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824 - Dosage Forms > Aerosols for Lung Delivery > Flashcards

Aerosols for Lung Delivery Flashcards

1
Q

Aerosol

A

A dispersion of fine particles or liquid droplets suspended in a gas or vapor

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2
Q

Aerosol Limitations

A

Inefficient delivery

  • Lungs generally designed to prevent inhalation of exogenous compounds/particulates
  • Some devices only deliver around 10% of dose to lungs
  • Oropharyngeal irritation, taste
  • Reproducibility is a big concern
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3
Q

Local Delivery to Site of Action

A
  • Asthma, COPD, etc.
  • Avoids systemic effects (corticosteroids)
  • Rapid onset (B-agonists in acute asthma)
  • No interactions w/food
  • Sterility
  • Acceptability (compare injections)
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4
Q

Delivery of Systemic Acting Drugs

A
  • No degradation by stomach, enzymes, avoids first-pass metabolism in liver
  • Insulin
  • Large SA of lungs (120-160 m^2, ~ tennis court) - high absorption area
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5
Q

Particle Size Deposition in the Respiratory Tract

A
  • 10-30 um (trachea, lungs, bronchus) – inertial impaction
  • 3-10 um (trachea, bronchial, bronchiolar region) – sedimentation
  • 1-3 um (alveolar region) – diffusion
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6
Q

Methods of Determining Particle Size

A
  • Microscopy
  • Sieving
  • Sedimentation
  • Electrical Resistance
  • Laser diffraction
  • Aerodynamic diameter
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7
Q

Compounds Administered to Lungs

A
  • Asthma (B-2 agonists, Glucocorticoids, Mast cell stabilizer)
  • Cystic Fibrosis
  • Emphysema (COPD)
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8
Q

pMDI Components

A

Propellants

  • Provide pressure to expel product
  • Also act as dispersion medium
  • Occasionally exhibit solvent properties

Solvents

  • Bring active ingredient into solution
  • Cosolvent for immiscible liquids
  • Influence particle size
  • Reduce vapor pressure

Active ingredient/other additives

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9
Q

Valves (2 Types)

A
  1. Continuous Valves (topical aerosols)
    - Continuous production of aerosol when the actuator is pressed down
  2. Metered Valves (for accurate dosing, inhalation and some topical)
    - Finite volume is released when actuator is pressed
    - Inhalers = 25-100 ul
    - Topical can be up to several mls
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10
Q

Containers/Canisters

A

Aluminum
- Lightweight, seamless, compatible and cheap, printable, easy filling and sealing, can anodize w/some solvents, internal coating (epoxy, epoxy resin, polymamide resin), opaque)

Glass - coated (visible formulation)

PET

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11
Q

Functions of Activators

A
  • Allow release of formulation from valve
  • Generate aerosol through the orifice
  • Direct aerosol
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12
Q

Propellant Types (2)

A

1) Chlorofluorocarbons

2) Hydrofluoroalkanes

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13
Q

1) Chlorofluorocarbons (CFCs) – (advantages & disadvantages)

A

Advantages

  • Low toxicity
  • High stability
  • Good solvents

Disadvantages

  • Destroys Ozone
  • Greenhouse gas
  • Cost
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14
Q

2) Hydrofluoroalkanes (HFAs) – (advantages & disadvantages)

A

Advantages

  • Low toxicity
  • High stability
  • Non-ozone depleting

Disadvantages

  • Poor solvents
  • Greenhouse gas
  • Cost
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15
Q

Transition from CFC to HFA

A

HFAs vs CFCs

  • GWP 6x less w/HFAs
  • HFA based inhalers are 3x expensive
  • I.e. Proventil HFA (Albuterol) and QVAR (Beclomethasone)
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16
Q

Formulation Factors (4)

A
  1. Drug Solubility
    - Either soluble or insoluble (don’t want in between)
    - Solution or suspension
    - Oswald ripening (crystal growth)
  2. Vapor Pressure
    - Particle size
    - Droplet evaporation
    - Velocity
  3. Surface Tension (droplet size formation)
  4. Density (stability of suspension)
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17
Q

Surfactants & What They’re Used For

A
  • Anionic, Cationic, and Non-ionic
    Used for:
  • Valve lubrication
  • Aid in the dispersion of particles in suspension
  • Stabilize foaming aerosols
  • Emulsifying agents for emulsion aerosols
  • To decrease surface tension and particle size
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18
Q

Solution Systems

A
  • Drug is DISSOLVED in propellant system
  • Smaller particle size of aerosol
  • Simplified manufacturing, drug must be soluble
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19
Q

Suspension Systems

A
  • Drug is suspended or dispersed in the propellant system
  • For drugs that are insoluble
  • Higher doses can be delivered
  • Stability and manufacturing are challenges
20
Q

Particle Size

A
  • Select particle size of suspension based on intended use (<5 microns for inhalation aerosols)
  • Particle size depends on:
    formulation, valve design, actuator, propellant
21
Q

Cosolvents

A
  • Less volatile than propellants
  • Uses:
    • Helps dissolve drug in the propellant system
    • Lower vapor pressure (modulate particle size)
    • Promote miscibility of propellants and immiscible solvents
  • Solvents commonly used: water & ethanol
22
Q

Calculations for Vapor Pressure (2)

A
  1. Raoult’s Law
  2. Dalton’s Law
    - Assumes that solutions are ideal (no attraction between molecules)
    - Application: behavior of high vapor pressure liquid propellant systems
23
Q

1) Raoult’s Law

A

P’ = P°X

- Partial pressure of a gas (one compartment) = vapor pressure of pure component X the mole fraction

