The DDL Lecture 2016

THE CHALLENGE OF DELIVERING INHALED DRUGS TO THE LUNGS

Dr Stephen Newman

Scientific Consultant, Norfolk, UK

HISTORICAL BACKGROUND

Pulmonary drug delivery used for > 3000 years Inhalation of smoke from burning herbal preparations

19th century Inhaled creosote, chlorine, hemlock, etc……. (BP, 1867) Ceramic and metal vapour inhalers

First half of 20th century Inhaled adrenaline, insulin, antibiotics Lack of success owing to poor understanding of scientific, technical

and medical issues? Second half of 20th century / 21st century

Modern inhalers and modern drugs Much improved understanding Journals, conferences, educational courses, networking

Stein S and Thiel C, J Aerosol Med Pulm Drug Deliv 2016; 29: epub.

PULMONARY DRUG DELIVERY ROUTE:TOPICAL AND SYSTEMIC APPLICATIONS

Asthma / COPD maintenance therapy Bronchodilators – beta-adrenergic; anti-muscarinic – long-acting Inhaled corticosteroids (ICSs) Combination products, e.g. Advair® Diskus®

Other topically acting drugs: treatment of orphan diseases Antibiotics, mucolytics in cystic fibrosis (CF) Prostacyclin analogues in pulmonary arterial hypertension (PAH) Potential future therapies, e.g. treatment of lung transplant rejection,

idiopathic pulmonary fibrosis.

Systemically acting drugs for common medical conditions Fast acting small molecules, e.g. analgesics Peptides and proteins, e.g. insulin Vaccines, e.g. measles vaccine

ADVANTAGES OF PULMONARY ROUTE

Topically acting drugs Drug is targeted to its site of action Systemic absorption not required for efficacy Low dose compared to oral therapy Low incidence of systemic side-effects, e.g. corticosteroids Rapid onset of drug action, e.g. bronchodilators

Systemically acting drugs Drug is targeted to its site of absorption Avoids injection for drugs not absorbed from GI tract Pulmonary epithelium: > 100 m2 with thin epithelial barrier Rapid onset of drug action, e.g. analgesics More advantageous pharmacokinetics, e.g. mealtime insulin

FOUR BASIC DEVICE TYPES OF INHALER

Pressurized metered dose inhalers (pMDIs)

Dry powder inhalers (DPIs)

Nebulizers

Next generation portable technologies

Each inhaler type has its own advantages and disadvantages

Formulation and device equally important

INHALER SELECTION:MASS OF DRUG CONTAINED IN ONE DOSE

1 µg 10 µg 100 µg 1 mg 10 mg 100 mg

pMDI, multi-dose (reservoir) DPI

Unit-dose DPI, multiple unit-dose DPI

High-payload unit-dose DPI

Nebulizer

Asthma and COPD drugs Insulin Antibiotics

WHAT IS THE CHALLENGE ?

“The major challenge in the development of inhalable compounds is limited understanding of the relationship between pharmacokinetic (PK) and pharmacodynamic (PD) effects in the lung” (Cabal A et al, DDL-27)

Converting a promising prototype inhaler into a commercial success ?

Collecting clinical data to secure approval of your product ?

To ensure a predictable, reproducible lung dose and clinical effect with each treatment, while minimising side-effects, and to achieve this at reasonable cost

The patient presents the biggest barrier to meeting this challenge Natural lung defence mechanisms evolved to prevent entry of inhaled particles…. …..and to eliminate them once deposited The need to use an inhaler, and use it correctly

Pulmonary drug delivery is much more complex than taking a tablet

THE RESPIRATORY TRACT: BASIC ANATOMYUPPER AIRWAYS(Extrathoracic airways)

BRONCHIAL TREE(Weibel model:23 branching generations)

TRACHEA

CONDUCTING (TRACHEOBRONCHIAL) AIRWAYS

Bronchi

Bronchioles

Nasal passages

ALVEOLATED AIRWAYS

Mouth, pharynx and larynx

PATIENT BARRIERS TO SUCCESSFUL DRUG DELIVERY

Non-adherence to treatment regimen

Poor inhaler technique

Actions of enzymes,surfactant, etc.

