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Pulmonary and Nasal Drug

Delivery Systems

Chapter 14

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Overview of Inhaled Therapy
• Drug
• Aerosol Generation and Delivery
• Inhalation
• Deposition
• Transport into Blood
• Biological Response

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Upper Airway
• Physiology of the Nose:
– Provides for:
• exchange of heat and moisture
– Purpose of the nose:
• Olfactory and conditioning of inspired air
– Nasal breathing more effective than mouth
breathing to heat and humidify inspired air
– Nasal filtration
• Particle clearance
• Particle deposition
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Nasal Delivery
Rapid clearance
Mucoadhesive hydrogels

PEG
HPMC

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Upper Airway
– Drug absorption depends on:
• 1.
• 2.
• 3.
• 4.
– Choosing a nasal delivery system:
• Drop bottle
• Aqueous pump spray
– Preservative use (phenylethanol; benzalkonium Cl)
• Metered-dose inhaler
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Upper Airway
• Pharynx and larynx
– Role in drug delivery
– Pharyngeal barrier
– Spacer devices

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Ace Spacer (DHD Healthcare)

$23.89 retail 11
Lower Airway
• Zones of lung:
– Conducting zone
– Transitional zone
– Respiratory zone
• What limits aerosol use?
– Patient compliance
– Breathing maneuvers
– Irritant activity
– Epithelial permeability
– Bronchoconstriction

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Lower Airway
• What controls drug deposition?
– Flow rate
• pMDI vs. DPI
– Patient factors
– Particle size distribution of emitted dose
– Particle density and shape
– Hygroscopic growth

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pMDI Deposition

Up to 82% of Improved lung


dose ingested deposition
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Types of drug delivery systems
• Nebulizers
• MDI
– Propellant driven
– Aqueous pump sprays
• DPI

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Nebulizers
• Types:
– Ultrasonic nebulizer
– Air jet nebulizer
• Performance influenced by:
– Type used and its operation
– Cost
– Brand vs. brand/within brand
– Evaporative losses

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Ultrasonic Transducer

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Ultrasonic Nebulizer (MedProducts International)

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Ultrasonic (MicroAir from Omron)

Uses Vibrating Mesh Technology


-Lov Voltage Ultrasonic horn pushes liquid
-Through metal mesh screen with 6000 holes

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Air Jet Nebulizer (Pari)

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Air Jet (CompAir)

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Portable Air Jet Nebulizer (compressor built in)

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8 micron
Oropharnyx

7 – 8 micron
Large conducting

< 5 micron
alveoli

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1
2
Pari LC Plus Nebulizer

3 1. Inspiratory Valve Cap


2. Top of Nebulizer
3. Nebulizer Semi-Circle (half
4 moon)
4. Mouthpiece with Expiratory
Valve
5. Nebulizer Outlet
6. Bottom of Nebulizer
5 7. Air Intake
6 8. Tubing
7 9. Tubing Adapter for Pari
8 Compressors

$14.90
9 Reusable – replace 6-12 month
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Pari LC Plus Nebulizer

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Pari LC Plus Nebulizer – Open Vent System

More efficient
Output rate controlled by patient breathing by means of a valve
system
Lower compressed air pressure and flow rate required 31
Pari LC Plus Nebulizer

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Traditional Air Jet Nebulizer

Closed system
Output not influenced by patient breathing
50% of drug is wasted
Longer treatment times
Higher compressed air pressure and flow (6L/min)
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“Bubbles the Fish” Pari Pediatric Mask
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Nebulizers
• Formulation components
– Drug
– Solvent
– Osmotic agent
– Chemical stabilizer
– Buffer
– Preservative(s)

