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Dr. Heidi M. Mansour, Ph.D., R.Ph.The University of Arizona Colleges of Pharmacy & Medicine

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

I have nothing to disclose.

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

•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 :

BCC market research report. http://www.marketwatch.com/story/pulmonary-drug-delivery-systems-technologies-and-global-markets-2014-06-10 (accessed July 1,2014).

GLOBAL IMPACT & FORECAST

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.

A Brief History of Inhaled Medicines

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

• What was the first asthma treatment?• Local & Systemic

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

Targeted Lung Delivery for Pulmonary Disease Treatment & Prevention

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

Aerosol Particle Deposition for Targeted Pulmonary Delivery

Inhaled Particle Deposition

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

large surface area of 100 – 150 m2 

(~tennis court)

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

• Shape factor=1

• All below 10 microns • Shoot for 5 microns

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”

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Lung Anatomy

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

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

Inhaled Nitric Oxide Gas for Pulmonary Hypertension

Nitric Oxide Gas for Inhalation (dissolves and passive diffusion across membranes)in preterm and near-term ventilated babies with PH

NICU (neonatal intensive care unit)

MARKETED INHALER DEVICES

Nebulizer pMDI (pressurized Metered Dose Inhaler) eg. single drug or

combination drugs

Dry Powder Inhalers (DPIs)

Unit Dose DPI for drugs

Multi-Unit Dose DPI eg. Single drug or combination

drugs

Multi-Unit Dose Anti-Viral DPIVaccine DPI

Respimat SMI®

(Soft-Mist Inhaler)

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•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)‐pulmonary bacterial infections that occur secondary to CF‐pulmonary viral infections due to RSV (respiratory syncytial virus)‐pulmonary hypertension

NEBULIZERS

•Great in more severe stages of lung disease•Great in patients having difficulty taking deep breaths, as these are active devices•Used in animals with respiratory disease

Types of Nebulizer Devices

• Air‐Jet (Compressor) Nebulizer: standard (“sidestream”)vs. breath‐enhanced  (more output during inhalation, blue expiratory valve) vs. breath‐activated (output only during inhalation)

e.g. Pari LC Sprint, Pari LC Plus for TOBI®, Philips Respironics

• 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 risk e.g Omron

• 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

– 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/oscillating membrane nebulizer (i.e. electronic): silent, lightweight, handheld, portable, battery‐operated, still relatively bigger than pMDIs, DPIs, and SMIs, faster treatment times, less loss/less residual volume

– Can be breath‐enhanced or breath‐activated

– e.g. Altera eFlow rapid nebulizer by Pari for Cayston® inhaled aztreonam 

– Aerogen Pro, Aerogen Ultra, Omron MicroAir, Philips Respironics I‐Neb ADD, Pari eFlow

breath-activatedbreath-enhanced

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.

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

• Iloprost is a synthetic analog of prostacyclin (oily drug, triple bond, racemic mixture: R-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

• Breath-activated vibrating mesh nebulizer device that delivers precise individualized dosing only during personal inspiratory phase with continuous monitoring and adjustment

• 2.5-5 micrograms iloprost emitted out of mouthpiece• Short administration treatment time with more inhaled drug and little drug loss• High frequency of administration of 6-9 times a day needed (short plasma t1/2 as within 30

minutes to 1 hr drug is no longer detected in the plasma after inhalation tx)• Small, hand-held, portable, battery-operated inhaler device• Aerosolized droplets have aerodynamic size under 3 microns • Clean in distilled water with liquid detergent (no dishwasher nor microwave)

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• 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• Chronic use affects blood clotting (check drug ixs with warfarin/anticoags). • Optineb ultrasonic device, treatment time 2-3 minutes per neb treatment plus prep plus

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)

Ultrasonic Nebulizer: Optineb 

PDE-5 inhibitor=phosphodiesterase type 5 inhibitorsGC stimulator=soluble guanylate cyclase stimulatorERA=endothelin receptor antagonist

Face masks for neonates, infants, and small children (up to 3 y.o.)

• 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)

• A good seal is crucial• A small leak can make a big difference in delivered lung dose• During crying, dose reaching the lungs is minimal.

US Pediatric Aerosol Formulation Working Group, NIH NICHD (Mansour H.M., Fink, J.)

