Aerosal&aerosal drug delivery system

Aerosals and Aerosal Drug
Delivery System

Anyarat Wanitchakorn
Fellow in training
Pediatric Allergy and Immunology
Ramathibodi hospital

Scope for today
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Aerosolized medications
Definition and Types of Aerosols
Factors That Affect Aerosol Deposition
Categories of aerosol drug delivery
devices
• Points to consider in selection device

• Current treatment guidelines for the
management of asthma and COPD
– recommend inhaled therapy as the
primary route for administering
• β2-agonists
• Anticholinergics
• corticosteroids
Middleton’s 8th edition

Aerosolized medications
Drug formulation properties
• particle size distribution
• selected the delivery system

Selection of an inhalation device
• appropriate particle size and lung delivery

Inhalation technique
• inspiratory flow rate, inspiratory volume,
and breath-holding time
• determines the dose of inhaled drug
that deposits in the lung

Revolution
in 1989
• The Montreal Protocol called for the elimination
of chlorofluorocarbons (CFCs) in pMDIs as a
response to the depletion of the earth’s ozone
layer by CFCs
• The introduction of hydrofluoroalkane (HFA) as
an alternative propellant for pMDIs has led to the
availability of low-velocity propellant-driven
aerosols

Revolution
• major design changes in all 3 categories of
aerosol drug delivery devices
• pMDIs
• dry powder inhalers (DPIs)
• nebulizers

• The innovation of DPIs has eliminated the need
for the actuation-inhalation coordination that is
required for pMDI drug delivery


Definition and Types of Aerosols
An aerosol
• a two-phase system defined as a
dispersion or suspension of solid particles
or liquid droplets in a gaseous medium
(e.g., air, oxygen, heliox)
• Living environments
• natural : pollen, bacteria, viruses, house dust
• man-made aerosols, : asbestos fibers, coal
and mineral dusts, cigarette smoke

ADVANTAGES AND DISADVANTAGES IN
RESPIRATORY DISEASE

ADVANTAGES
– noninvasive and painless
– delivers drugs directly to the airway surfaces,
receptor sites
– delivery of high drug concentrations to the airway
– more rapid onset of action
– inhaled β2-agonist bronchodilators aerosal vs oral

– reduced systemic dose and side effect


ADVANTAGES AND DISADVANTAGES IN
RESPIRATORY DISEASE

DISADVANTAGES
– Less-than-optimal technique   drug delivery
  potentially and efficacy
– Techniques differ between device categories and
devices within a specific category
– less convenient than oral drug administration
– more time is required for drug administration

Definitions for Commonly Used Terms
The prediction of deposition : efficiency for a
therapeutic aerosol based on
• Mass Median Aerodynamic Diameter (MMAD) :
– Divides the aerosol size distribution in half diameter at which
50% of the particles of an aerosol by mass are larger and
50% are smaller than the median diameter

• Fine Particle Fraction (FPF)
– the fraction of particles that can achieve deposition in the
lower respiratory tract

(a) cumulative
(b) distribution curves
for Beclovent (MDI)
used with an
Aerochamber

Br J Clin Pharmacol2003, 56, 588–599
Dolovich MB. Aerosols In Asthma,
Philadelphia: Lippincott-Raven
Publishers, 1997; 1349–1366.

• Labeled dose (LD)* or nominal dose
– dose that is metered and specified on the
inhaler package

• Emitted dose (ED) or delivered dose
– The mass of drug emitted per actuation that is
actually available for inhalation at the mouth

Factors That Affect Aerosol Deposition

(1) Physical factors
(2) Ventilatory
(3) Anatomic factors
(4) Patient-related factors

PHYSICAL FACTORS:
PARTICLE SIZE DISTRIBUTION
• The size of an aerosol particle is the primary
determinant of the site of lung deposition,
distribution of the drug within the lung, and
resulting deposition efficiency
• Therapeutic aerosols targeted to the lower
respiratory tract are composed of particles
typically between 0.5 μm and 10 μm in diameter


PHYSICAL FACTORS:

Deposition of particles onto surfaces in the lung mainly

three physical mechanisms:
• impaction
• a function of particle inertia and affects particles
greater than 5 μm