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Pressurized Metered Dose Inhalers
• Definition: Pharmaceutical aerosols are pressurized
dosage forms containing one or more active ingredients
which upon actuation emit a fine dispersion of liquid
and/or solid materials in a gaseous medium
• Similar to other dosage forms in that they require the
same types of considerations with respect to formulation,
stability, etc (i.e. PSD, solubility)
• They differ in their dependence upon the function of the
container, its valve assembly, and an added component
—the propellant—for the physical delivery of the
medication to the patient in the proper form

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pMDIs
• Pressurized Dosage Form
--One or more gaseous or liquefied propellants
--Upon activation of the valve assembly, it is the
pressure exerted by the propellant(s) that forces the
contents of the package out through the valve
opening
• Particle size
-- < 5 μm—respiratory bronchioles, alveoli
-- ~7-8 μm – large conducting airways
-- >~8 - 10 μm -- oropharnyx

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Advantages of Aerosol Dosage
Form
• Medication can be withdrawn in portions without
contamination – aliquot from reservoir
• Due to hermetic nature of package—protection
from oxygen, moisture, and light
• Topical applications without touching affected
area—less irritating
• Through metered valves, dosage may be
controlled—also efficiency of particle size control

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pMDI Principle

• The Formulation (two-phase


system)consists of:
--the product concentrate
-required adjuncts (SSA, Solvents, antioxidants, etc.)
-drug or drugs

--the propellant
-Gas at room temperature
-Liquid when cooled or compressed
-CFCs vs. HFCs
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Vapor Pressure
• Pressure developed as propellant
molecules leave the liquid state and enter
the vapor state until equilibrium is attained

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Propellants
• Types
– CFC-11 Trichloromonofluoromethane
– CFC-12 Dichlorodifluoromethane
– CFC-114 Dichlorotetrafluoroethane
– HFA-134a Tetrafluoroethane
– HFA-227 Heptafluoropropane

• Density, Boiling Point, Vapor Pressure


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Designation Density BP VP
(g/mL) (oC) (at 20oC)

P11 1.49 23.7 -1.8

P12 1.33 -29.8 67.6

P114 1.47 3.6 11.9

P134a 1.21 -26.5 68.4

P227 1.41 -17.3 56.0

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3M's CFC-Free Technology Improves Lung Deposition

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Containers
• Types
– Glass
• Plastic coated or laminated
• Fragile
• Not for light sensitive drugs
– Aluminum
• Interior coating
• Light weight, not fragile
• Good for light sensitive drugs
• Typical volume capacity

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Metering Valve
• Generally designed to work in inverted position
• Critical component
• Primary function – reproducibly delivery an
aliquot of liquid phase in which drug is dissolved
or suspended
• Composed of multiple parts that must be
assembled
• Composition –
• Dispensing volumes –
• Valve dispenses volumetrically
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Canister
(holds formulation

Metering Valve

Plastic Mouthpiece Spray Orifice

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Actuator
• Purpose – provides means to depress the
valve stem in the metering chamber, and
for patients to inhale the dose
• Spacer devices
• Composition –
• Cleaning -

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Two-phase Aerosol System
Schematic – Continuous Spray
Valve

• Fig 13.12 Cross-section sketches of contents and operation of a typical two-phase


aerosol system (Armstrong Laboratories Inc. Division of Aerosol Techniques, Inc.) 51
Applications &
Advantages/Disadvantages
• Nasal
--Nasal dropper bottle or spray bottle
--Aqueous pump spray (Vancenase AQ)
--Metered Dose Inhaler (pMDI)
• Pulmonary Delivery
--Nebulizers
--pMDIs (Azmacort)
--Dry-powder Inhalers (DPI)
• Topicals
--Tinactin
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Anatomical Representation of a
Cascade Impactor
• Cascade Impactor: For determination of particle size and doses of each actuation

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Compliments of Robert O. Williams, III, Ph.D.—Pharmaceutics Group—The University of Texas at Austin
How to use a pMDI
1. Remove cap and hold inhaler upright
2. Shake the inhaler
3. Tilt head back and breathe out
4. Open mouth
5. Hold inhaler 1-2 inches away
6. Press down on inhaler to release medicine
7. Breathe in slowly for 3 to 5 seconds
8. Hold breath for 10 seconds
9. Repeat puffs as directed
10. Wait 1 minute between puffs

