pulmonary and intranasal administration Flashcards
what factors affect deposition?
- Environmental humidity
- chemical composition
- solvent evaporation
- aerosol velocity
- respiratory tract physiology
why does environmental humidity affect deposition?
the lungs have a higher humidity so condensation of water on particle surface will occur as particles move to high humidity
water-soluble particles will also grow in size and affect where deposition occurs
how do hydrophobic and hydrophilic particles differ with deposition in the body?
hydrophobic particles will sit on the water surface
hydrophilic will solublise in the humid environment of the lungs
why does solvent evaporation affect deposition?
important for pMDI devices
- the propellant in these devices mean a large size droplet will have not enough time for propellant evaporation and this impact where it deposits
it will most likely deposit in the back of the throat
why does chemical composition affect deposition?
pMDI drug suspensions can have physical instability such as flocculation, bulk separation, irreversible aggregation
this increases suspended particles size’ and where they are released so could be deposited in the wrong part of the lung or the throat
why does aerosol velocity affect deposition?
there is a high initial velocity of aerosol leaving the inhaler
- they have an increased momentum and will evaporate quicker
can cause them to deposit ay back of the throat as they cant change direction to go back into the lung
why does respiratory tract physiology affect deposition?
anatomical and physiological differences influence deposition;
- age
- gender
- body size
- ethnicity
- lung state
what methods can improve deposition?
- Spacer devices
- reduces droplet velocity and allows propellant evaporation - breath-actuated pMDI devices
- device first at correct points of inspiratory cycle - breathing patterns
- slow, deep inhalation followed by breath-hold
- breath holding allows deposition by diffusion and sedimentation to occur
- allows greater peripheral distribution of particles to occur and and increase inhalation flow rate increases deposition
- too rapid can cause back of the throat deposition
how can you assess deposition?
using gamma scintigraphy
- measures deposition in lung, stomach etc.
- krypton gas used and radio labelled with technetium 99m
- can use MSLI, NGI, TSI, ACI to measure particle size used and clinical performance
what are dis/advantages of the pulmonary route?
\+ non-invasive and easily accessible \+ can give low doses as had rapid uptake and OoA \+ lower proteolytic activity than GI \+ avoids first pass metabolism - poor reproducibility - ability of lung macrophages to engulf particles - inefficiency of drug delivery devices - metabolic capacity of lungs
what delivery method do most devices aim for?
pulmonary drug delivery as it allows delivery to the central regions of the lung
new delivery devices are needed for systemic delivery
why should you use nasal administration?
it has quick systemic absorption so get to the brain quicker
- convenient
- useful area for absorption
- good systemic blood flow
what kind of nasal preparations can you get?
you can get preparation used for nasal mucosa e.g. antibiotics, antihistamines
can be administered as in solution form in drops or sprays
can get suspensions, gels, ointments, creams and dry powders can also be used
what are the limitations to nasal delivery?
- many drugs aren’t absorbed
- can have nasal irritation
- some drugs might undergo nasal metabolism
- the lack of aqueous solubility might be a problem
what are the functions of the nose?
it is a sensory organ so detects olfactory stimuli
- > filters against airborne particles
- > generates turbulent flow
- > chemical sensor for environmental irritants
how does nasal deposition occur?
initial removal is by the nasal hairs
then further deposition occurs by inertial impaction; for particles >1mm
- optimum particle size is 10mm
what is the primary site of deposition and absorption?
- the respiratory epithelium
has columnar cells that are ciliated and goblet and basal cells that secrete mucus
what factors can affect absorption?
- foreign materials trapped in viscous mucous
- much moved from nasal cavity to nasopharynx via mucociliary transport
- epithelium is an extra barrier to absorption
how can you improve nasal absorption?
- increase nasal residence time
- enhance nasal absorption
- modify drug structure to change physiochemical properties
what are physicochemical factors and what effect do they have on nasal absorption?
- effect of size and MW
- > amount of drug absorbed is inversely proportional to the MW
- >important for absorption of small hydrophilic drugs
- >absorption occurs through aqueous channels between cells - effect of pH and partition coefficient
- > most drugs can be ionised
- > partition coefficient depends on environmental pH
- > depends on degree of ionisation ; hydrophilic drugs use aqueous channels - effect of lipophilicity
- higher lipophilicity means faster absorption
- drug must be ionised to be absorbed effectively
how can you increase residence time?
- apply the drug to the anterior part of the nasal cavity ; depends on drug delivery system
- metered- dose pumps have greatest control of direction and drops are inaccurate and too rapid - reduce rate of clearance
- use microsphere technology
- use gel formulation to increase viscosity
how can you enhance nasal absorption?
