Pulmonary + Intranasal Flashcards
By the end of weeks 1 and 2, you should be able to:
To describe the anatomy, physiology and function of the airways
To describe and discuss the mechanisms of, and barriers to, pulmonary drug absorption
To discuss the effects of formulation and physicochemical properties on pulmonary drug delivery using aerosols
To describe and discuss barriers and opportunities for pulmonary delivery of macromolecules
To understand the anatomy and function of the nasal cavity
To describe mechanisms of, and barriers to, nasal drug absorption
To discuss the effects of formulation and physicochemical properties on nasal drug delivery
To describe and discuss barriers and opportunities for nasal delivery of macromolecules
What type of diseases is pulmonary administration used to treat?
the prophylaxis /treatment of airways disease
Name 4 examples of airways disease
- asthma
- cystic fibrosis
- COPD
- infection
What advantages does pulmonary administration have over the oral route? (onset of action, dose, metabolism - 4)
- delivers drug directly to the site of action = rapid onset (in e.g. asthma attack)
- smaller doses than oral req
- useful for poorly absorbed/rapidly metabolised drugs
- avoids first pass metabolism
What are 7 types of drugs administered by the pulmonary route?
- bronchodilators
- corticosteroids
- anti-allergy
- mucolytics
- anti-infectives
- oxygen
- inhalational anaesthetics
What are 3 examples of bronchodilators?
- salbutamol
- ipratropium
- theophylline
What are 2 examples of corticosteroids?
- beclomethasone
- fluticasone
What are 2 examples of anti-allergy drugs?
- sodium cromoglicate
- nedocromil
What is an example of a mucolytic and what does it do?
- Pulmozyme™
- breaks down overproduction of mucus in lungs to make breathing easier
What are 2 examples of anti-infectives administered through the pulmonary route?
- colistin
- pentamidine
What are 2 examples of inhalational anaesthetics?
- halothane
- N2O
What are the 2 functions of the lung?
- oxygenation of blood, elimination of CO2
- preventing entry + promoting efficient removal of airborne foreign particles
The lungs are able to oxygenate and eliminate CO2 from the blood. This is accomplished by interaction and coordination of the lungs with what? (4)
- central nervous system
- diaphragm
- chest wall musculature
- circulatory system
What are the 3 regions of the respiratory system?
- nasopharynx region
- tracheobronchial region
- pulmonary region
- nasopharynx region
- nose
- mouth
- pharynx
- larynx
What makes up the tracheobronchial region? (3) What is it also known as?
- trachea
- bronchi
- bronchioles
conducting zone: helps air in and out of lungs
What makes up the pulmonary region? (2) What is it also known as?
- respiratory bronchioles
- alveoli
respiratory zone: O2, CO2
what does right lung have that left doesnt?
middle lobe.
still has inferior and superior though
what part of lungs is it most important whilst difficult to deliver drug to?
deep part of lungs: most alveoli, very narrow paths and more difficult to deliver drug
How many alveoli within the alveolar sacs? What is the surface area in an adult male?
Alveolar sacs contain ~ 3 x 10^8 alveoli
surface area ~ 70 - 80 m^2 in adult male
Greater SA = greater drug absorption
What specialised cells line the conducting airways? What do they do?
- lined with ciliated columnar epithelial cells, goblet cells and submucosal glands
- mucus moistens inspired air, prevents drying of the walls, and traps particulate matter (foreign particles, wafted out)
What cells are alveoli lined with? (2 types)
- Type 1 pneumocytes - 95% of SA, 40% of cells present
- Type 2 pneumocytes - 3% of SA, 60% of cells present
3 types of pulmonary drug devices?
nebulisers
DPI
pMDI
what is in an aerosol? used to delivery pulmonary drugs?
dispersion of solid/liquid in gas
What is the simplest method of producing a therapeutic aerosol?
nebulisation
What are nebulisers capable of delivering?
large volumes of drug solutions and suspensions
w diff pharmacokinetics
How do nebulisers allow drug administration during normal tidal breathing? What’s the disadvantage?
