Pulmonary drug delivery Flashcards
In addition to pulmonary delivery, aerosols have been used as what types of topical dosage forms?
sublingual, dermal, rectal, vaginal
Define aerosols
Products that depend on the power of a compressed or liquefied gas to expel the contents from the container
What product forms can be delivered by aerosols?
Preparations like suspensions, emulsions, creams, powders
Can also be dispensed as a fine or wet spray, a foam, a semisolid, or dry particles
Define Pharmaceutical aerosols
Aerosol products containing pharmacologically active ingredients dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant, and intended for administration orally as fine solid particles or liquid mists through the pulmonary airways, or for admin. into one of the body cavities (nose, rectum, vagina) or for topical admin to the skin.
MDIs
Metered dose inhaler; the general aerosol for oral inhalation
t/f: aerosols are mainly for pulmonary drug delivery
False; mostly topical. Not many for inhalation
Active ingredients in aerosols take 3 main forms
Spray, dry powder, foa
List 2 types of propellants
liquefied gas, compressed gas
List advantages to pharmaceutical aerosols (inhaled) compared to other dose forms
- Good alternative to parenterals when aerosol given by inhalation
- noninvasive and hence accepted by patients
- fast onset of action
- Direct systemic absorption (avoids 1st pass)
- low dose
- minimal side effects
- accurate doses (due to use of metered valves)
- good stability
- minimal potential for contamination
- tamper-proof
Why is pulmonary a good alternative route when a drug exibits erratic PK with oral or parenteral admin?
- avoids drug degradation in the GI tract
- avoids first-pass metabolism
- direct systemic absorption
- fast onset of action
The minimal side effects of pulmonary drugs are largely due to the low dose administered: T/F
often is true.
Why are we not worried about contamination of aerosols?
No danger of envr contamination due to complete closure of the containers (tamper-proof). No moisture, bacteria, air and foreign particles can enter the container as long as adequate pressure is maintained within the container.
What’s a main advantage of topical aerosols?
Topical aerosols, sprays, foams can reduce drug irritation an expand drug contact to the application sites.
Why are aerosols considered more efficient?
No waste or need for using other applicators
What are some disadvantages to aerosols?
- local actions
- admin techniques
- patient compliance
- limited applications
- special drug properties
- unique production leading to high unit cost
- explosive and flammable
- environmental hazards
Is pulmonary drug delivery considered to be a mainstream route of admin? Why or why not?
No. Special storage conditions have to be met bcause aerosols are under pressure. Therefore, not every drug compound can be formulation into an aerosol preparation.
List 5 basic drug characteristic required for aerosol development
1) No or low irritation to drug absorption site
2) Reasonable solubility in respiratory fluids
3) Be therapeutically effective at a low dose
4) Physical/chemical compatibility (btw drug and propellant) and exhibit passive drug transport through resp. membranes
5) pH range: 5.5-7.5
List the various divisions of the lungs (airways)
Bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, and alveolar ducts in between
The deeper the airway passages go, the larger the diameters and the smaller the surface areas are: T/F
False! The deeper the passageways go, the smaller the diameters (alveolar diameters are small) and the larger the surface areas are (alveolar diameters are smaller, but there’s so many of them that the area is large)
Describe the epithelium of the airways
A continuous sheet of cells lining the lumenal surface of the airways, which separates the internal envr of the body from the external envr.
T/F: under normal physiological conditions, it is harder for larger molecules to pass through the airways epithelium
True! If the epithelium is damaged, however, then enhanced penetration of substances will exist in the airways
Describe the rate of absorption in the airway passagges
Drug absorption mechanisms in central airways and alveolus are different. The rate of absorption from the alveolus is approx 2X faster than in the central airways; suggesting greater membrane permeability in alveoli than in the tracheobronchial region
What are common medical conditions that may made use of inhaled aerosols?
- asthma
- allergies
- inflammation
- COPD
What are common drug types that are administered to the lungs?
- Corticosteroids
- bronchodilators (ex: LABAs)
- Non-steroid anti-inflammatory compounds
=> POTENTIAL formulations of proteins and peptides
Divide the CV system into two components and describe
Components: pulmonary circulation and systemic circulation
- Pulm: carries deoxygenated blood from the right ventricle to the lungs and returns O2 blood from the lungs to the left atrium.
- Systemic: carrie O2 blood from the left ventricle to body tissues and returns deO2 from the body to the right atrium.
What are 5 things that may occur to a drug once it reaches the alveoli?
A drug may:
1) be diluted/diffused laterally in surfactant
2) be taken up by alveolar macrophages
3) diffuse throuogh the interstitium and be removed by lymphatic capillaries
4) be biotransformed by enzymes
5) reach systemic circulation
What are 5 things that may occur to a drug once it reaches the central airways?
A drug may:
1) interact with the mucus layer
2) be removed by the mucociliary escalator
3) have limited access through the epithelium, interact with epithelium components
4) be removed by diffusion into submucosal blood vessels
5) reach smooth muscle cells
What is the healthcare cost associated with lung diseases/disorders?
