Aerosols

Aerosol

Overview

• Introduction

• Definition and types of aerosols

• Definitions for Commonly Used Terms in

Aerosol Delivery

• Factors affect Aerosol Deposition

• Aerosol Drug Delivery Devices

Introduction

• Inhaled therapy was the primary route for

administering β2-agonists, anticholinergics, and

corticosteroids in asthma and COPD

• Challenging due to

– Drug formulation properties

– Particle size distribution

– Delivery system

– Inhalation technique

Definition and Types of Aerosols

• An aerosol is a two-phase system defined

as a dispersion or suspension of solid

particles or liquid droplets in a gaseous

medium (air, oxygen, heliox)

Middleton 8th edition

Definitions for Commonly Used

Terms in Aerosol Delivery

• The prediction of deposition efficiency and

therapeutic effect based on

– Traditionally: mass median aerodynamic

diameter (MMAD)

– More recently: fine particle fraction (FPF)

Factors affect Aerosol Deposition

1. Physical factors; particle diameter, FPF

2. Ventilatory factors; inspiratory volume,

inspiratory flow rate, breath-hold time,

breathing rate, and nose versus mouth

breathing

3. Anatomic factors; airway caliber and distortion

due to disease

4. Patient-related factors; technique, complicance

Physical factor: Particle size distribution

• Aerosol diameter determined site of lung

deposition, distribution of the drug within the

lung; deposition efficiency

• Sizes for environmental and occupational

aerosols diameter range from 0.001 μm

(nanoparticles) to 1000 μm (supercoarse)

• Therapeutic aerosols targeted to the lower

respiratory tract are 0.5 μm - 10 μm in diameter

• Impaction: particle inertia, particles >5 μm

• Sedimentation: particles 0.5 - 5 μm

• Diffusion: brownian motion, particles <1 μm

Deposition of particles in the lung

Total curve represents the sum of tracheobronchial and pulmonary values Middleton 8th edition

Correlation between aerosol particle

size and whole-lung deposition

Small MMADs and high FPFs to enhance delivery

of drug to the lungs of patients with airway disease


Ventilatory factors: inspiratory flow rate and breath hold

• Airflow directly influences impaction of

particles onto airway walls

• Particle <5 μm

– low flow rate to minimize impaction in the

larger conducting airways

– prolonged breath hold will allow greater time

for sedimentation and diffusion to occur in the

peripheral airways

Ventilatory factors: inspiratory flow rate and breath hold

• Maximum deposition in the pulmonary

region for particles approximately 3 μm in

size

• At 0.5 μm, <5% deposited in the lung

(maximal deposition in respiratory

bronchioles)

• Altering particle size while maintaining inspiratory

flow at slow (30-60 L/min) rates on albuterol

aerosol distribution within the lungs of a patient with

asthma

• MMAD of 1.5 μm, 3 μm, and 6 μm


• Total lung deposition (TLD) was greater with the 1.5 μm

aerosol (56%) than with the 6 μm aerosol (46%) (P <0.01)

• Peripheral region deposition was significantly greater with

smaller particles; 1.5 μm (25%) > 3 μm (17%) > 6 μm (10%)

(P <0.001)


Ventilatory factors

• Larger particles produced greater

bronchodilation measured using forced

expiratory volume in 1 second (FEV1):

• 6 μm > 3 μm > 1.5 μm

• At 15 μg doses (484 ± 183, 420 ± 121, 337 ± 169)

• At 30-μg doses (551 ± 221, 457 ± 200, 347 ± 172)