• Sedimentation
• gravitational forces acting on particles primarily
between 0.5 and 5 μm

• Diffusion
• brownian motion and affecting particles smaller than
1 μm in low-flow regions of the lung

PHYSICAL FACTORS:

การเคลือนทีแบบบราวน์
่ ่
Brownian motion
ตั้งชื่อตามนักพฤกษศาสตร์ โรเบิร์ต
บราวน์) หมายถึงการเคลื่อนที่ของ
อนุภาคในของไหล (ของเหลวหรื อ
ก๊าซ) ที่เชื่อว่าเป็ นไปโดยสุ่ ม หรื อ
แบบจาลองคณิ ตศาสตร์ที่ใช้เพื่ออธิบาย
การเคลื่อนที่แบบสุ่ มดังกล่าว มักเรี ยก
กันว่า ทฤษฎีอนุภาค

PHYSICAL FACTORS:

Mechanisms of lung deposition
>10um
Oropharyngeal

10-5 um large
conducting airway
oropharynx

<5um
(>50%=3um)
F.Pereira Muchão.J Pediatr.2010

The effect of aerosol particle size on the site of
preferential deposition in the airways

The effect of altering particle size

Total lung deposition
56%

46%

posterior thorax images of technetium-99m–labeled
albuterol aerosol deposition in the lungs
Am J Respir Crit Care Med 2005;172:1497-1504.

ANATOMIC FACTORS:
AIRWAY CALIBER AND DISTORTION DUE TO DISEASE

Healthy vs asthma pt with FEV1 =31%

The image on a gamma camera scan of lungs
after inhaling 0.9% saline aerosol containing
technetium-99m sulfur colloid
JAMA 1993;269:2106-9.

VENTILATORY FACTORS:
INSPIRATORY FLOW RATE AND BREATH HOLD

• Deposition at airway bifurcations
– exaggerated in airway narrowing secondary to disease

• Particles larger than 5 μm
• deposit to a greater extent in conducting airway surfaces
and less in the peripheral lung

• Particles smaller than 5 μm
• tend to deposit by sedimentation and diffusion on
successively smaller airways

VENTILATORY FACTORS:
INSPIRATORY FLOW RATE AND BREATH HOLD

• Particles between 0.1 and 1.0 μm
• remain suspended, these particles tend to be exhaled
rather than deposited
• 20% of these extrafine pMDI aerosols will be exhaled

• Aerosol particles and the air stream velocity
• inhaling an aerosol at a low flow rate
impaction in larger airways
• inhalation with a prolonged breath hold
 allow greater time for sedimentation and diffusion to
occur in the peripheral airways

• Maximum deposition is obtained in the pulmonary
region for particles approximately 3 μm in size

The effect of the drug aerosol’s particle size on
therapeutic efficacy

(a) Percent improvement in forced expiratory volume in 1 s (FEV1) following inhalation
of two different size aerosols of salbutamol, 3.3 um and 7.7 um
(b) FEV1 following inhalation of two different size aerosols of ipratropium bromide, 3.3
um and 7.7 um
Johnson MA et al. Chest1989; 96: 1–10 [9].

PATIENT-RELATED FACTORS:
ABILITY TO CORRECTLY USE THE DELIVERY SYSTEM AND COMPLIANCE

– pt have never been taught
– pt have modified the technique after instruction
– the various techniques that are appropriate for each
device
– the advantages and disadvantages of each device

• Health care providers should ensure that their
patients can and will use these devices correctly


NEBULIZERS FOR LIQUID FORMULATIONS

Jet Nebulizers
Conventional pneumatic nebulizers

Jet Nebulizers
• The MMAD of jet nebulizers used for therapy should
be between 2 and 4 μm
• jet nebulizer delivers aerosol continuously while the
patient inhales and exhales.
– 30% to 40% of the nominal dose is trapped in the
nebulizer
– 60% of the ED is wasted to the atmosphere during
exhalation
– < 10% of the nebulizer contents to the patient


