‐based) (blister strip foil) (powder bed reservoir) • First available pharmaceutical product DPI was cromolyn sodium (mast cell inhibitor) in the 1960s using the Spinhaler DPI device (internal propeller) • Montreal Protocol (1987) 2016 Montreal Protocol Revision‐phase out of HFA proplellants, 2020, 2045 • HFA propellant chemical compatibility problems with drugs • newer pulmonary drugs needing solid‐state delivery • No hand‐lung coordination required with actuation • No spacers needed which are actually contraindicated with DPI devices • Stability advantages (solid vs. liquid) • Dose advantages (i.e. higher, since solid‐state) • Versatility in types of dry powder inhaler devices, solid‐state stability, particle design (e.g. size, morphology) for improved regional targeting, poorly water soluble drugs, unfavorable for microbial growth

• Growing market: ~80% of pulmonary inhalation pharmaceutical products are DPIs • Chronic meds/disease management & prevention (not rescue therapy of acute attacks which needs solution)

Courtesy of Novartis Muralidharan, P., Hayes Jr., D., and Mansour, H.M. Expert Opinion on Drug Pharmaceuticals Delivery: Special Issue on Pulmonary Drug Delivery (2014): 12 (6): 947‐962.

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Passive DPI Devices SYSTEMIC TX: Pulmonary Inhalation Aerosols • Passive DPIs depend on the patient's inspiratory efforts (ie. Patient inspiratory flow rate‐dependent) to provide the energy needed for dispersing the powder. These are also called “breath‐actuated” DPIs.

• Thin film of pure drug in the solid state (nanofilm) • Pure drug aerosol i.e. no excipients

Muralidharan, P., Hayes Jr., D., and Mansour, H.M. Expert Opinion on Drug Delivery: Special Issue on Pulmonary Drug Delivery (2014): 12 (6): 947‐962.

Fasudil Nrf2 Activator SYSTEMIC TX: Passive DPI Device Inhaled Insulin Nanoparticulate/Microparticulate Nanoparticulate/Microparticulate Afrezza® Dreamboat® DPIs DPIs

Passive device: energy source is the patient’s breath •Very small handheld DPI device •Indicated for the Tx of Type I & II diabetes •Solid dispersion & lactose carrier-free Muralidharan, P., Hayes, D. Jr., Black, S.M., and Mansour, •Marketed as superior to SQ injxn H.M. Royal Society of Chemistry (RSC) Molecular Systems  Faster onset than injection NIH R01 Black, S.M. and Fineman, J.R. Design & Engineering (2016): Front Cover and 1-18  Longer glucose control than injection Simvastatin Simvastatin:L-Carnitine Dual Drug Nanoparticulate/MicroparticulateNanoparticulate/Microparticulate DPIs DPIs

The Dreamboat® passive DPI device (left image) and an electron micrograph of Technosphere® particles technology (right image).

Mansour, H.M., Myrdal, P.B., et al. Book Chapter 11: Pulmonary Drug Delivery. Drug Delivery & Targeting Second Edition, CRC Press/Taylor & Francis, Inc., (2016): 249-277. NIH R01 Black, S.M., Fineman, J.R., and Mansour, H.M.

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Inhalable PEGylated Lung Surfactant-Mimic Microparticles/Nanoparticles: Biomimetic, Stealth, Controlled Release, Cell Targeting, and Cell Penetrating Summary & Conclusion: Inhalation Therapy

1. Inhaler devices can treat as “rescue therapy” with short-acting drugs (i.e. hydrophilic for 95DPPC:5DPPE-PEG2k 95DPPC:5DPPE-PEG3k 95DPPC:5DPPE-PEG5k nebulizers, SMIs, pMDIs) and provide maintenance preventative therapy through long-acting drugs (i.e. hydrophobic for DPIs).

2. Dual-drug and triple-drug aerosols containing 2 or 3 therapeutics from 2 or 3 different therapeutic classes in the same aerosol are currently available for all inhaler devices and Primary Particle Size Range growing due to unique advantages for multifactorial pulmonary diseases. System (μm) 100DPPC (Low P) 0.274 – 1.157 100DPPC (Med P) 0.228 – 1.755 100DPPC (High P) 0.220 – 2.000 3. Inhaler devices have unique advantages which relate to device design, drug formulation 95DPPC:5DPPE-PEG2k (High P) 0.360 – 4.068 properties, and patient factors. 95DPPC:5DPPE-PEG3k (Med P) 0.303 – 3.775 95DPPC:5DPPE-PEG3k (High P) 0.034 – 5.298 95DPPC:5DPPE-PEG5k (Med P) 0.316 – 1.759 4. Much lower doses efficiently exert a therapeutic effect due to direct organ targeting and 95DPPC:5DPPE-PEG5k (High P) 0.326 – 2.966 enhanced regional deposition targeting giving a high local drug concentration at the site of action.

5. Incorporating advanced particle engineering design technologies and nanotechnology into Meenach, S.A. Vogt,F.G., Anderson, K.W., Hilt, J.Z., McGarry,R.C., and Mansour, H.M. inhalation therapeutics can enable effective treatment of complex lung diseases with current International Journal of Nanomedicine (2013) 8:275-293. unmet medical needs.

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