An Overview of Pharmaceutical Inhalation Technology

Aryo Nikopour

March 2015

Chapman University, Pharmaceutical Sciences

Why Should We Inhale?

One of the oldest forms of drug delivery

A patient compliant route (think of smokers)

An instantaneous route (think of smokers)

A robust delivery route (think of smokers)

Why is it effective? Part 1

Why is it effective? Part 2

Relatively low metabolic activity of the lungs

Moist surface with surfactants

This organ is designed for absorption

Many diseases affect the lung

Parameters for Success

Reproducible - UniformReproducible - Uniform Pure - ChemicallyPure - Chemically Efficient – SmallEfficient – Small Specific – Not too Small, nor too BigSpecific – Not too Small, nor too Big Cost – Not too expensive relative to current Cost – Not too expensive relative to current

therapiestherapies

Applicable Therapies

Local Delivery Asthma COPD Lung Surfactant

Deficiency Anti-infective

Systemic Delivery Diabetes Low gut

absorption API’s Rapid onset

therapeutics

Dosage Forms pressurized Metered Dose Inhaler (pMDI)

o Breath-actuated

Dry Powder Inhaler (DPI)o Active

Nebulizerso Jeto Ultrasonico Mesh

Organization Involved in OINDP Regulatory bodies in the European Union, Japan

and USA International Regulation and Harmonization

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use (ICH)

Drug Safety, Quality and Efficacy-The Pharmacopoeia USP, EP, BP,JP

Device Safety, Quality and Efficacy – International Standards Organization (ISO), ISO27427:2009

Organization Involved in OINDP

Expert Groups European Pharmaceutical Aerosol Group

(EPAG) International Pharmaceutical Consortium On

regulation and Science (IPAC-RS) Product Quality Research Institute (PQRI)

Guidelines

Guidance for Industry: MDI and DPI Drug Products, CMC

ICH (www.ICH.org) ICH Q1 Stability

ICH Q2 (R2) Analytical Method Validation

ICH Q8(R1) Pharmaceutical Development

ICH Q9 Quality Risk Management

ICH Q10 Pharmaceutical Quality Systems

pMDI Components

Propellents

Actuator Formultion

Container

Metering Valve

pMDI – Valve

pMDI - Propellant

Propellant? CFC ban!

A major component of the pMDI is the propellant Clean Air Act of 1990 & Montreal Protocol of 1997

Phases out the use of CFC’s in consumer products… Including medicinal

Alternative is HFA’s

CFC’s versus HFA’s

Propellant

Designation CFC-11 CFC-12 CFC-114 HFA-134a HFA-227ea

B.P. (ºC) +23.7 -29.8 +3.6 -26.5 -17.3

Vapor Pressure(psig @ 20ºC)

1.8 67.6 11.9 68.4 56.0

Density (g/mL) 1.49 1.33 1.47 1.21 1.41

H20 Solubility (ppm)

110 120 130 610 2200

Dipole Moment (debye) 0.45 0.51 0.66 2.06 0.93

More info can be found @

http://www.solvay-fluor.com/product/properties/0,0,-_EN-1000700,00.html

DPI – Components

A P I D isp e rsio n E xc ip ie n ts

S ta b ility E xcip ie n ts

D ry P o w d er

D isp e rsive M ec h a n ism P a cka g ing

D e v ice

D ry P o w d er In h a le r C o m p on e n ts

DPI – New & Old Traditional – Lactose Blends w/ API Modern – Engineered Particles of API

DPI – Devices

Nebulizers – Jet

A Nebulizer is a device that can convert a liquid into aerosol droplets to produce a respirable cloud suitable for inhalation

Jet Nebulizers use a compressed sir to atomize drug solution to produce a fine mist using the Bernoulli principal.

Nebulizers – Jet

Jet nebulizers are sub-divided in three types:

Standard Constant output throughout the respiratory cycle

Breath Enhanced Constant output but provides higher output during

inhalation Breath Actuated

Nebulizers – Ultrasonic

Ultrasonic Nebulizers use electricity to vibrate a piezoelectric crystal at high frequency.

The resultant vibration are transmitted to a reservoir containing the liquid drug, creating a series of waves from which liquid droplets separate to form an aerosol.

MiniBreeze Ultrasonic Nebulizer

Nebulizers – Mesh

There are two categories of mesh-type nebulizers: static mesh and vibrating mesh nebulizers:Static mesh nebulizers apply pressure on the inhalation solution in order to force it through a static sieving mesh.

OMRON HEALTHCARE, INC

Nebulizers – Mesh (Conti.) Vibrating mesh nebulizers work by using deformations

or vibrations of the mesh to push the inhalation solution through the aperture plate. A ring-shaped piezoelectric element having contact with the mesh plate sets same into vibrations.

The inhalation solution is in direct contact with the sieving mesh. Mesh plate apertures are ca. 3.8 µm in diameter, which is the smallest size technically achievable (for reasons of blocking).