- they continuously produce aerosol which the patient can breathe in
- a large proportion of the dose is lost
What types of patients are nebulisers useful for? (3)
- children
- elderly
- unconscious
What can physical properties of the liquid formulation can affect a nebuliser’s efficiency? (5)
- surface tension
- viscosity
- osmolarity
- pH
- ionic strength
2 types of nebulisers?
airjet
ultrasonic
How does an airjet nebuliser work?
- using Bernoulli principle
- compressed air/oxygen carries liquid medication through a narrow hole (baffle) at high velocity turning it into an aerosol which is subsequently inhaled by the patient
How does an ultrasonic nebuliser work? (3)
- a pizoelectric transducer generates an ultrasonic wave which vibrates a diaphragm at high frequency, in contact w liquid medication
- high frequency vibrating converts the liquid into a vapour mist
- the higher the frequency of vibration the smaller the vapour droplets
still lot of aerosol lost
What are 2 advantages of nebulisers?
- Can aerosolise most liquid medications = freedom in formulation
- Can dleiver large doses, with limited skill/ training required by the patient
What are 2 disadvantages of nebulisers?
- Expensive and time consuming
- most of drug never reaches lungs: either retained within nebuliser’s dead volume / released into environment
- Approx. 10% dose from nebuliser reaches lungs
How much drug do dry powder inhalers (DPIs) deliver? What are devices said to be?
- they deliver a metered quantity of powder
- devices are ‘breath-actuated’
What is done to drug that’s used in dry powder inahlers and why?
- it’s micronised
- bulking/flow aiding excipients might be added
- particle size must be controlled as critical for efficient deposition
What is meant by dry powder inhalers (DPI) being ‘breath-actuated’?
- powder dispensed into stream of air drawn through the device by the patients’ own inspiratory effort
- no coordination required between activation and inhalation
- BUT requires substantial effort to disaggregate and liberate the powder particles- : older patients may not have breath required
whys DPI not always ideal for older patients?
Some requires substantial effort to disaggregate and liberate the powder particles- : older patients may not have breath required
3 types of DPIs?
single dose DPI
multi dose DPI
resevoir DPI
What are 4 examples of single-dose dry powder inhalers?
- spinhaler
- rotahaler
- cyclohaler
- aerohaler
How is the drug for a single-dose DPI formulated?
- drug mixed w lactose- carrier/bulking agent (only excipient)
- each dose supplied packed in gelatine capsules - new capsule must be inserted for each dose
Capsules individually loaded into DPI by patient
What does priming a single-dose DPI do to the drug capsule?
pierces it, allowing (inhaled) air flow into the capsule and release of the drug (dispersion)
benefit of single dose DPI?
patients can easily see hm capsules/ dose left
What are 2 examples of multidose DPIs?
- Diskhaler
- Accuhaler
How do Diskhalers work? (3)
- drug + lactose filled into individually-sealed aluminium foil blisters
- around 4-8 blisers per disc
- disc loaded into device by patient
How do Accuhalers work?
- 60 drug-filled blisters on a coiled foil strip, contained within device
- Dose counter incorporated into device (so patient knows how many doses remaining)
What is an example of a reservoir DPI?
Turbohaler
How does a Turbohaler work?
- powdered drug contained in a storage reservoir in base of the device
- twisting the base dispenses a metered dose into the dosing chamber
- contains up to 200 doses w a dose counter
How does ease of use compare between Turbohalers and Accuhalers?
- turbohalers require more effort to use than Accuhaler
- however overall better lung deposition (deeper)
How do DPIs work?
- deliver med in form: dry powder + where developed to overcome the coordination issues associated with MDIs
- air forced through powder w drug, carrier (e.g. lactose) and other stabilising excipients potentially
- turbulent air created inside powder container breaks down (deaggregates) large particles -> smaller, capable of penetrating into lungs, while removing drug from carrier powder
whats the activator in DPIs?
Activator between airflow + powder that will only open with breath.
What are the advantages of dry powder inhalers? (3)
- propellant and excipient free (other than lactose)
- don’t need to coordinate inhalation with actuation
- most give high protection against humidity (multidose devices as not packaged in capsules, but individually in foil)
What are the disadvantages of dry powder inhalers? (4)
- energy source for delivery provided by patient (need enough breath)- COPD affects
- dose delivered dependent on inspiratory effort
- device operation varies between products
- not a suitable format for all drug substances
What are the consequences of not breathing deeply enough for a dry powder inhaler?