24
Q

2) Dalton’s Law

A

PT = PA’ + PB’ + ….. + Pn’

- The total vapor pressure = sum of the partial pressures

25
Q

Advantages of MDIs

A
  • Portable
  • Perceived as easy to use and convenient
  • Remaining product is not contaminated during use
  • Aerosol can be filled aseptically
  • Stability - protects unstable drugs from light, oxygen, and water
  • Tamper proof
  • Metered dose given (Quantifiable)
26
Q

Disadvantages of MDIs

A
  • Expensive
  • Pressurized contents - can be flammable (safety)
  • Prone to incorrect use (hand eye coordination)
27
Q

Auxiliary Systems

A

Spacer Devices (add-on devices)

  • Evaporation
  • Loss of inertia
  • Lung particle sedimentation
28
Q

Dry Powder Inhalers (DPIs)

A
  • First DPI developed in 1970s
  • Further DPIs development in response to phase out of CFCs (1990’s up to now)
  • No coordination required with actuation
  • Stability advantages (dry form) - biotechnology compounds
29
Q

Mechanism of DPI

A
  • DPIs provide drugs to the lungs in a powder form
  • The powder needs to be fluidized before being delivered to the patient during inhalation
  • Physics behind fluidization of powder is complex and involves: particle size and varying attractive forces between particles
  • Forces between particles <5 microns often prevent fluidization (inter-particulate forces, carrier particles (>60 microns) i.e. lactose)
30
Q

Dose Received by a Patient Using a DPI Depends on..

A
  • Properties of drug formulation, especially powder flow, particle size and drug-carrier interaction
  • Performance of inhaler device, including aerosol generation and delivery
  • Correct inhalation technique
  • The inspiratory flow rate
31
Q

Types of DPIs (2)

A

1) Passive Inhalers
- 1st generation: breath actuated single dose
- 2nd generation: breath actuated multi-dose
2) Active Inhalers
- 3rd generation: active inhalers

32
Q

Passive DPIs

A
  • Depend on the patient’s inhalation to provide the energy needed for dispersing the powder
  • Often requires the patient to inhale at a max rate for the inhaler to work properly
  • Strength of patient’s airflow determines does that is administered – problematic for children or airflow whose airflow is not as strong – also for asthmatic patients when having an attack
33
Q

Active DPIs

A
  • Use an external energy source to generate powder dispersion, which means dosage is not as dependent on the patient’s efforts
34
Q

DPI Evolution

A
  • 1st generation: Rotacaps/Rotahaler
  • 2nd generation: Rotadisk/Diskhaler
  • Blister Strip/Multi-dose Powder Inhaler (M-DPI, Diskus)
35
Q

DPI Advantages

A
  • No use of propellant gas
  • No need for hand eye coordination
  • Easy to use and no need for spacers
  • Dry powder form provides stability to drug
  • Not a pressurized container
  • Lactose carrier particles mask the bitter taste of the drug
36
Q

DPI Disadvantages

A
  • Sometimes bulky and non-portable
  • Variable dose delivered which is dependent on inspiratory flow rates
  • Not widely available worldwide
  • Humidity protection
  • More expensive than MDIs
  • Not all drugs available as a DPI
37
Q

Nebulizer Formulation Considerations

A
  • Physical and chemical drug properties
  • Stability of drug in the dosage form (solution, suspension), storage
  • Possible degradation cause by nebulization
  • Drug taste, dose and treatment regimes
  • Manufacturing and sterility issues and costs
38
Q

Formulations Suitable for Nebulization

A
  • Solutions

- Dispersed systems: suspensions, emulsions, liposomes, colloidal systems

39
Q

Broad Nebulizer Classification (2)

A
  • Nebulizers classified accordance to the mechanism used to create the fine respirable aerosol cloud:
    1) Air-jet nebulizer- Pressurized air
    2) Ultrasonic nebulizer- Mechanical or vibrational aerosolization (ultra sonication)
40
Q

Ultrasonic Nebulizers

A
  • Use high frequency vibration to generate the respirable aerosol
  • Typically, these units are compact and generally have a high output rate
  • The ‘quality’ of the aerosol varies according to the energy that is supplied and some portable batter powered unit may generate coarser aerosols
41
Q

Nebulizer Mechanism

A

Droplet size depends on:

  • Surface tension
  • Density
  • Nebulizer make/model
42
Q

Nebulizer Advantages

A
  • Dose not dependent on patient inspiratory force
  • Aqueous solutions
    • ease of manufacture
    • no environmental concerns
    • good for biotech compounds
  • Do not have to hold their breath, patients who cannot use inhalers
  • Less expensive in the long run
43
Q

Nebulizer Disadvantages

A
  • Bulky/not portable/noisy
  • Long treatment times
  • Expensive
  • Poorly optimized
    • devices designed independently of drug
    • wastage (delivers when patients exhale)
    • particle size varies from brand to brand
  • Contamination of the atmosphere
  • There are niche products
    • pediatric, geriatric, hospital use predominates
44
Q

Future Direction: Inhaled Insulin

A

Exubera

  • Bulky
  • Additional cost
  • Dose variability
  • Clinical trials - 6 out of 4740 patients developed lung cancer (known smokers)

Afresa

  • Small inhaler
  • Less expensive
  • Ultra-fast acting, more effective
45
Q

Future Direction: Afrezza Dry Powder Insulin

A
  • Approved by FDA in June 2014 for Mannkind Inc.
  • Sanofi brought the product in August 2014
  • Sanofi stopped marketing in February 2016 (low profits due to low prescription)
  • Mannkind relaunched Afrezza in July 2016

824 - Dosage Forms (4 decks)

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