These results suggest that regional targeting of

inhaled β2-agonist to the proximal airways may be

more important than distal alveolar deposition for

bronchodilation

Anatomic factors

• A reduction in airway caliber, as from disease,

alters the airflow pattern in the lung and affects

the distribution of inhaled aerosol


Aerosol Drug Delivery Devices

• Nebulizers for liquid formulations

– Jet Nebulizers

– Ultrasonic Nebulizers

• New-generation nebulizers

– Breath-Actuated Nebulizers

– Breath-Enhanced Nebulizers

– Vibrating Mesh Devices: Passive

– Vibrating Mesh Devices: Active

– Soft Mist Inhalers

• Pressurized metered-dose inhalers

– Breath-Actuated pMDIs

– pMDIs and Spacers and Valved Holding Chambers

• Dry powder inhalers

Aerosol Drug Delivery Devices

Jet Nebulizers

• Use compressed air/oxygen to break up a thin

film or jet of fluid into droplets suitable for

inhalation

• Venturi effect

Jet Nebulizers

• 30-40% of the nominal dose is trapped in the

nebulizer, and more than 60% of the ED wasted

to the atmosphere during exhalation

• <10% of the nebulizer contents to the patient

• MMAD of jet nebulizers used for therapy should

be between 2 and 4 μm

• Low cost

• Little patient effort

Jet Nebulizers

• The rate of evaporation depends on the volume

of fluid placed in the reservoir

– Volume of 3-5 mL longer treatment time compared

with the 2 mL

• Typical treatment times: 5-15 min

• At the end of nebulization, when no further

aerosol is produced, 0.5-1.5 mL of solution is left

in the reservoir; dead volume

Ultrasonic Nebulizers

• Vibrated at a high frequency to create waves on

the liquid overlying the crystal

• Above 1 MHz, producing aerosols with MMADs

2-12 μm that is 2-3 times higher than with most

jet nebulizers

Ultrasonic Nebulizers

• The temperature can rise 10-15°C over a 10-

minute treatment period, which may adversely

affect heat-sensitive components of formulations

• Ultrasonic nebulizers also are not suitable for

nebulizing suspensions

Breath-Actuated Nebulizers

• generate aerosol only during

inspiration

New-generation nebulizers

Soft Mist Inhalers

• uses mechanical energy to create an

aerosol with a low-velocity spray

• aerosol ranges 2.2-5.5 μm MMD


Vibrating Mesh Devices: Passive

• generate aerosol only during

inspiration

Vibrating Mesh Devices: Active

• vibrates at a high frequency

• high FPFs and very low dead

volumes

• battery-operated


Pressurized metered-dose inhalers

• Most commonly used

• Portable, compact, and relatively easy to

use

• Uniform dose


• As a result of the Montreal Protocol in 1989,

transition from chlorofluorocarbon (CFC)

propellant pMDIs to HFA (hydrofluoroalkane)

propellant pMDIs

• HFA is medically safe, nontoxic, co-solved

with corticosteroids

• Lung deposition averages 7-30%

HFA plume is softer, not as narrow, not travel

as far as the CFC propellant

HFA albuterol

CFC albuterol



• For most albuterol HFA pMDIs, the reduction in

dose is still an issue when the pMDI is first used,

and priming is required


Breath-Actuated pMDIs

• Improve lung deposition over that achievable

with pMDIs alone

• Autohaler automatically actuates at inspiratory

flow rates of approximately 30 L/min

• Easibreathe actuates at 20 L/min

pMDIs and Spacers and

Valved Holding Chambers

• Easy to use: reduces the need for patients

to coordinate inhalation

• Improve drug targeting: retaining the large

particles that would normally be deposited

in the oropharynx

• Can be used with a face mask

pMDIs and Spacers and

Valved Holding Chambers

Reservoir chamber with a valve:• allows the aerosol to be

held in the chamber until the

patient inhales

Open tubeFor reverse-flow devices

• pMDI is removed from its

actuator mouthpiece and

placed proximally, adjacent

to, or in the mouthpiece

• With reverse flow, the pMDI

is fired in the direction away

from the patient


• Volumes for the various devices range 15-750 mL

• Any size of spacer but lower volume (<350 ml) is

more advantageous in very young children

• Electrostatic charge on the plastic spacers decrease

drug output

• Metallic-coated device, nonelectrostatic plastic, or

washing the plastic device periodically with deionizing

detergentMiddleton 8th edition

Spacers

• Pre-school children

• Inhaled glucocorticosteroids with a low first pass

metabolism in all age groups

• Who cannot use pMDIs or DPIs

Mask should cover nose

and mouth

Dry powder inhalers

• Some dispense individual doses of drug from

punctured gelatin capsules such as the Aerolizer

(Novartis Pharmaceuticals, United States) and

HandiHaler (Boehringer Ingelheim, Germany)

• A tape system containing multiple sealed, single

doses in a blister (Diskus, Glaxo, United

Kingdom)

• Turbuhaler (Astra Draco, Sweden) is an

example of a multidose reservoir powder system

Dry powder inhalers

• Aerosols of dry powder are created by directing

air through an aliquot of loose powder

• Hold the drug powder in bulk in a reservoir

• breath-actuated, the need to synchronize

inhalation with actuation is eliminated

• Dependent on the creation of turbulent flow in

the inhaler

• The peak inspiratory flow rate to dispense

powder is 30 - 60 L/min

Dry powder inhalers

• The specific resistance of a DPI device affects

the maximal inspiratory flow rate (IFR)