- low inhalation flow rate = poor powder deaggregation
- reduced dose delivery, some hits back of throat and is swallowed
- poor device performance
- disease state can worsen: COPD, asthma
In pressurised metered dose inhalers (pMDIs), how is the drug formulated?
- dissolved/suspended in 1 or more liquefied propellant gases
- excipients include surfactants (e.g. oleic acid) and co-solvents (e.g. thanol)
How is the drug in a pMDI packaged?
in a pressurised canister fitted with a metering valve, housed in a plastic actuator
What does the propellant do in a pMDI?
- it drives a liquid formulation through a narrow nozzle at high velocity
- throughout this process the propellant is evaporating, propelling, shearing, and ultimately reducing the size of the mist droplets produced
How does a pMDI work?
most commonly used inhaler and most complex
- actuating device depresses stem of metering valve, allowing contents to be discharged
- once opened to atmosphere, high vapour pressure of contents of the metering valve immediately begin to equilibrate with atmospheric pressure
- this causes contents to be propelled rapidly through the nozzle, which causes shear and droplet formation
How is a dose emitted from a pMDI?
- the dose is predetermined
- emitted as a spray: flash evaporation of the propellant results in a respirable mist of the drug
After actuation, what does the metering chamber of a pMDI do?
it refills with liquid from the bulk
what to remember about pMDIs?
v pressurised- thus have headspace empty
spray coupple times before use
What are 2 types of pMDI propellants?
- chlorofluorocarbons (CFC) e.g. CFC-11, CFC-12, CFC-114
- hydrofluoroalkanes (HFA) replacing CFCs e.g. HFA-134a, HFA-227
What are the advantages (2) and disadvantage of CFCs as pMDI propellants?
- non-toxic, non-flammable, non-reactive
- no unpleasant odour /taste
- BUT react with ozone, contribute to global warming (hence why being replaced with HFAs and alternative propellants - slight global warming)
why are HFAs being used more commonly than CFCs now as pMDI propellants?
no ozone depletion, but slight global warming
What are 6 advantages of pMDIs?
- energy source for drug delivery is provided by the device
- dose delivered is independent on patient inhalation
- device operation similar for all products
- high protection against humidity and contamination
- available for all inhaled medications
- portable, compact, inexpensive and can provide multiple reproducible dosing
What are 3 disadvantages of pMDIs?
- patient must be able to coordinate actuation with inhalation
- particle droplets leave inhaler at a high velocity, leading to substantial oropharnygeal impaction (may adhere to back of throat - irritation)
- replacement of CFC propellants with non-ozone depleting alternatives is not straightforward
Part 2: Mechanisms of pulmonary deposition
what form must drug be in to be delivered to resp tract?
aerosol
• 2 phase system of solid particles/ liquid droplets dispersed in gaseous phase e.g. air
what does pulmonary deposition depend on? (4)
- Physicochemical characteristics of drug
- Formulation: size of droplets, viscosity if liquid
- Delivery device
- Patient factors: disease state, physiology of lungs
Most important physical property:
regarding pulmonary deposition
Aerodynamic diameter (d.ae) - Diameter of a unit density sphere which settles with same velocity as particle in equation
whats the Aerodynamic diameter (d.ae) equation?
For roughly spherical particle (assumed),
dae = d x √ p d = physical diameter of particle p = density of particle
what does aerodynamic diameter (d.ae) depend on?
particle size, shape, density
aerodynamic diameter (d.ae).. .what type of system do you want ideally?
require monodisperse system butin practise usually polydisperse
what indicates Degree of polydispersity?
- geometric standard deviation (GSD)
- Monodisperse systems: GSD=1
- GSD around 1.2 is limit at which polydispersity starts
what does Efficiency of a clinical aerosol depend on ?
on deposition in respiratory tract
Size of deposition dependant on particle size
pulmonary deposition 6 subcategories
and where deposited?