- absorption enhancers; alters epithelial cell structure to increase rate
- > disrupts membranes, inhibits enzymes and opens tight junctions - surfactants; but can cause mucosal damage
- bile salts are more effective and less damage but can damage epithelial cells
- phosphatidylcholine can enhance absorption without causing damage; can carry the drug across membrane with them
how could you modify drug structure for better delivery and absorption?
- alter the solubility or partition coefficient; salt formation or changing substituent groups
- use cyclodextrins ; increases drug bioavailability by increasing aqueous solubility
- use pro-drug technology
- > add bio-cleavage group to drug
- has better absorption properties
- metabolised to active drugs in nasal epithelium
what route is most beneficial for systemic therapy?
nasal route may be advantageous for systemic delivery of drugs that are:
- subject to significant gut wall and first pass metabolism
- possess poor stability in GI tract fluids
- polar compounds exhibiting poor oral absorption
has a rapid systemic effect
what is dis/advantages of nasal administration of protein and peptides?
+ easily accessible route
+ fast uptake
+ lower proteolytic activity than GI tract
+ avoids first pass
- low bioavailability
peptides are hydrophobic with a high charge density and large MW
aqueous solubility lowest at isoelectric point
how can you increase absorption of proteins and peptides
co-adminster protease inhibitors
- use absorption enhancers
- use mucoadhesives; prolongs presence of peptides at absorption surface
why should you use pulmonary administration?
- rapid onset of action
- smaller doses needed
- avoids first pass metabolism
- useful is drug is rapidly metabolised or has poor oral absorption
what type of drugs can be administered through pulmonary delivery?
- bronchodilators
- corticosteroids
- anti-allergy
- mucloytics
- anti-infectives
- oxygen
- inhalation anaesthetics
what are the respiratory systems three regions?
- nasopharynx region; nose, mouth, pharynx, larynx
- tracheobronchial region; trachea, bronchi, bronchioles
- pulmonary region; respiratory bronchioles, alveoli
how must pulmonary drug devices deliver the drug? and what are the three types of devices?
- must deliver the drug as an aerosol ; dispersion of a solid or liquid in a gas
three types of devices:
- nebuliser
- pressure- metered dose inhaler (pMDI)
- dry powder inhalers (DPI)
what are nebuliser?
simple method of producing an aerosol
- can deliver large volumes of drug solutions/suspensions
- allows drug admin during normal tidal breathing ; large % of dose is lost
- can be affected by surface tension, pH, viscosity, ionic strength
how does an air jet nebuliser work?
- works using Bernoulli principle
- > compressed air carries liquid medication through a narrow at high velocity, then hits baffle making it an aerosol that patient inhales
how does an ultrasonic nebuliser work?
- a transducer generates an ultrasonic wave which vibrates a diaphragm at high frequency that has contact with liquid medication
- the high frequency converts liquid -> vapour mist
- carrier gas enters and carries droplet to mouth piece
high frequency -> smaller droplets
what are the dis/advantages of a nebuliser?
+ can aerosolise most liquid medications
+ large dose delivery
- expensive and time consuming
- majority of drug doesn’t reach lung; stays in nebuliser or goes into the environment; approx 10% hits lugs
what are dry powder inhalers?
they deliver a metered quantity of powder
- they are breath ‘actuated’
- > powder dispensed in a stream of air and patient draws it in with their own inspiratory effect
- no coordination needed for activation and inhalation
- need effort to liberate and disaggregate the powder particles
- size of particles matter for deposition
what is a single dose DPI? name some examples of these?
e. g Spinhaler, Rotahaler, Cyclohaler, Aerohaler
- drug plus lactose in gelatin capsules
- capsules are individually loaded into the DPI by patient
- priming device pierces the capsule and inhaled air flow disperse powder of capsule
what is a multi dose DPI? name some examples of these?
e. g DIskhaler
- drug + lactose filled into SEALED aluminium foil blisters with four or eight blister per disc
- disc is loaded into device by patient
e. g Accuhaler
- 60 drug filled blisters on a coiled foil strip in the device
what is a Reservoir DPI? name some examples of these?
Turbohaler
- powder drug contained in a storage reservoir in the base of the device
- twisting the base dispenses a metered dose into the dosing chamber
- can have unto 200 doses
- better lung deposition
what are the dis/advantages of a DPI?