• High resistance

– Decreases the ability to draw air through the

inhaler

– Proper inhalation produce greater FPF and

increase delivery of drug to the lower

respiratory tract

• The clinical significance of this is not known

β2-agonists

NB MDI DPI Oral

Salbutamol Ventolin Ventolin

Evohaler

Ventodisk

Buventol

Ventolin

Terbutaline Bricanyl Bricanyl Bricanyl Bricanyl

Fenoterol Berotec Berotec - Berotec

Salmeterol - Serevent Serevent -

Formoterol - - Oxis -

Procaterol - Meptin - Meptin

Bambuterol - - - Bambec

β2-agonistsNB MDI DPI Oral

Salbutamol Ventolin(2.5mg/2.5ml)

Ventolin

Evohaler

(100 mcg/dose,

200 dose)

Ventodisk

Buventol

Ventolin(2 mg,

2mg/5ml)

Terbutaline - - - Bricanyl

(2.5 mg)

Fenoterol Berotec Berotec - Berotec

Salmeterol - Serevent Serevent -

Formoterol - - Oxis -

Procaterol - - Meptin Meptin(50 mcg)

Bambuterol - - - Bambec(10 mg)

Inhaled β2-agonists

• Short-acting (SABAs): duration 3-4 hr

– Salbutamol, terbutaline

• Long-acting (LABAs): duration 12-24 hr duration

of activity

– Salmeterol, formoterol

• Ultra-long-acting (ultra-LABAs):

duration at least 24 hr

– Indacaterol

LABAs

• Salmeterol: developed from salbutamol,

modified to attach the drug molecule near the

β2-receptor by extending its aliphatic side-chain

• Formoterol

– Initially as an oral β2-agonist and its long duration

of activity when inhaled was discovered

serendipitously

– Duration depended on route of administration

Intracellular signaling after activation of

the β2-receptor by a β2-agonist

• β2-agonists + the receptor’s G protein trimer; Gs

• Gs disassociates into a Ga subunit and a β/γ dimer

• Ga binds to and activates adenylyl cyclase → increased cAMP

• cAMP activates protein kinase A (PKA)

• PKA

– phosphorylates myosin light chain kinase (MLCK) → airway

smooth muscle relax

– Rho kinases (ROCK), which are needed for contraction, also are

targeted

• activates some transduction pathways

– sodium-hydrogen exchanger regulatory protein

– couples directly to potassium channels linked to relaxation of

airway smooth muscle

Ventolin MDI, DPI

Bricanyl DPIFenoterol MDI

Procaterol DPI

Salmeterol MDI, DPI

Formoterol DPI

Combined β2-agonists

β2-

agonists

Steroid NB MDI DPI

Salmeterol Fluticasone - Seretide

evohaler

Seretide

accuhaler

Formoterol Budesonide - - Symbicort

- Fluticasone - Flixotide Flixotide

- Budesonide Pulmicort Pulmicort /

Inflammide

Pulmicort

- Beclomethasone - Beclomin +


Drugs MDI DPI

Salmeterol +

Fluticasone

Seretide evohaler

25/50, 25/125, 25/250 mg,

120 dose

Seretide accuhaler

50/100, 50/250 mcg/dose,

60 dose

Formoterol +

Budesonide

- Symbicort

80/4.5, 300/9, 60 dose

160/4.5, 120 dose

Fluticasone Flixotide evohaler

50, 125, 250 mcg/dose,

120 dose

Flixotide accuhaler

100, 250 mg

Budesonide Pulmicort

100, 200 mcg/dose,

100 dose

Pulmicort easyhaler,

turbuhaler, swinghaler

Beclomethasone Beclomethasone50,100, 200, 250 mcg/dose

Beclomethasone

Easyhaler

Seretide MDI, DPI Symbicort DPI

Budesonide MDI, DPI

Beclomin

MDI

Flixotide MDI, DPI


β2-agonists Anticholinergic NB MDI DPI

Ipratropium

bromide

Atrovent Atrovent -

Salbutamol Ipratopium

bromide

Combivent Combivent -

Fenoterol Ipratopium

bromide

Berodual Berodual -

Iprotopium MDI Salbutamol + Iprotopium MDI

Fenoterol + Iprotopium MDI

Dry powder inhalers

• Humid environment decreas emitted dose

• Store DPIs in a cool, dry environment

• Mostly require carrier substance including

lactose and glucose

• The particle size of dry powder: 1-2 μm

• Size of the lactose/glucose particles: 20-65 μm

and mostly deposits in the oropharynx

• Oropharyngeal doses comparable with pMDI

without an add-on device

• Deposition in the lungs varies from 12- 32%

• Similar to or slightly better than those observed

with pMDI

Aerosols

Health & Medicine

Transcript of Aerosols