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Mast Cell Stabilizers (anti-
inflammatory)

Intal (cromolyn sodium) Tilade (nedocromil)

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Bronchodilators (short acting)

Generic Albuterol Proventil HFA


Albuterol Ventolin albuterol

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Bronchodilators (short acting)

Alupent (metaproterenol) Maxair Autohaler (pirbuterol)

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Bronchodilators (short acting)

Combivent (ipratropium bromide and albuterol)

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Bronchodilators (long-acting)

Serevent pMDI (salmeterol)

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Inhaled Corticosteroids

Azmacort (TAA) Aerobid M (flunisolide; mint flavor)

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Other Products

Safe Count with inhaler


(Safe Count, Inc.)

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Spacer Devices
• Valved chamber – with exhalation ports is useful
to prevent exhalation into the chamber and allow
inhalation of drug remaining in the chamber after
the first breath
• Flow rate signal – warns user that the inhalation
is too fast
• Universal inhaler adapter – conforms to the
mouthpiece of any metered dose inhaler,
whereas others have rigid adapters that fit only
one type of mouthpiece

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Ace Spacer (DHD Healthcare)

$23.89 retail 63
Aerochamber (Forest
Pharmaceuticals)

With Ventolin With child’s mask With medium size mask

$38.79 retail

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E-Z Spacer (WE Pharmaceuticals)

$30.69 retail

One collapsed, two with inhalers inserted 65


Inspirease (Key Pharmaceuticals)

With Ventolin canister


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$30.69 retail
Breathe in slowly
Expand the bag

Bag collapses
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Medispacer (Allegiance Healthcare)

With Ventolin canister

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LiteAire Pop-up Spacer (Thayer
Medical)

With inhaler 69
Optichamber (Respironics
Healthscan)

With Ventolin inhaler


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$29.18 retail
Nebuhaler (AstraZeneca)

With terbutaline

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Use in
Valved Flow rate
Device Small Volume Inhaler adapter
Chamber signal
Children

Yes (with 
Ace 170 ml Yes Yes Fits in device
mask)
Yes (with 
Aerochamber 145 ml Yes Yes Universal
mask)
Yes (with 
Easivent 140 ml Yes Yes Universal
mask)
Ellipse  No 175 ml No No Ovoid
Yes (with 
E-Z Spacer  700 ml Collapsible No Fits in device
mask)

Inspirease No 700 ml Collapsible Yes Fits in device

Yes (with 
Medispacer 175 ml  Yes Yes Fits in device
mask)
LiteAir No  158 ml Yes No  Universal
Yes (with 
Optichamber 218 ml Yes Yes Universal
mask)
Nebuhaler No 750 ml Yes No Oval 72
Ventahaler No 750 ml   No  
Cleaning Spacer Devices
• Water
• Water with mild detergent
• Daily, weekly, several times a week
• Avoid dishwasher
• Replace if damaged

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Nasal Metered Dose Inhalers

Nasacort
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Nasal Metered Dose Inhalers

Nasacort AQ

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Nasal Metered Dose Inhalers

Rhinocort Aqua

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Examples of pMDI Products
• Oral
– Beclovent
– Proventil Inhalation Aerosol
– Aerobid Aerobid M
– Duo-Medihaler
– Maxair Autohaler**
– Isuprel Mistometer
– Azmacort
– Nitrolingual Spray
– Serevent
– Proventil HFA
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Examples of pMDI Products
• Nasal
– Beconase
– Beconase AQ
– Nasalcrom
– Nasalide
– Vancenase
– Vancenase AQ
– Decadron Turbinaire
– Nasacort
– Syntocinon
– Rhinocort
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