Pulmonary Drug Delivery Flashcards
What other forms of drug deliver utilized aerosols other tha pulmonary?
Topical, SL, dermal, rectal, and vaginal
Define aerosols.
Products that depend on the power of a compressed or liquefied gas to expel the contents from the container.
Can be fine, wet spray, foam, semisolid stream or dry particles
Define pharmaceutical aerosols.
Products containing pharmacologically active ingredients dissolved, suspended or emulsified in a propellant; or a mixture of solvent and propellant.
Intended for administration as fine solid particles or liquid mists
What are the advantages of pharmaceutical aerosols?
- Drugs given parenterally my be given by inhalation
- Rapid onset of action, avoid GI tract and first pass metabolism. Can be used to avoid DI
- accurate and efficient drug delivery
- Low doses, therefore minimal SE
- Complete container closure, so no contamination
- For topical, sprays and foams can reduce drug irritation and expand drug contact. Also more efficient
Why can not every drug compound be formulated into a aerosol?
High manufacturing cost
Selection and formulation of correct propellant
Special storage conditions due to pressure
What are the drug characteristics necessary for aerosol products?
No irritation to drug absorption site
Be reasonably soluble in respiratory fluids
Be therapeutically effective at relatively low dose
Exhibit passive drug transport mechanism through respiratory membrane
Be stable and compatible with the propellants and have a pH between 5.5 and 7.5
Define the lungs.
A series of dividing passageways originating a the trachea and terminating at the alveolar sac.
There are various divisions including bronchi, bronchioles terminal, bronchioles, respiratory bronchioles and alveolar ducts.
What separates the internal environment of the body from the external environment?
The epithelium (continuous sheet of cells lining the luminal surface)
What is the difference between the dug absorption mechanism in the central airway versus the alveolus?
The rate of absorption of a compound in the alveolus is approximately 2x faster. (Greater membrane permeability)
What are the 5 different mechanisms that can occur to a drug once in alveolus?
Drug may be diluted/diffused laterally in surfactant
Can be taken up by alveolar macrophages
Diffuse through the interstitium and be removed by lymphatic capillaries
Can be biotransformed by enzymes
Can reach blood circulation
What are the two components of the cardiovascular system?
Pulmonary circulation and the systemic circulation.
This circulation carries deoxygenated blood from the right ventricle to the lungs and returns oxygenated blood to the left ventricle.
Pulmonary circulation
This circulation carries oxygenated blood from the left ventricle to the tissue of the body ad returns deoxygenated blood to the right atrium.
Systemic circulation
Selection of what may permit drug deposition to the central or peripheral airways?
An appropriate aerosol with a uniform small particle size
What is the correlation between the particle size and where it is deposited?
Oropharynx: > 10 micrometers Central airways (tracheobrnochial): > 5 micrometers Peripheral airways (alveolus):< 3 micrometers
What physiological factors also affect the deposition of drugs in the airways?
The rate and depth of breathing
Rapid, shallow: central deposition
Slow, deep: peripheral deposition
What can patients do to facilitate drug deposition through sedimentation and diffusion?
Holding breath at the end of inspiration
How can we adjust formulation properties to improve drug deposition in the airways?
- synchronize drug delivery rate from the device with patients inspiratory flow rate.
- reducing particle size
- increasing drug density
- controlling hygroscopic growth of particles
What do the use of aerosols exploit?
The ability to deliver high concentration of a drug locally without side effects
What are the three different functional components to deliver the drug content?
Propellants
Valves or actuators
Containers
Define propellants.
Liquefied gas with a vapor pressure greater than atmospheric pressure at a temperature of 40 degrees Celsius.
It is the heart of the aerosol and supplies the power to expel the drug content.
What are the three most common propellants used for oral and nasal inhalations?
Dichlorodifluoromethane (Propellant 12)
Trichloromonofluoromethane (Propellant 11)
Dichlorotetrafluoroethane (Propellant 114)
The most common propellants used for topical are what?
Hydrocarbons such as butane, isobutane, and pentane
What propellant was the optimal for inhalations but are now believed to destroy the ozone?
Chlorofluorocarbons
What is now beginning to replace CFC propellants, a liquefied gas used normally for topical formulations?
Hydrocarbons
What component is the mostly used compressed gas as aerosol propellant, used for topical aerosol products?
Nitrogen
Various valves can dispense what kind of formulations?