Pari Baby Aerosol Masks (4 sizes)

• Baby bend + baby mask=stress‐free inhaln while sitting or lying

Face masks for neonates, infants, and toddlers

Pari Baby Face 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• Size 1=age 0‐1 year i.e. neonate/newborn (age 0‐1 month) and infants (age 1 month‐1 y.o.)• 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.)

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Pacifier Aerosol Device for Infants

• 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

US Pediatric Aerosol Formulation Working Group, NIH NICHD (Mansour H.M., Fink, J.)

Tucker the Turtle

Peds Neb Facemasks (ages 3 and older)

Eden (Ellie) the ElephantNick the Dragon

Spot the Dog

Bubbles the Fish

Spike the Dog

Sami the Seal

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

Beagle air compressor

Panda air compressor

Penguin air compressor

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

Adult soft face mask with blue expiratory valve (Pari)i.e. breath-enhanced nebulizer

Adult face mask with air ports (Philips Respironics, Pari)i.e. standard continuous “sidestream” neb

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•Ventavis™ (iloprost) for PH•Tyvaso™ (treprostinil) for PH•Arikace™ (nanoliposomal amikacin in CF)

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.

Respimat ® Soft Mist Inhaler (SMI)

Spiriva® Handihaler ® DPI vsSpiriva® Respimat ® SMI

(tiotropium)

Combivent® Respimat ® SMI(ipratropium bromide/albuterol)

• 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)

Dry Powder Inhalers (DPIs): Drug‐Device Combination Products with Increasing Growth

• 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)

Unit‐dose (capsule‐based) 

Multi‐unit‐dose (blister strip foil) 

Multidose (powder bed reservoir)

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.

General Types of DPI Devices

Courtesy of Novartis Pharmaceuticals

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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.

• 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. 

Passive DPI Devices SYSTEMIC TX: Pulmonary Inhalation Aerosols

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

Afrezza® Dreamboat®

•Very small handheld DPI device•Indicated for the Tx of Type I & II diabetes•Solid dispersion & lactose carrier-free•Marketed as superior to SQ injxn

Faster onset than injection Longer glucose control than injection

SYSTEMIC TX: Passive DPI Device Inhaled Insulin

Passive device: energy source is the patient’s breath

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.

Fasudil Nanoparticulate/Microparticulate

DPIs

Simvastatin Nanoparticulate/Microparticulate

DPIs

Nrf2 Activator Nanoparticulate/Microparticulate

DPIs

Simvastatin:L-Carnitine Dual Drug Nanoparticulate/Microparticulate DPIs

Muralidharan, P., Hayes, D. Jr., Black, S.M., and Mansour, H.M. Royal Society of Chemistry (RSC) Molecular Systems

Design & Engineering (2016): Front Cover and 1-18NIH R01 Black, S.M. and Fineman, J.R.

NIH R01 Black, S.M., Fineman, J.R., and Mansour, H.M.

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95DPPC:5DPPE-PEG2k 95DPPC:5DPPE-PEG3k 95DPPC:5DPPE-PEG5k

SystemPrimary Particle Size Range

(μm)100DPPC (Low P) 0.274 – 1.157100DPPC (Med P) 0.228 – 1.755100DPPC (High P) 0.220 – 2.000

95DPPC:5DPPE-PEG2k (High P) 0.360 – 4.06895DPPC:5DPPE-PEG3k (Med P) 0.303 – 3.77595DPPC:5DPPE-PEG3k (High P) 0.034 – 5.29895DPPC:5DPPE-PEG5k (Med P) 0.316 – 1.75995DPPC:5DPPE-PEG5k (High P) 0.326 – 2.966

Meenach, S.A. Vogt,F.G., Anderson, K.W., Hilt, J.Z., McGarry,R.C., and Mansour, H.M. International Journal of Nanomedicine (2013) 8:275-293.

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 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 growing due to unique advantages for multifactorial pulmonary diseases.

3. Inhaler devices have unique advantages which relate to device design, drug formulation properties, and patient factors.

4. Much lower doses efficiently exert a therapeutic effect due to direct organ targeting and 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 inhalation therapeutics can enable effective treatment of complex lung diseases with current unmet medical needs.