Jet Nebulizers
“breath-enhanced” devices
• allows additional room air to be entrained during
inspiration
• increasing the amount of useful aerosol for inhalation
• air also may be entrained through a T-piece or face mask
supplementing the jet air flow rate to meet the inspiratory
flow requirements of the patient
• increase in the total drug delivered to the patient per unit
time from nebulizers with additional air entrainment

Jet Nebulizers
Solvent evaporates during nebulization
• rate of evaporation depends on the volume of fluid placed in
the reservoir
• reservoir fill volume of 3 to 5 mL
• the dead volume, at the end of nebulization(no further
aerosol is produced)
• 0.5 to 1.5 ml of concentrated solution is left
 drug that is unavailable to the patient


Jet Nebulizers
The driving pressure or the flow rate of compressed air
• affects aerosol output and particle size from jet NB
• higher the pressure or flow rate, the greater the output
over time in terms of total solution aerosolized, and the
smaller the particle size

• time required to deliver the medication
– varies with the airflow rate used to drive the nebulize
– Typical treatment times range between 5 and 15 minutes


Jet Nebulizers
Face masks
• acutely ill or uncooperative patients such as infants and
toddlers
• face mask with vent holes should be used  reduce
deposition on the face and in the eyes


Jet Nebulizers
Mouthpiece
• direct the aerosol toward the nose and mouth
• usually in a child
• “blow-by” technique


Exercise
• Which one is suitable for this patient?
A

B

Ultrasonic Nebulizers
• a piezoelectric crystal
– vibrated at a high frequency
– create standing waves on the surface of the
liquid overlying the crystal



operate at frequencies above 1 MHz
producing aerosols with MMADs between 2 and 12 μm
an output that is two to three times higher than with most jet nebulizers

F.Pereira Muchão.J Pediatr.2010

• Droplets are formed that remain within the nebulizer until
they are swept out by a fan or the patient’s inspiratory
breath
• Produced heat along with the aerosol, however
– the ultrasonic nebulizer solution is sonicated
– temperature can rise 10° to 15° C over a 10-min
– adversely affect heat-sensitive components of formulations,
such as proteins

• not suitable for nebulizing suspensions


NEBULIZERS: POINTS TO CONSIDER IN
SELECTION OF DEVICE


PRESSURIZED METERED-DOSE INHALERS
Formulation Issues
• CFC propellant pMDIsHFA propellant pMDIs
(mandated by the Montreal Protocol)
• HFA
–
–
–
–

medically safe
nontoxic to animals and humans
devoid of pharmacologic activity,
can be co-solved with corticosteroids

HFA, hydrofluoroalkane
CFC, chlorofluorocarbon


High-speed photographs of the plume geometry
of albuterol aerosols

• Top, HFA albuterol (Airomir, 3M Pharmaceuticals)
• Bottom, CFC albuterol (Ventolin, GlaxoSmithKline)
Dolovich M, Leach C. Drug delivery devices and propellants. In: Busse W, Holgate S,
editors. Asthma and rhinitis. 2nd ed. Oxford: Blackwell Science; 2000

PRESSURIZED METERED-DOSE INHALERS
Formulation Issues

• For salbutamol, fluticasone, budesonide, and beclomethasone,
– particle size of the HFA suspension = CFC formulation
– lung deposition averages 7% to 30%

• Some HFA pMDIsreformulation as a solution and the introduction
of ethanol as a cosolvent
• Some have concentrations of alcohol up to 37% (w/w)
– may cause irritation on inhalation

• Beclomethasone dipropionate (BDP) was formulated as a solution
when it transitioned to an HFA pMDI
– led to production of a finer aerosol with an increased
– HFA BDP is called an extrafine aerosol


Similarities and Differences between
HFA, pMDI ICS Aerosols


Scintigraphic images of the lungs

• patient with asthma after inhalation of two different formulations of
radiolabeled beclomethasone dipropionate (BDP) pressurized aerosol
Dolovich MB, Labiris NR.Proc Am Thorac Soc 2004;1:329-37

Breath-Actuated pMDIs
• For poor actuation-inhalation coordination with use of
standard pMDIs
• The Autohaler automatically actuates at
– inspiratory flow rates of approximately 30 L/min
– the Easibreathe actuates at 20 L/min

