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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

PEG

HPMC

Mucoadhesive hydrogels

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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

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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 dose ingested

Improved lung 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 micronOropharnyx

7 – 8 micronLarge conducting

< 5 micronalveoli

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Pari LC Plus Nebulizer

1. Inspiratory Valve Cap2. Top of Nebulizer3. Nebulizer Semi-Circle (half moon)4. Mouthpiece with Expiratory Valve5. Nebulizer Outlet6. Bottom of Nebulizer7. Air Intake8. Tubing9. Tubing Adapter for Pari Compressors

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3

4

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9$14.90Reusable – replace 6-12 month

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Pari LC Plus Nebulizer

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Pari LC Plus Nebulizer – Open Vent System

More efficientOutput rate controlled by patient breathing by means of a valve systemLower compressed air pressure and flow rate required

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Pari LC Plus Nebulizer

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Traditional Air Jet Nebulizer

Closed systemOutput not influenced by patient breathing50% of drug is wastedLonger treatment timesHigher compressed air pressure and flow (6L/min)

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35“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

(g/mL)

BP

(oC)

VP

(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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Metering Valve

Spray Orifice Plastic Mouthpiece

Canister(holds formulation

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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.)

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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

Compliments of Robert O. Williams, III, Ph.D.—Pharmaceutics Group—The University of Texas at Austin

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How to use a pMDI

1. Remove cap and hold inhaler upright2. Shake the inhaler3. Tilt head back and breathe out4. Open mouth5. Hold inhaler 1-2 inches away6. Press down on inhaler to release medicine7. Breathe in slowly for 3 to 5 seconds8. Hold breath for 10 seconds9. Repeat puffs as directed10.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 HFAAlbuterol 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

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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)

One collapsed, two with inhalers inserted

$30.69 retail

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Inspirease (Key Pharmaceuticals)

With Ventolin canister$30.69 retail

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Expand the bagBreathe in slowly

Bag collapses

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Medispacer (Allegiance Healthcare)

With Ventolin canister

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LiteAire Pop-up Spacer (Thayer Medical)

With inhaler

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Optichamber (Respironics Healthscan)

With Ventolin inhaler$29.18 retail

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Nebuhaler (AstraZeneca)

With terbutaline

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DeviceUse in Small Children

VolumeValved Chamber

Flow rate signal

Inhaler adapter

AceYes (with mask)

170 ml Yes Yes Fits in device

AerochamberYes (with mask)

145 ml Yes Yes Universal

EasiventYes (with mask)

140 ml Yes Yes Universal

Ellipse No 175 ml No No Ovoid

E-Z Spacer Yes (with mask)

700 mlCollapsible

No Fits in device

Inspirease No 700 ml Collapsible Yes Fits in device

MedispacerYes (with mask)

175 ml Yes Yes Fits in device

LiteAir No 158 ml Yes No Universal

OptichamberYes (with mask)

218 ml Yes Yes Universal

Nebuhaler No 750 ml Yes No Oval

Ventahaler No 750 ml   No  

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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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