Sprays, foams, and semi solids
What is the use of metered valves?
Deliver very accurately measured drug doses. The metering chamber is directly responsible for measurement
What are the two basic types of metered valves available?
One for inverted use
One for upright use
What is the most commercially available pharmaceutical inhalations deliver drug dose?
The range from 50-75 microlitre
At are the most commonly used containers in aerosols?
Glass, stainless steel and aluminum due to their excellent compatibility
What is the reason most bottles are plastic coated?
To protect from flying glass when the container is accidentally dropped. Also serves as a protecting layer to sensitive drugs to light or UV rays.
What is done to prevent drug content from reacting with the metal of aluminum or steel containers?
Internal vinyl or epoxy resin coating on the interior wall of container
Most propellants are nonpolarcompounds, making them what kind of solvent?
Poor, for most medications
How can varying solubility is be achieved?
Selecting appropriate co-solvent
Most commonly used is ethanol.
What are some other common cosolvents, other than ethanol?
Polyethylene glycol Dipropylene glycol Ethyl acetate Hexylene glycol Acetone and glycol ethers
What is the general formulation of aerosol solutions?
50-90% propellant
10-50% active ingredients
Cosolvent for topical application
Up to 99.5% propellant for nasal/oral
The _____ the amount of propellant present, the _____ will be the degree of dispersion and the finer the spray.
Greater; greater
As propellant amount decreases, the wetness will increase
What are the 5 factors that have to be taken into account when developing a solution-type aerosol?
1) Effect of solvent-propellant blends on the solubility and stability of the active ingredients
2) Particle size and the surface tension of the droplets
3) Irritation potentials of various additives such as antioxidants and preservatives
4) Esophageal irritability of the formulation
5) Toxicity pharmacological activity of all solubilizing agents
What can be done when medication is insoluble in the propellant or propellant-solvent mixture, or when cosolvent is not desirable?
Can suspend the propellant vehicle.
Suspension is emitted followed by rapid vaporization of propellant, leaving behind finely dispersed active ingredients.
What are some problems that can occur with suspension aerosols?
Caking, agglomeration, particle size growth and clogging of the valve.
The active and inactive ingredients must be kept essentially anhydrous or made anhydrous by drying process. Th optima moisture content is no more than:
200- 300 ppm
What is important to maintain formulation stability and quality?
Particle size and size distribution
Oral: 1-10 micrometer
Topical: 40-50 micrometer
Drug solubility s a crucial parameter in formulation performance and stability. Do you want maximum or minimum solubility of the active ingredient in propellant?
Minimum because it will result in particle size growth and consequent stability issues.
However should have sufficient solubility in body fluids for therapeutic effects, otherwise will be irritating to respiratory tract.
What is the criteria for dispersion agent sin suspension aerosols?
Nontoxic, Biodegradable, and minimally irritating to the airways.
What are some surfactants for oral inhalation products and topical formulations?
Inhalation: Polysorbates, sorbitan esters, lecithin derivatives, oleyl alcohol and ethanol.
Topical: isopropyl myristate and mineral oil (not surfactants)
Define emulsion aerosols.
Composed of active ingredients, aqueous or a non aqueous vehicle, surfactant and propellant (generally insoluble, either internal or external phase)
What are emulsion aerosols normally intended for?
External usage, especially on skin surface because foam an easily spread.
Additives can be incorporate into emulsion aerosol formulations to provide what?
Extra properties such as softening, statin, cooling, and smoothing
Also decreases the potential for airborne particles and inhalation risk.
What populations are edible foams optimal for?
Children and elderly who have difficulty swallowing other dosage forms.
- cough remedies, Ca supplements, antacids, vitamins
What do edible foams consist of?
Active ingredient dissolved or suspended in vegetable oil and emulsified with food-grade emulsifier such as glyceryl monostearate (non-ionic surfactants)
What propellants can be used in edible foams?
Nitrogen, nitrous oxide, carbon dioxide, or hydrocarbons
What are the five future development goals for aerosols for inhalation and topical?
- reevaluate lung as more than just a “target organ” for therapies
- develop alternative dosage forms for those drugs that are poorly or erratically absorbed
- better understand Biopharmaceutics and pharmacokinetics of drugs aerosolized into airways
- improve technical aspects of all hardware
- increase education of correct administration techniques in patients and consumers