• improve lung deposition over that achievable with
pMDIs alone


PRESSURIZED METERED-DOSE INHALERS (pMDIs):
POINTS TO CONSIDER IN SELECTION OF DEVICE


pMDIs and Spacers and Valved Holding Chambers
• developed for use with pMDIs in response to difficulties encountered
• problems are related to timing or hand-breath coordination
– coordination of actuating the pMDI and inhaling the spray at the same time

• increasing the probability of optimal delivery of the drug to the lung


pMDIs and Spacers and Valved Holding Chambers
• Volumes for the various devices range from 15 to 750 mL
• aerosol characteristics and drug yield affect by
– one-way valve to convert an open tube into a reservoir
– shape and volume of the device, flow of air through the device
– face masks’ mouthpieces, and manufacturing materials all

• inhalation valve
– used to contain the aerosol and reduce oropharyngeal deposition
(as a baffle)
– must be able to withstand the initial pressure from the pMDI on
firing
– must have a sufficiently low resistance to open readily on
inhalation

pMDIs and Spacers and Valved Holding
Chambers
• Coordination is still required with all three types of
spacer design
• decrease in drug output from plastic spacers is largely
due to the presence of electrostatic charge on the plastic
• To decrease electrostatic charge
– metallic-coated device
– device manufactured from a nonelectrostatic plastic
– washing the plastic device periodically with deionizing detergent


SPACERS AND VALVED HOLDING CHAMBERS (VHCs):


DRUGS IN POWDER FORM:
DRY POWDER INHALERS
• Aerosols of dry powder are created by directing
air through an aliquot of loose powder
• the dispersion of the powder into respirable
particles is dependent on the creation of
turbulent flow in the inhaler
• a function of both the patient’s (ability to inhale the
powder at a sufficiently high inspiratory flow rate) and
the design of the powder device

DRY POWDER INHALERS
• individual doses of drug from punctured gelatin
capsules
• a tape system containing multiple sealed, single
doses in a blister
• a multidose reservoir powder system


DRY POWDER INHALERS
• most powder-dispensing systems require the use of
a carrier substance
• vehicle substance enable the powder to more readily
pass out of the device
• carriers that are used include lactose and glucose
– Fewer allergenic than to the surfactants and propellants
used in pMDIs


Electron micrographs of
a 2% albuterol sulphate–lactose powder blend

• (a) lactose particle with drug on its surface
• (b) The higher magnification shows individual drug
particles (elongated crystals) on the lactose

Br J Clin Pharmacol2003, 56, 600–612

DRY POWDER INHALERS
• particle size of dry powder particles is on the
order of 1 to 2 μm
• the size of the lactose or glucose particles can
range from approximately 20 to 65 μm
• most of the carrier deposits in the oropharynx


DRY POWDER INHALERS

• commercially available
– passive, or patient-driven
– rely on the patient’s inspiratory effort to dispense
the dose from the device

• resistance of a DPI
– classified with respect to the inhalation flow
– to produce a pressure drop 4 kPa across device

DRY POWDER INHALERS
•
•
•
•

low-resistance device : inspiratory flow of > 90 L/min
medium-resistance : inspiratory flow of 60 to 90 L/min
medium- to high-resistance : 50 to 60 L/min
high-resistance device allows < 50 L/min

Potential deposition of aerosol in
upper and lower airways


DRY POWDER INHALERS
• appropriate procedure is described in the
package insert/patient information leaflet
• Patients who do not perform these procedures
correctly may receive no dose!!
• irrespective of the inhalation maneuver they
subsequently adopt

DRY POWDER INHALERS (DPIs):


Inhaler strategy, optimal inhalation technique and most
common problems with correct inhaler use in children

Primary Care Respiratory Journal (2010); 19(3): 209-216

Proportion of patient age and aerosal device

Primary Care Respiratory Journal (2010); 19(3): 209-216

Summary
• Aerosal therapy  good route for drug
administration
• A number of factors effect deposition of
aerosal in the lung
• Aerosal particle size play important role in
targeting lung region
• Appropriate drug formulations and device
need for improve its efficacy

Aerosal&aerosal drug delivery system

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