Engulfment by alveolar macrophages

Impaction of particles and droplets in nose and mouth

Poor aerosol penetration to lung periphery

Lung mucociliaryclearance of drug

MECHANICALBARRIERS

CHEMICALBARRIERS

BEHAVIOURALBARRIERS

IMMUNOLOGICALBARRIERS

Effects of disease

From Heyder J et al, J Aerosol Sci 1986; 17: 811-825

Controlled breathing of monodisperse particles; Inhaled volume 1.5 L, Inhaled flow rate 45 L/min

DEPOSITION OF DIFFERENT PARTICLE SIZES FOR MOUTH BREATHING

From Heyder J et al, J Aerosol Sci 1986; 17: 811-825

Controlled breathing of monodisperse particles; Inhaled volume 1.5 L, Inhaled flow rate 45 L/min

DEPOSITION OF DIFFERENT PARTICLE SIZES FOR NOSE BREATHING

THE UPPER AIRWAYS: A VARIABLE APERTURE

Cross-sectional area, mm2

200

400

600

800

Mouth Oropharynx Larynx

DPI

pMDI

Mean and SD data from Ehtezazi T et al, J Aerosol Med; 2004: 17; 325-334

DEPOSITION IN THE RESPIRATORY TRACT: SUMMARY

Respiratory tract has evolved to keep inhaled particles out of the lungs

The nasal passages are a very effective aerosol filter

Aerodynamic particle diameter < 5 µm for whole lung delivery

Aerodynamic particle diameter < 3 µm for peripheral lung delivery

Inhaled flow rate, inhaled volume and carrier gas important

Most inhalers deposit less than 20 % of the dose in the lungs

Lung deposition is potentially highly variable

LUNG DEPOSITION FROM INHALER DEVICESFrom Borgström L et al, J Aerosol Med 2006; 19: 473-483

Coefficient of Variation

%

30

60

90

Mean lung deposition, % ex-valve20 40

Data from 71 deposition studies Poor inhaler technique will lead to additional variability

ASTHMA / COPD:(most products)Low-cost potent molecules ORPHAN DISEASES /

SYSTEMIC DELIVERY:Dosing precisionEfficient delivery to lungsCost-effectiveness

FATE OF INHALED DRUGSFigure adapted from Patton JS et al, J Aerosol Med Pulm Drug Deliv 2010; 23: S71-S87

Depositing drug particle

Dissolution

Mucociliaryclearance

Topical efficacy

Absorption

Enzymatic degradation

Engulfment by alveolar macrophages

Small molecules(e.g. loxapine, MW 328 Da; fentanyl, MW 336 Da) Rapid and efficient absorption, particularly

lipophilic compounds

Peptides(e.g. calcitonin, MW 3418 Da; insulin, MW 5786 Da) Absorption slower and less efficient Bioavailability highly compound-specific Enzymatic degradation potentially reduces

absorption

SMALL MOLECULES vs PEPTIDESFOR SYSTEMIC ACTION

STRATEGIES FOR ENHANCING DELIVERY OF INHALED DRUGS

Reducing chemical and immunological barriers PEGylation Absorption enhancers Novel particle strategies, e.g. Large porous particles

Active transport of large molecules (conducting airways)

Increasing retention / duration of action Controlled release

Bioadhesive formulations, e.g. PLGA microparticles “Molecular engineering”, e.g. LABAs

Increasing efficiency of delivery system Device and / or formulation “Engineered particles”

AERx®, Aradigm

Large porous particles, Alkermes

THE CHALLENGE OF DELIVERING INHALED INSULIN

Requires efficient and reproducible pulmonary delivery Alveolar targeting Bioavailability limited: 2 in 3 deposited molecules usually not absorbed intact 1

Narrow therapeutic window Most developments have involved dry powder formulations