12.2 billion (1993)
What is one of the most important factors that can influence drug absorption and bioavailability in the lungs?
Drug deposition in the airways
Associate particle sizes to drug deposition sites
- Oropharynx: >10um
- Central airways (tracheobronchial): >5um
- peripheral airways (alveolus): <3um
In practice, what % of an inhaled dose ends up in the GI tract?
85-95%
What is one way to ensure the drug goes to the lungs rather than Gi once inhaled?
Selection of an appropriate aerosol with a uniform small particle size may permit drug deposition to the central or peripheral airways, benefiting drug target for local or systemic actions.
How does rate and depth of breathing affect drug deposition in the airways?
- rapid, shallow breathing promotes central deposition of a drug
- Slow, deep inspiration leads to peripheral (alveolar) airway deposition.
- Furthermore, the rate and volume of ventilation determines the residence time of the drug in the lungs
holding your breath at the end of inspiration of an aerosol facilitates drug disposition through sedimentation and diffusion: T/F
True!
What happens if a drug gets caught in the mucus layer of the central airways?
It will be expelled from the body
Compare bioavailability of a drug given by inhalation and by IV
IV: 100%
Inhaled: ~68%
- some drug is lost in inhalation due to mucus and macrophages, so bioavailability is less
How can we adjust aerosols or inhalation devices to improve drug deposition in the airways?
- Can synchronize drug delivery rate from the device with the person’s breathing (ie drug releases when they inspire)
- Use of a spacer device can slow down aerosol cloud, evaporate volatile components, and improve pulmonary delivery
How can we adjust drug particles to increase drug deposition in the lungs?
- reduce particle size (the smaller the better)
- reduce particle size distribution
- increase drug density
- control hygroscopic growth of particles
aerosol preparations of drugs are most commonly used for what?
For the Tx of diseases involving airway obstruction
In general, current therapeutic uses of aerosols exploit what?
Exploit the ability of an aerosol to deliver a high concentration of a drug locally to the airways without eliciting the side effects.
Pharmaceutical aerosols rely on what 3 different functional components to deliver the drug content
- Propellants
- Valves or actuators
- containers
Define propellant
A liquefied gas with a vapor pressure greater than atmospheric pressure at a temperature of 40 degrees Celcius
Propellant is the heart of an aerosol: T/F
T
most common propellants for oral/nasal inhalation
dichlorodifluoromethane (Propellant 12), trichloromonofluoromethane (propellant 11), dichlorotetrafluoroethane (Propellant 114)
=> CFCs are propellants of choice, essentially
Name the types of compounds that are typically propellants
- CFCs
- HFCs
- hydrocarbons
Most common propellants for topical aerosols
hydrocarbons like butane, isobutene, pentane
disadvantage to CFCs
Believed to destroy the ozone layer in the atmosphere, resulting in an increase in the incidence of skin cancer
Describe hydrocarbons
Are also liquefied gases, normally used for topical aerosol preparations.
- Are environmentally acceptable
- relatively inexpensive
- disadvantage: are flammable and explosive
Compare hydrochlorofluorocarbons and hydrofluorocarbons (HFCs) to CFCs
HCFCs and HFCs belong to the broader CFC category, but can break down in the atmosphere at a faster rate than the CFCs, thus resulting in a lower ozone-destroying effect.
Liquefied gas and compressed gas are the two types of propellants: List the example of the only compressed gas propellant currently in use and describe it briefly
Nitrogen is the mostly used compressed gas as an aerosol propellant. It is inexpensive, nontoxic and nonreactive. Normally used for topical aerosol products
Advantages to CFC propellants
- low toxicity
- nonflammable
- inertness
- good boiling/vapour points
- heavy density
T/F: development of novel propellants is a research area of high interest
F: unlikely we will develop new propellants. Will focus instead on developing new devices and promote admin skills
Purpose of metered valves
Designed to deliver very accurately measured drug doses
Describe the two basic types of metered valves available
- one for inverted use
- one for upright use
What chamber within the valve is directly responsible for the measurement of the drug dose in an MDI?
the metering chamber
Most inhalation devices deliver drug doses in what range?
50-75 uL
Describe the upright position vs inverted
- Upright: propellant sits on top of the drug product (whether compressed gas or liquefied propellant)
- Inverted: Drug product will have contact with valve and is more mixed with the propellant and surfactants/co-solvents
Most common containers for aerosols
- glass bottles
- stainless steal cans
- aluminum cans
- tinplated steel cans (need interior coating to prevent leeching)
What is the reason to have a plastic coating over a glass container?
If the container is dropped, it prevents glass from flying everywhere.
Also serves as protecting layer for drugs sensitive to UV light
What can we do to prevent the drug from reacting with an aluminum or steel container?
An internal vinyl or epoxy resin coating is applied to the interior wall of the container
Which container is more expensive: glass, Al, steel?