+ propellant and excipient free
+ dont need coordination for inhalation and actuation
+ high protection against humidity
- patient must provide energy source
- dose dependant on inspiratory effect
- operation varies between product and not suitable for all drug types
what are pMDI’s?
this is when the drug is dissolved/suspended in one or more liquefied propellant gases
- have excipients e.g. surfactants or co-solvents
- it is a pressured canister with metering valve in a plastic container
- has propellant for liquid formation to go through narrow nozzle at high velocity
what are some pMDI propellants used?
usually chlorofluorocarbons (CFC)
- non toxic, non reactive and non flammable
- do have an unpleasant taste and react with ozone
now using hydrofluroralkanes (HFA)
- no ozone depletion
what are dis/advantages of pMDIs?
+ energy source for drug delivery
+ dose delivered is independent of patient inhalation
+ device operations similar
+ high humidity and contamination protection
+ portable, compact, inexpensive and multiple dosing
- patient needs coordiantion
- droplets leave at high velocity so can have oropharyngeal inhalation
- replacing CFC with HFA can lead to redness/itchiness at back of throat and impact swallowing
what is the most important physical property for pulmonary deposition? what does this depend on?
the aerodynamic diameter ; the diameter of a unit density sphere which settles with the same velocity as particle
- depends on particle shape, size and density
- you want a mono disperse system
- GSD decides degree of polydispersity ; mono disperse GSD= 1
depending on particle size, where is the site of deposition?
> 10um = in throat 5-10um = upper airways 2-5 um= in lower airways 0.5-2 um = in alveolar region < 0.5um = exhaled without deposition <0.1 um = in alveolar region
where are most beta2 receptors and M3 receptors located?
in the pulmonary region and tracheobronchial region respectively
with lower particle size, we get deposition in the pulmonary region so better response
what mechanisms are there for deposition?
- inertial impaction
- gravitational sedimentation
- brownian diffusion
can have interception or electrostatic attraction
what is inertial impaction?
the particle is carried in aerosol stream; has its own momentum
aerosol stream meets an obstacle or bend the gas flow direction changes
- inertial force of particle resists change in direction
- particle can continue original flow or impact on surface of obstacle
how does particle being large effect inertial impaction?
for large particles they will usually deposit in upper respiratory tract
- have less contribution to therapeutic effect
what is gravitational sedimentation?
sedimentation of particles occur due to gravitational force action
- rate of sedimentation is determined by Stokes’ Law ; directly proportional to particle density and diameter 2
- happens in small bronchi, bronchioles, alveolar region
- medium particles of 1-5 um
what is brownian diffusion?
particles smaller than 0.5um are to small for impaction or sedimentation
they are bombard by surrounding molecules in RT
they move to low concentration areas e.g. airways walls
- get knocked around until they eventually stick
when does interception occur?
when dimensions of particle are similar to the airway diameter
particle edge makes contact with airway surface and particle is trapped
not important for spherical particles only elongated
when does electrostatic attraction occur?
this is when charged particles can be formed during generation of an aerosol
- induces opposite charge on walls of airways
- leads to increased deposition due to electrostatic attraction between opposite charges
what are the barriers to absorption?
- rate of absorption of hydrophobic drugs depend on partition coefficient
- high Log P and hydrophobicity means higher absorption
- hydrophilic drugs are poorly absorbed through pores
- smaller MW means better absorption
- formulation; solution drug/droplet will have rapid absorption
what are some physiological barriers that prevent drug reaching target site?
- mucus layer
- mucocilary escalator
- macrophage and other cells
- enzymes
- alveolar epithelium
how does mucus layer act as a barrier to absorption?
- covers walls of RT
- first barrier
- composition and thickness vary along RT
- is mainly water with mucin, carbs, lipid and surfactant
- dissolution of particle depends on composition of mucus layer at deposition site
how does mucociliary escalator act as a barrier to absorption?
- self cleaning mechanism
- uses cilia and mucus
- coordinated movement of cilia propels mucus towards pharynx to be swallowed
- protects bodies against foreign bodies
how does macrophages act as a barrier to absorption?
- they wander throughout lung
- they can rapidly ingest particles and molecules in solution
- granulocytes migrate to airways ; phagocytose materials and release proteases
- lymphocytes respond to antigenic material ; sensitise lung to future doses
how does alveolar epithelium act as a barrier to absorption?
- tightly knit barrier
huge SA - transport across this is by:
1. intracellular tight junctions; solutes, ions, fluids
2. membrane pores; fluid and macromolecules
3. vesicles; fluid and macromolecules
how does enzymes act as a barrier to absorption?
can have Phase I oxidation enzymes; reduction and hydrolysis metabolism
or Phase II conjugation reactions
- these Phase II can add sulfur groups onto the drug making it -ve