The mesh generates a mono disperse aerosol cloud whose finest droplets are only slightly smaller than the aperture diameter. Larger droplets are then formed by coagulation while the smaller ones are formed by evaporation.

Characterization Of Inhalation Products

There is no truth in particle sizing!

Stakeholders in Quality Analytical Testing During Drug Development

Tox/PKRA

Aerodynamic Particle SizeGiven by the Equation:

StokesAero DD

18

2gDVt

Stokes Law:Stokes Law:

For optimal aerosol performance, it is desirable to have a small and For optimal aerosol performance, it is desirable to have a small and light particlelight particle

Aerodynamic Diameter

The behavior (settling velocity) of spherical particle can be described

by Stokes law:

2r²g(ρp – ρf)Vs = _________________

9 ηwhere:

Vs is the particles’ settling velocity

g is the acceleration due to gravity

ρp is the density of the particles

ρf is the density of the fluid

r is the Stokes radius of the particle

η is the fluid viscosity.

Lung Physiology

Inhalation and Disposition

The behavior of inhaled particles differs significantly from that of inhaled gaseous or volatile compounds. The deposition of volatile compounds in the lungs is mainly dependent on the water solubility of the compound – the more the compound is water soluble the less deep it will penetrate in the lung.

The deposition of particulate matter is mainly dependent on its aerodynamic diameter.

Particle Size (Aerodynamic Size Distribution)

Together with delivered dose uniformity, the Aerodynamic Particle Size Distribution (APSD) is widely recognized as a Critical Quality Attribute (CGA) in the in vitro characterization of inhaled and nasal products since it is the APSD of an aerosol cloud that defines where the particles in that cloud are deposited following inhalation.

It is generally accepted that to be therapeutically effective, the particles should be in the range of 1 to 5 microns since particles > 5 microns will generally impact in the oropharynx and be swallowed whereas those < 1 micron may remain entrained in the airstream and be exhaled during the next breathing cycle.

Particle Size (Aerodynamic Size Distribution)

The preferred instrument of choice for measuring the APSD of inhaled and nasal products is the cascade impactor because:

• Cascade impactors measure aerodynamic particle size

• Cascade impactors measure active pharmaceutical ingredient

• Cascade impactors measure the entire dose

The Gold Standard – ACIAndersen Cascade Impactor

ACI Deposition Correlation

The New ACI – NGI

Next Generation Impactor

Dosage Unit Sampling Apparatus (DUSA)

Delivered Dose The Delivered or Emitted Dose is the total amount of drug

emitted from the inhaler device and hence available to the user.

Its uniformity is a Critical Quality Attribute (CQA) in determining the safety, quality and efficacy of an orally inhaled and nasal drug product (OINDP).

Based on an original design by Charles Thiel in 3M’s laboratories in Minneapolis, USA, the Dosage Unit Sampling Apparatus (DUSA) for MDIs has been designed specifically for the sampling and testing of Metered Dose Inhalers (MDIs).

It is used to perform those tests specified in the Pharmacopoeias relating to “delivered” or “emitted” dose, namely “Delivered Dose Uniformity” and “Delivered Dose Uniformity over the Entire Contents”.

Copley Scientific

Dose Content Uniformity Is the simplest, yet hardest assay

50

70

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110

130

150

0 25 50 75 100Shot #

API C

onte

nt (m

g)

60

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0 25 50 75 100Shot #AP

I Con

tent

(mg)

Dosage Unit Sampling Apparatus for Nebulizers

Dosage Unit Sampling Apparatus for Nebulizers

Nebulizers convert liquids into a cloud of droplets suitable for respiration. Conventional nebulizers are widely used in both hospital and home. Their main advantage is that unlike other devices, they require little or no coordination on the part of the patient in order to use them.

The breathing pattern employed in the testing of nebulizers is particularly important since in vivo this determines the amount of active available to the user.

For this reason, the two tests specified in the Pharmacopoeias to characterize delivered dose, Active Substance Delivery Rate and Total Active Substance Delivered are based on tidal flow conditions generated by a breath simulator, as opposed to fixed flow rates.

The Dosage Unit Sampling Apparatus (DUSA) for Nebulizers consists of a Breath Simulator to generate the specified breathing profile, a filter holder containing the filter to capture the drug and a suitable mouthpiece adapter to connect the filter holder to the nebulizer under test.

Various patterns are available for neonatal, infant, child and adult applications.

Copley Scientific

Non-Traditional Techniques

A brief overview

Laser Diffraction

Aerosizer – Time of Flight

Summary

Pulmonary aerosols are an effective and accepted dosage form

IAL can now support all required analyses Simple physics can explain most techniques Thanks for your time, questions and attention

It may be the Best Drug Delivery System, but It will Kill you

Alexza:Staccato® system

References

1. Copley Scientific2. MSP