Stability; low susceptibility to bacterial growth

First inhaled insulin product (Exubera®, Nektar / Pfizer), 2006 Large active DPI; novel formulation (PulmoSol® particles) Standing cloud, MMAD 3.5 µm 2

High delivery efficiency to compensate for losses Many “firsts” for pulmonary drug delivery Withdrawn in 2007

Second inhaled insulin product (Afrezza®, MannKind), 2015 Sophisticated powder formulation (Technosphere® FDKP particles) Compact breath-actuated DPI (Dreamboat®)

Technosphere®

particles, MannKind

Dreamboat® inhaler, MannKind

Nektar Pulmonary InhalerTM

1: Patton JS et al, Adv Drug Deliv Revs 1999; 35: 235-247 2: Harper NJ et al, Diabetes Technol Ther 2007; 9 (Suppl 1): S16-S27

RELATIVE BIOAVAILABILITY AND TIME TO MAXIMUM PLASMA LEVELS (Tmax) FOR DIFFERENT INHALED INSULIN PRODUCTS

Bioavailability (%) Tmax (min) Refvs. subQ

Afrezza® 26-50 15-20 121-30 12-15 2

Exubera® 10-12 45-55 1

AIR® LPP*, Alkermes 10 45-55 1

AERx®, Aradigm 15-20 45-55 1

1: Pfüzner A and Forst T, Expert Opin Drug Deliv 2005; 2: 1097-11062: Goldberg T and Wong E, Pharmacy and Therapeutics 2015; 40: 735-741

*Large Porous Particles

THE CHALLENGE OF DELIVERING INHALED ANTIBIOTICS

Respiratory tract infections in CF and other conditions Doses typically > 100 mg: nebulizers Off-label use of nebulizers in 1980s; carbenicillen and gentamicin Patients disliked taste and smell

Tobramycin (300 mg, TOBI®, Novartis) approved 1998 Specific jet nebuliser systems recommended by regulators 4-weeks on, 4-weeks off regimen But jet nebulizer systems inconvenient and inefficient

More convenient and efficient DPI systems: TOBI® PodhalerTM DPI + PulmoSphere® particles (Novartis) 112 mg tobramycin (4 DPI capsules) Lung dose virtually independent of inspiratory effort

LC® Plus nebulizer, Pari

PulmoSphere® particles, Novartis

PodhalerTM DPI, Novartis

DEPOSITION OF TOBRAMYCIN BY DPI AND NEBULIZERMean data from Geller D et al; J Aerosol Med Pulm Drug Deliv 2011; 24: 175-182

150

100

50

Tobramycin deposition (mg)

Lungs Oropharynx Device Exhaled

DPI + PulmoSphere® particles (80 mg)Jet nebulizer (300 mg)

Treatment timesDPI: secondsNebulizer: minutes

Mean and SD data from Zhu B et al, Int J Pharm 2016; 514: 392-398

COMPARISON OF PODHALERTM DPI AND ORBITAL® HIGH DOSE DPI FOR DELIVERY OF PULMOSPHERE® TOBRAMYCIN

PodhalerTM DPI (Novartis): 4 x 28 mg capsules

20

100

60

40

80

Fine particle fraction (%)

Orbital® DPI (Pharmaxis): single 100 mg+ dose

NON-ADHERENCE (NON-COMPLIANCE) TO INHALATION THERAPY

Adherence: the degree to which patient behaviours coincide with the clinical recommendation of healthcare providers

Non-adherence: not taking the medication as prescribed Non-adherence is widespread Not filling prescription Taking less or more doses than prescribed May be intentional or non-intentional Contrivance: patient knows what to do, but does something else

Electronic data loggers more accurate than patient records or weighing inhalers

NON-ADHERENCE TO INHALATION THERAPY

100

80

60

40

20

1 2 3 4 5 6

Percentage underuse or overuse days

Study number

Percentage underuse days

Percentage overuse days

UNDERUSE OR OVERUSE OF INHALED STEROIDS IN SIX STUDIESFrom Cochrane M et al, Chest 2000; 117: 542-550