>10 μM: in throat 5-10 μM: in upper airways 2-5 μM: in lower airways 0.5-2 μM: in alveolar region <0.5 μM: exhaled w/out deposition <0.1 μM: in alveolar region
size of particel deposition graph: fraction deposited/ aerodynamic diameter (microM) shows what?
and look at pic of graph
biggest particles stay in throat, very small + mediumones -> alveolar and lower airways.
very specific medium particles stay in upper airways
where does pulm. dpeosition decrease?
Deposition decreases in lungs: alveolar.
Anything deposited in throat: above 1, but this doesn’t mean what?
Anything deposited in throat: above 1, but doesn’t mean everything above 1 is deposited in throat
Clinical aspect of drug deposition
Where are receptors for the B2 agonist, salbutamol and the muscarinic-3 (M3) antagonist, ipratropium bromide located and significance?
NOT uniformly distributed throughout lung. Have to ensure particle size deposited in right place and calculations are correct
what % of B2 receptors are located in the pulmonary region?
More than 90% of all B2
Where are M3 receptors located? whats this mean for drug delivery?
high density of M3 recep- in tracheobronchial region, with a lower amount in the pulmonary region.
Reduce particle size, more deposited in pulmonary region. Depends on density of receptors present
what does location of B2/M3 receptors suggest in regards to salbutamol and Ipratropium bromide?
Ipratropium bromide needs to be delivered to tracheobronchial region of the respiratory tract
Delivery to the pulmonary region -> response due to the presence of receptors
Salbutamol requires delivery to the Pulmonary region
when are inhaled steroids (beclomethasone) most beneficial (in contrast to bronchodilators?
when evenly distributed throughout the lung
what emphasises importance of drug delivery to appropriate part of lungs?
Inflammatory cells, such as lymphocytes and macrophages are present throughout the airways as well as the alveolar region in asthma. Want even distribution
3 main mechanisms of deposition
and 2 more of secondary importance
- inertial impaction
- gravitational sedimentation
- Brownian diffusion
- interception
- electrostatic attraction
describe 1. inertial impaction mechanism of deposition
Enter mouth at relatively high velocity
• Particle carried in aerosol stream has its own momentum (product of mass and velocity)
• When aerosol stream meets obstacle/bend, direction of gas flow changes
• Inertial force of particle resists change in direction
• Particle continues in original direction of motion
• Particle may impact on surface of obstacle rather than follow aerosol stream
High and low density particles, given at same velocity
__ / /
—– \ \
describe 2. Gravitational sedimentation mechanism of deposition
what does sedimentation occur due to.. whats it determines by… whats it directly proportional to?
• Sedimentation of particles occurs due to action of gravitational force
• Rate of sedimentation determines by Stokes’ Law
- Directly proportion to particle density and diameter2
\ \
\ \
\ \
Inertial impaction deposition tends to occur where and why?
occur in upper respiratory tract: air velocity high, airflow turbulent
what size particles deposited in upper resp tract by inertial impaction?
especially when? and what happens to the parts?
• Large particles (dae > 5 μm) tend to be deposited by impaction in upper respiratory tract
- Esp if device used for delivery requires high inhalation flow rate (e.g DPIs)
- OR device has high forward velocity such as metered dose inhalers
• These larger particles are subsequently swallowed but have limited contribution to therapeutic effect of dose.
describe 3. Brownian diffusion mechanism of deposition
what particles most likely in?
- Particles <0.5 μm too small to be deposited by impaction/sedimentation during normal breathing. Floating about in lungs
- Particles bombarded by surrounding mols in resp tract, bounce off each other
- = movement of particles to low conc areas such as airways walls
_______
________
Brownian diffusion mechanism of deposition
more likely to happen with…?
Very light
smaller particle size, more likely to happen
in brownian diffusion: dissusion linked w particle size how?
diffusion = inversely proportional to particle size
Describe Secondary method of deposition: interception
when does it occur?
what particles not affected, which most?
Occurs when dimensions of particle - similar to airway diameter through which its passing,
Particle edge contact with airway surface and becomes trapped.
With alveolar region
Unimportant for spherical particles: smooth surface.
Significant for elongated particles e.g. fibres
Describe Secondary method of deposition: Electrostatic attraction
when does it occur?
