Inhalation 2015

1. An Overview of Pharmaceutical
Inhalation Technology
Aryo Nikopour
March 2015
Chapman University, Pharmaceutical Sciences

2. 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)

5. Why is it effective? Part 1

6. 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

7. 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

8. Applicable Therapies
Local Delivery
Asthma
COPD
Lung Surfactant
Deficiency
Anti-infective
Systemic Delivery
Diabetes
Low gut
absorption API’s
Rapid onset
therapeutics

9. Dosage Forms
pressurized Metered Dose Inhaler (pMDI)
oBreath-actuated
Dry Powder Inhaler (DPI)
oActive
Nebulizers
oJet
oUltrasonic
oMesh

10. 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

11. 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)

12. 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

13. pMDI Components

14. Propellents
Actuator
Formultion
Container
Metering
Valve

15. pMDI – Valve

16. pMDI - Propellant

17. 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

18. CFC’s versus HFA’s
Propellant
DesignationCFC-11CFC-12CFC-114HFA-134aHFA-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
H
20 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

19. DPI – Components
A P I D i s p e r s i o n E x c i p i e n t s
S t a b i l i t y E x c i p i e n t s
D r y P o w d e r
D i s p e r s i v e M e c h a n i s m P a c k a g i n g
D e v i c e
D r y P o w d e r I n h a l e r C o m p o n e n t s

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

21. DPI – Devices

22. 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.

23. 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

24. 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

25. 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

26. 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.

27. Characterization Of Inhalation
Products
There is no truth in particle sizing!

28. Stakeholders in Quality Analytical Testing
During Drug Development
Tox/PKRA

29. Aerodynamic Particle Size
Given by the Equation:
r
StokesAeroDD=
m
r
18
2
D
=
gD
V
t
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

30. Aerodynamic Diameter
The behavior (settling velocity) of spherical particle can be described
by Stokes law:
2r²g(ρp – ρf)
Vs = _________________
9 η
where:
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.

31. Lung Physiology

32. 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.

33. 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.

34. 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

35. The Gold Standard – ACI
Andersen Cascade Impactor

36. ACI Deposition Correlation

37. The New ACI – NGI
Next Generation Impactor

38. Dosage Unit Sampling Apparatus (DUSA)

39. 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

40. Dose Content Uniformity
Is the simplest, yet hardest assay
50
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0 25 50 75 100Shot #
A
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I

C
o
n
t
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n
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(
m
g
)
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0 25 50 75 100Shot #
A
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C
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(
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41. Dosage Unit Sampling Apparatus for
Nebulizers

42. 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

43. Non-Traditional Techniques
A brief overview

44. Laser Diffraction

45. Aerosizer – Time of Flight

46. 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

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

48. Alexza:Staccato
®
system

49. References
1.Copley Scientific
2.MSP