POOR INHALER TECHNIQUE

Using an inhaler incorrectly is very common for all inhaler types Correct technique involves preparing inhaler for use as well as

inhaling from it

pMDIs: Not firing inhaler while breathing in slowly “Cold Freon” effect

DPIs: Not inhaling hard enough Device-specific handling errors

Errors may be: Crucial Non-crucial

ADHERENCE, INHALER “COMPETENCE” AND “TRUE ADHERENCE”

Non-adherence and poor inhaler technique have similar clinical and economic consequences Variable lung dose Reduced disease control Waste of resources Need for more expensive treatment options

Has pulmonary drug delivery underachieved because of failure to solve adherence and inhaler competence issues? 1

True adherence %: (% adherence to regimen) x (% inhaler competence) / 100

Maximizing true adherence essential for successful disease management

1: Everard ML, J Aerosol Med Pulm Drug Deliv 2014; 27: A2

TACKLING NON-ADHERENCE AND POOR INHALER TECHNIQUE: EDUCATION

Management of chronic respiratory diseases:“10 % medicine, 90 % education” 1

Ensuring patients understand their illness, treatment and inhaler Healthcare professionals may not understand either

Messages need to be repeated and reinforced One-on-one; healthcare professional and patient Group sessions, internet training Written treatment plans

Switching inhalers: re-education needed Adherence: understanding and influencing patient behaviour

Addressing misconceptions, lack of trust, family dysfunction Increasing acceptability of inhalers in developing countries: social stigma

1: Fink JB, Respir Care 2005; 50: 598-600

TACKLING NON-ADHERENCE AND POOR INHALER TECHNIQUE: TECHNOLOGY

Correct inhaler selection: choose an inhaler the patient will use, and can use correctly Same inhaler to deliver multiple drugs if possible: combination inhalers Meeting patient preferences Simple DPI instructions, e.g. Open, Inhale, Close

Training aids: coordination and flow rate Dose counters Electronic data loggers

Reminders and feedback Connections to mobile phones, computers, servers

“Intelligent” inhalers: reminders, feedback, efficient delivery I-neb AAD: vibrating mesh nebulizer, controlled inhalation Potential for depositing 50 % of nebulizer fill in lungs 1

Advair® Diskus®, GSK

In-Check Flo-tone®,Clement Clarke

Propeller Sensor,Propeller Health

I-neb® AAD® nebulizer, Philips Respironics

1: Häussermann S et al, J Aerosol Med Pulm Drug Deliv 2016; 29: 242-250

SPECIAL PROBLEM GROUPS?

Very young patients Probably cannot use pMDIs, DPIs correctly

Nebulizers, pMDI plus spacers

Facemasks convenient but inefficient

Very old patients May lack inspiratory muscle strength to use DPIs

Co-morbidities

Cognitive issues

May be reassured by nebulizers

Lowest adherence in adolescents and young adults, 15-40 y 1

Intubated or ventilated patients Potential for aerosol losses in tubing

1: Morton RW and Everard ML, ISAM Textbook of Aerosol Med 2015, 925-960

“INHALATION IS BETTER”?: NOT ALWAYS

Inhaled pentamidine in HIV disease Prevention of Pneumocystis carinii pneumonia Initially (1980s) seen as effective and safe: Respirgard nebulizer Later proved to be less effective than oral therapy Effectiveness limited by inadequate delivery to poorly ventilated areas Re-occurrence of P. carinii pneumonia in lung apices

Treating solid lesions (tumours) Lung often the site of metastases Not possible to target drug with sufficient precision? May need delivery to whole of tumour, not just surface

Combination of inhaled and oral / parenteral delivery sometimes the answer?

CONCLUDING REMARKS

Successful pulmonary drug delivery presents many scientific and medical challenges

The advantages offered by pulmonary drug delivery currently considered to justify the additional complexity in many situations

The future….. Asthma and COPD: treatments evolving Topical delivery: repurposing / fulfilling unmet needs Systemic delivery: small versus larger molecules Improving bioavailability and longevity Improving true adherence: technology, education

Interest in pulmonary route seems greater than ever