Charged particles formed during generation of aerosol
Induces opposite charge on airway walls
Between opposite charges -> increased deposition
Significance of this process for therapeutic aerosols is unknown
what are we relying on after drug has got to lung?
absorption (and barriers to this)
what must drug follow for any pharmacological effect to occur
deposition
hydrophilic vs hydrophobic drugs in absorption?
Hydrophilic: POORLY absorbed through pores
Rate: inversely proportional to MW (smaller MW = better absorption)
Rate of absorption of hydrophobic (lipophilic) drugs depends on LogP. Partition coefficient
Higher LogP extremely hydrophobic, more rapid absorption
more lipophil/hydrophobic = better absorption ☺
what tyoe of drugs best absorbed in lungs?
more lipophil/hydrophobic = better absorption ☺
higher log P
whats absorption affected by other than hydrophobicity?
Formulation:
Solutions more rapidly absorbed than suspensions. Pressure dose inhaler
5 Physiological barriers that may prevent drug reaching target site:
Mucus layer Mucociliary escalator Macrophage and other cells Alveolar epithelium Enzymes
Physiological barriers to pulmonary absorption:
whats the mucus layer consisting of?
water, with mucin (glycoprotein), carbohydrate, lipid, surfactant
whats the first barrier encountered after deposition? describe it
Mucus layer
Thin layer covers walls of entire repiratory tract
Composition and thickness vary along length of respiratory tract
• Penetrate through and reach mucosa
physio barriers to drug absorption: whats Dissolution of particle depending on?
composition of mucus (first) layer at site of deposition
describe physiological barrier: Mucociliary escalator
Self-cleansing mechanism, through action of cilia and mucus
- Coordinated movement of cilia propels mucus (and trapped material) towards the pharynx, swallowed
- Approx. 1L mucus is cleared every 24 hours –can be reduced in disease states
how do ‘Macrophage, Granulocytes, Lymphocytes’ contribute as a physiological barrier to drug absorption?
Macrophages wander throughout the lung
– higher numbers in infection/inflammation
– can rapidly ingest particles and molecules in solution
– release peroxides, degrade proteins
Granulocytes can migrate to the airways
– phagocytose material and release proteases
Lymphocytes may respond to antigenic material
– phagocytotic, sensitise lung to future doses
Physiological barriers
whats Alveolar epithelium composed of?
alveolar type I and type II cells
– tightly knit barrier, huge surface area
Transport across alveloar epithelium may be by what? (3)
– intracellular tight junctions: movement of small solutes, fluid, ions
– membrane pores: movement of fluid and macromolecules
– vesicles: “ “
how do enzymes act as a barrier to drug absorption?
describe the 2 phases (CfP)
metbaolic barrier present in every region of the lungs
– most found in liver are also present in the lung
Phase-I oxidation, reduction and hydrolysis metabolism involve:
– oxygenases, oxidases, dehydrogenases, reductases,
esterases, hydrolases
Phase-II conjugation reactions involve:
– methyl-, acetyl-, sulpho-transferases
5 factors affecting drug deposition
Environmental humidity Solvent evaporation Chemical composition Aerosol velocity Respiratory tract physiology
whys Environmental humidity higher than ambient in lungs and affect on depostion?
(up to 99%) in lungs due to breathing in air, water
• Water condensation -> particle surface occurs as particle moves from ambient to high humidity:
very thin film on water-insoluble particles (film on hydrophobic)
surface solution on water-soluble particles
• water-soluble particles grow in size: will affect where particle is deposited
Solvent evaporation affects deposition and is an important factor for what?
pMDI devices
how does Solvent evaporation affect deposition?
- propellant associated with aerosol droplets = mean emitted size > 40 μm- deposited to back of throat, swallowed, no therapeutic effect
- may have insufficient time for propellant evaporation-> impaction due to large droplet size. Fairly high forward velocity
- important to achieve this in that time
why may Chemical composition affect deposition in pMDIs? (4)
pMDI drug suspensions may exhibit physical instability
• flocculation
• bulk separation
• irreversible aggregation
• crystal growth due to temperature cycling (Ostwald ripening)
can all increase particle size in storage- suspended particles.
Deposit in wrong part of lung/ back of the throat and swallowed. In upper resp tract. Important to deliver to correct site.