Al and steel
Describe solution aerosols
Consist of therapeutically active ingredients in pure propellant, or a mixture of propellant and solvents
T/F: most propellants are polar compounds
False, think CFC, HFC. They’re nonpolar
Why might we need to add a co-solvent to a pharm. aerosol preparation?
For solution aerosols, recall that propellants are nonpolar compounds, thus can be poor solvents for some commonly used polar drugs. Selecting a good co-solvent can help that
Most commonly used co-solvent
Ethanol
List other examples of co-solvents
- ethanol*
- polyethylene glycol
- dipropylene glycol
- ethyl acetate
- acetone
- glycol ethers
=> think polar, water soluble
Describe the ‘breakdown’ of solution aerosols for both inhaled and topiical application
- 50-90% propellant and 10-50% drug for topical application
- up to 99.5% propellant for oral/nasal application (remember low dose)
Why do we want such a high % of propellant in solution aerosols for inhalation?
The greater the amnt of propellant present, the greater will be the degree of dispersion and the finer the spray.
Average particle size for topical and inhaled aerosols
inhalation: 5-10um or less (<3)
topical: 50-100um (10X bigger)
Describe some quality control factors/parameters to take into account in drug manufacturing
- drug content
- delivery rate and amnt
- dose uniformity
- particle size
- total discharge numbers (ie if it is made to dispense 100 doses, it has to do so)
- pressure testing
- water content
Factors to consider for aerosol formulations
- therapeutic purposes
- drug properties
- stability
- compatibility
- production cost
- solutions or suspension or emulsions
- capsules/devices
- solutions/devices
When developing solution-type aerosols, what factors have to be taken into account? (5)
1) Effect of solvent-propellant blends on the solubility and stability of the active drug
2) particle size and surface tension of droplets
3) irritation potentials of various additives such as antioxidants, preservatives
4) Esophageal irritability of the formulation
5) toxicity and pharmacological activity of all solubilizing agents
When are suspension aerosols useful?
For meds that are insoluble in the propellant or propellant-cosolvent mixture, or when a co-solvent is not desirable
Suspension aerosols are easier to formulate than solutions: T/F
False, suspensions are harder to formulate
Common problems with suspension aerosols
- caking
- agglomeration
- particle size growth
- clogging of valve
Moisture content of suspension aerosol must be kept below what
200-300 ppm
Ideal particle size range for suspension aerosols (inhalation vs topical)
- inhalation: 1-10um
- topical: 40-50um
How does the desirable drug solubility differ for suspension aerosols
Normally good solubility is desirable, but for suspension aerosols, solubility of active drug in propellants should be as minimal as possible. If it is soluble, it will lead to particle size growth through aggregation, clotting, etc.
What is the main cause of irritation in the respiratory tract?
highly insoluble drug particles
List surfactants for oral inhalation
- polysorbates
- sorbitan esters
- lecithin drivatives
- oleyl alcohol
- ethanol
List surfactants for topical aerosols
- isopropyl myristate
- mineral oil
While not actually surfactants, are frequently incorporated for their lubricating properties
Describe an emulsion aerosol
Mixing of two immiscible liquids, so no particle matter should be present like a suspension. Think water and oil
emulsion aerosols are composed of what
- active ingredients
- aqueous or nonaqueous vehicle
- surfactant
- propellant
Emulsion aerosols are good for delivering drugs for COPD: T/F
False. Are normally used for external usage, especially on skin surface
Give an example of an emulsion aerosol
- whipped cream! Think ‘foam’
Advantage to emulsion aerosols
This formulation can prevent drug materials from becoming airborne from the aerosol, decreasing the potential of being inhaled by the user
What is the point of particle delivery with a propellant?
We want the propellant to evaporate quick, and we will be delivered nothing but the drug product
Describe particle delivery without a propellant
- Usually will consist of the drug electrostatically bound to a carrier
- the carrier-drug aggregate will flow together and hit a membrane in the device when you inhale, causing them to break apart and allow for particle dispersion.
Lactose is a common carrier used for particle delivery without a propellant: T/F
True
Example of particle delivery without a propellant
Spinhaler and rotahaler: put the capsule inside and it disperses it. Contains a mesh membrane to release the drug from carrier
How to use metered dose inhalers
- shake inhaler
- breathe out
- press canister, inhale deeply and slowly
- hold breath for 10s, exhale
- wait 30s before next dose
How to use: other inhalers (like propellant-free ones)
- Load drug capsule
- release drug contents
- breathe out
- breathe in deeply
- hold breath for 10s, exhale
- get next dose ready
Future direction aerosols
1) use for local and systemic drug actions
2) Good alternative dose form for drugs poorly or erratically absorbed orally or parenterally
3) better undeerstant bioceutics and PK of drugs aerosolized into the airways
4) Invent better devices and improve valves, actuators, containers
5) increase patient and consumer education of product to increase therapeutic outcomes
