Aerosols for Lung Delivery Flashcards
Aerosol
A dispersion of fine particles or liquid droplets suspended in a gas or vapor
Aerosol Limitations
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
Local Delivery to Site of Action
- Asthma, COPD, etc.
- Avoids systemic effects (corticosteroids)
- Rapid onset (B-agonists in acute asthma)
- No interactions w/food
- Sterility
- Acceptability (compare injections)
Delivery of Systemic Acting Drugs
- 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
Particle Size Deposition in the Respiratory Tract
- 10-30 um (trachea, lungs, bronchus) – inertial impaction
- 3-10 um (trachea, bronchial, bronchiolar region) – sedimentation
- 1-3 um (alveolar region) – diffusion
Methods of Determining Particle Size
- Microscopy
- Sieving
- Sedimentation
- Electrical Resistance
- Laser diffraction
- Aerodynamic diameter
Compounds Administered to Lungs
- Asthma (B-2 agonists, Glucocorticoids, Mast cell stabilizer)
- Cystic Fibrosis
- Emphysema (COPD)
pMDI Components
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
Valves (2 Types)
- Continuous Valves (topical aerosols)
- Continuous production of aerosol when the actuator is pressed down - 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
Containers/Canisters
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
Functions of Activators
- Allow release of formulation from valve
- Generate aerosol through the orifice
- Direct aerosol
Propellant Types (2)
1) Chlorofluorocarbons
2) Hydrofluoroalkanes
1) Chlorofluorocarbons (CFCs) – (advantages & disadvantages)
Advantages
- Low toxicity
- High stability
- Good solvents
Disadvantages
- Destroys Ozone
- Greenhouse gas
- Cost
2) Hydrofluoroalkanes (HFAs) – (advantages & disadvantages)
Advantages
- Low toxicity
- High stability
- Non-ozone depleting
Disadvantages
- Poor solvents
- Greenhouse gas
- Cost
Transition from CFC to HFA
HFAs vs CFCs
- GWP 6x less w/HFAs
- HFA based inhalers are 3x expensive
- I.e. Proventil HFA (Albuterol) and QVAR (Beclomethasone)
Formulation Factors (4)
- Drug Solubility
- Either soluble or insoluble (don’t want in between)
- Solution or suspension
- Oswald ripening (crystal growth) - Vapor Pressure
- Particle size
- Droplet evaporation
- Velocity - Surface Tension (droplet size formation)
- Density (stability of suspension)
Surfactants & What They’re Used For
- 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
Solution Systems
- Drug is DISSOLVED in propellant system
- Smaller particle size of aerosol
- Simplified manufacturing, drug must be soluble
Suspension Systems
- Drug is suspended or dispersed in the propellant system
- For drugs that are insoluble
- Higher doses can be delivered
- Stability and manufacturing are challenges
Particle Size
- Select particle size of suspension based on intended use (<5 microns for inhalation aerosols)
- Particle size depends on:
formulation, valve design, actuator, propellant
Cosolvents
- 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
Calculations for Vapor Pressure (2)
- Raoult’s Law
- Dalton’s Law
- Assumes that solutions are ideal (no attraction between molecules)
- Application: behavior of high vapor pressure liquid propellant systems
1) Raoult’s Law
P’ = P°X
- Partial pressure of a gas (one compartment) = vapor pressure of pure component X the mole fraction
2) Dalton’s Law
PT = PA’ + PB’ + ….. + Pn’
- The total vapor pressure = sum of the partial pressures
Advantages of MDIs
- 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)
Disadvantages of MDIs
- Expensive
- Pressurized contents - can be flammable (safety)
- Prone to incorrect use (hand eye coordination)
Auxiliary Systems
Spacer Devices (add-on devices)
- Evaporation
- Loss of inertia
- Lung particle sedimentation
Dry Powder Inhalers (DPIs)
- 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
Mechanism of DPI
- 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)
Dose Received by a Patient Using a DPI Depends on..
- 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
Types of DPIs (2)
1) Passive Inhalers
- 1st generation: breath actuated single dose
- 2nd generation: breath actuated multi-dose
2) Active Inhalers
- 3rd generation: active inhalers
Passive DPIs
- 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
Active DPIs
- Use an external energy source to generate powder dispersion, which means dosage is not as dependent on the patient’s efforts
DPI Evolution
- 1st generation: Rotacaps/Rotahaler
- 2nd generation: Rotadisk/Diskhaler
- Blister Strip/Multi-dose Powder Inhaler (M-DPI, Diskus)
DPI Advantages
- 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
DPI Disadvantages
- 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
Nebulizer Formulation Considerations
- 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
Formulations Suitable for Nebulization
- Solutions
- Dispersed systems: suspensions, emulsions, liposomes, colloidal systems
Broad Nebulizer Classification (2)
- 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)
Ultrasonic Nebulizers
- 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
Nebulizer Mechanism
Droplet size depends on:
- Surface tension
- Density
- Nebulizer make/model
Nebulizer Advantages
- 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
Nebulizer Disadvantages
- 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
Future Direction: Inhaled Insulin
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
Future Direction: Afrezza Dry Powder Insulin
- 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