- Revise how to produce stable suspension/inhaler int his context: SoM1
Aerosol velocity affects deposition and is most important for what devices?
all because of velocity leaving inhaler
how does Aerosol velocity affect deposition
• high initial velocity of aerosol leaving inhaler. pMDI:a velocity help with evaporation of solvent
• individual particles have increased momentum
(momentum = mass x velocity)
-> large proportion to deposit at the back of mouth due to inertial impaction
- velocity too high, lot of momentum of particles, deposit at back of throat as cant change direction as go down.
what differences in Respiratory tract physiology will affect deposition?
Important to create robust preparation
anatomical and physiological differences between individuals will influence deposition:
• gender
• age
• body size
• ethnic group
• pathophysiology: asthmatic? Smoker? What stage lungs in?
3 methods to improve deposition
spacer devices
breacth activates pMDI devices
breathing patterns
how are spacer devices used to improve deposition?
benefit?
- Positioned between pMDI and patient
- Reduced initial droplet velocity
- Permits propellant evaporation
- Removed need for coordination between actuation and inhalation (pushing down button)
- Useful for children/ anyone struggling
2 examples of Breath-activated pMDI devices to improve deposition?
Autohaler, Easi-Breathe
how do Breath-activated pMDI devices work to improve deposition?
Device fires at correct point of patients inspiratory cycle
how may breathing patterns be altered to improve deposition?
whats the best pattern?
- Increased inhaled vol = greater peripheral distribution of particles
- Increased inhalation flow rate = increased deposition in larger airways
- BUT very rapid inhalation = deposition by impaction at back of throat
- Breath holding after inhalation = enhanced deposition by sedimentation and diffusion
- Slow, deep inhalation followed by breath-hold
what may redness/ swelling in throat indicate and what to do for this?
particles deposited at back of throat, need for counselling patient on how to use inhaler. May give spacer.
how is deposition assessed?
- in vivo
- in vitro
- in vivo: gamma scintigraphy
- in vitro: Particle size measurements, routine to predict clinical performance
describe Gamma scintigraphy (in vivo) as method of assessment of deposition
- Measures deposition in lung, oropharynx and stomach
- Krypton 81m gas used to show total lung area
- Formulation radiolabelled with technetium 99m and administered to patieint
- Gas, can just breathe in. not an aerosol
see what bits light up in pic, want: all of lungs bright light and not patches/ mainly in stomach as indicates where drug deposited.
DEVICES used to assess deposition? in vitro (4)
- ACI: Andersan cascade impactor
- MSLI: Multi-stage
- NGI
- TSI
Advantages of pulmonary route for systemic therapy? (6)
- Non-invasive
- Easily accessible
- Rapid uptake + onset of action. Not relying on dissolving as in bloodstream
- Lower proteolytic activity than GI tract
- Avoid first pass metab
- Can administer lower doses. No stomach. Provided into alveolar region
Disadvantages of pulmonary route for systemic therapy? (5)
- Poor reproducibility
- Smokers, pathological stated
- Ability of lung macrophages to engulf particles
- Metabolic capacity of lung
- Inefficiency of drug delivery devices! All drug to lung, more ot alveoli but still some likely in upper rep tract.
Why are some drugs e.g. insulin typically given as injection/inhaled and not using oral route?
- Lung is permeable to some peptides and proteins
- Inhaled insulin gives equivalent diabetic control to injection
- Rapid absorption of testosterone following pulmonary delivery
- Effective pulmonary delivery of recombinant human interferon-alfa-2b
- Inhaled leuprolide in phase 1 clinical trials
how does inhaled insulin (Exubera) compare to injection?
• Exubera launched few years ago but withdrawn from UK market inhaler too big, didnt allow for patient discretion
had good plasma profile
must consider user.
Good preparation but people don’t use it/not correctly = no use
- Short-acting insulin for administration 10 minutes before eating.
- Clinical trials: showed equivalence to injection
Most devices currently used for pulmonary delivery aim to deliver dose where?
central regions of lung
systemic therapy needs drug delivery to the….
and what size should particles be?
periphery.
Particle size should be less than 2 microM
New delivery devices required for systemic delivery, companies are working on systemic delivery of proteins and peptides
At least 5 companies working on systemic delivery of proteins and peptides.. what products are included? lungs
AeroDose: MDLI (liquid)
AERs: MDLI active breath control
AIR: specif designed particles breath activated inhaler
Spiros/Dura: battery operated DPI
Inhance: lipid-based emulsion system produces hollow partcs
Nasal drug delivery- 3 reasons why?
Convenient
Useful area for absorption: quicker onset of action
Good systemic blood flow
Nasal drug delivery: historical background- 3 drugs types used in this?
Snuff
Cocaine- nose to brain pathway. Absorption directly to brain, quicker onset of action
• Decongestants- local region to decongest nose
Nasal drug delivery: historical background- 3 drugs types used in this?
Snuff
Cocaine- nose to brain pathway. Absorption directly to brain, quicker onset of action
Decongestants- local region to decongest nose
3 nasal preparations
Many for topical activity on nasal mucosa
- Decongestants
- Antihistamines
- Antibiotics
how are the 3 common nasal preparations administered?
Administered as in solution form as drops, sprays (Squeezed bottles and metered dose pumps)
Suspensions, gels, ointments, creams, dry powders (snuff)
Range of preparations, in different forms
4 limitations of nasal preparations?
• Many drugs not absorbed • Lack of aqueous solubility = problems Entire dose must be given in mac 150 micro lp.n • Some drugs= nasal irritation. • Some undergo level of nasal metabolism
Nasal cavity: dimensions and features (size)?
- Large surface area
- Large volume
- Highly vascularised
- Olfactory region at top of cavity
how is the nasal cavity divided? name the strucs
Divided vertically by top of nasal septum, has 3 folds on each wall: superior, middle, inferior turbinates
5 Functions of nose
- Sensory organ: detects olfactory stimuli
- Chemical sensor for environmental irritants. Gas etc
- Filter against airbourne particulates
- Heater and humidifier of inspired air
- Generates turbulent flow
how does nose generate turbulent flow?
Sharp change in direction at nasal valve
Presence of turbinate
affect of nasal hairs on Nasal deposition ?
initially remove deposition
after nasal hairs, how does further deposition in nose occur?
optimum particle size?
via inertial impaction
Main method of deposition for particles larger than 1microM due to turbulence
Smaller parts trapped,
• Optimum particle/droplet size for nasal deposition is 10microM
Factors affecting absorption in nasal cavity
Get to nasal (resp) epithelium: Primary site of deposition + absorption
o Columnar cellS: ciliated
o Goblet and basal: secrete mucus
mucus layer
enzymes in mucus
epithelium = additional barrier
mucus layer in nasal cavity affects absorption
how thick is it, what does it consist of, whats its role?
Mucus layer 5-29microM thick
o Mostly water + glycoproteins, ions, other proteins sucha s enzymes and IG
Foreign materials trapped in viscous mucous
Mucus (and trapped material) moved from nasal cavity to nasopharynx via mucociliary transport
Rapid mucociliary clearance
o t1/2 approx. 20 min. 40 mins= complete clearance
name some enzymes in nasal mucus that are problem for drug absorption (enzymatic action_
affect of epithelium
o peptidases
o proteases
o proteinases
o Cytochrome P450 enzymes: monooxygenase content very high
Epithelium presents an additional barrier to absorption
o During, enzymes could begin to attack drug
Physicochemical factors affecting nasal absorption.
drug molecular size and weight
pH and the partition coefficient (LogP)
lipophilicity
how does of drug molecular size and weight affect nasal absorption?
- amount of drug absorbed is inversely proportional to the MW
- absorption thought via non-specific diffusion through aq channels between cells
- important method of absorption for small hydrophilic drugs
whats the important method of absorption for small hydrophobic drugs in nasal administration?
non specific diffusion across aq channels between cells
how does LogP affect nasal absorption?
what drugs most likely to use ion channels?
- most drugs can be ionised
- partition coefficient depends upon the environmental pH
- nasal absorption is dependant upon degree of ionisation of drug
- lipophilic, unionised form of a drug is absorbed by passive diffusion hydrophilic more likely to use aqueous channels
how does Lipophilicity affect nasal absorption?
• absorption increases with increasing lipophilicity
• however, this effect is not pronounced
• again, the drug should be in the unionised form for effective absorption
(logP card)
3 ways to improve Improving nasal absorption
Increase nasal residence time
Enhance nasal absorption
Modify drug structure to change physicochemical properties (SoM1 SOLUTIONS)
Lipophilicity enhances absorption
Improving nasal absorption affect of/ how to Increasing nasal residence time
2 ways
Apply drug to the anterior part of the nasal cavity
–dependant upon drug delivery system: drops associated with inaccuracies and too-rapid clearance/ squeezed bottles give better direction of dose, but subject to patient variation/ metered-dose pumps give greatest control
Reduce rate of clearance:
•use gel formulation to increase viscosity (e.g.methylcellulose) very low viscosity gel… but may get decreased diffusion of drug. Balance
•use microsphere technology. e.g. improved absorption of insulin from chitosan microspheres. Delivered as suspensions
Improving nasal absorption affect of/ how to enhance nasal absorption
absorption enhancers role and 3 main examples
• Absorption enhancers: alter epithelial cell structure to increase absorption rate
open tight junctions. EDTA, sodium deoxycholate
disrupt membranes. SDS, sodium deoxycholate
inhibit enzymes. sodium deoxycholate, amastatin
- Surfactants are effective absorption enhancers, but cause mucosal damage
- Bile salts are almost as effective, and less damaging than surfactants. may still damage epithelial cells
- Phosphatidylcholines are similar to cell membrane components. enhance absorption without causing damage
how to Modify drug structure to change physicochemical properties to improve nasal absorption? (3)
Alter drug solubility/ LogP
- salt formation, change substituent groups
Use cyclodextrins. surfactants
- drug ‘hides’ in centre of cyclodextrin molecule
- increases drug bioavailability by increasing aqueous solubility
more soluble, more drug into cavitry but through mucus layer? For enhancing solubility.
Use prodrug technology
- add bio-cleavable group to drug
- e.g. esterification of -OH or COO- groups
- prodrug designed to have better absorption properties
- metabolised to active drug by enzymes in nasal epithelium
Nasal route may be advantageous for systemic delivery of drugs that are (3)
–subject to significant gut wall and first pass metabolism
–possess poor stability in GI tract fluids
–polar compounds exhibiting poor oral absorption
use as alternative route which results in a rapid systemic effect
what administration initially has highest plasma conc?
IV as direct.
time to get to tissues. through epithelium to bloodstream (nasal spray NS and IM)
Proteins and peptides in nasal administration
research being done.
4 benefits/disadvantage?
–easily accessible route
–fast uptake
–lower proteolytic activity than GI tract. problem
–avoids first pass
• BUT low bioavailability as hydrophobic peptides.
Peptides are hydrophobic with a high charge density and large MW
–>10 a.a. long = bioavailability <1%
Aq. solubility lowest at isoelectric point
–e.g. insulin
–isoelectric point pH 5.4
–greatest absorption at pH 3.1
Undergo hydrolysis by peptidases in nasal epithelial membrane
• Approaches to increase absorption: Proteins and peptides in nasal admin
o co-administer protease inhibitors e.g. bacitracin, for insulin
o use absorption enhancers e.g. bile salts
o use mucoadhesives to prolong presence of peptide at absorption surface
3 groups of drugs delivered nasally for local effects and examples
Steroids: beclomethasone, budesonide, fluticasone, mometasone.
antiasthma (bronchodilators): salbutamol, ipratropium, montelukast
decongestants: Oxymetazoline, pseudoephedrine (Sudafed)
Local vs systemic effect
Local effects from chemical exposure occur at the site of contact, i.e., eye irritation, skin burns or blistering, respiratory distress, or pulmonary edema.
Systemic effects occur at a location distant from the point of contact, i.e., liver, CNS, heart, or kidneys.
Why should nasal drops be formulated at pH6.8?
pH of the formulation should be near to human nasal mucosa (5.0-6.5) to prevent sneezing
5 intranasal peptide products available and their uses
- Calcitonin: Osteoporosis (potent vasodilator)
- Desmopressin: Diabetes insipidus, Haemophilia A
- Oxytocin: Start/ strengthen uterine
contractions during labour - Nafarelin: part of a fertility
programme, endometriosis - Cyanocobalamin: Deficiency of vitB12
