Nasal Drug Delivery Flashcards
Why is nasal administration useful?
- nose to brain pathway
- convenient
- useful area for absorption
- good systemic blood flow - good to get drugs into systemic circulation
What are different nasal preparations?
- topical on nasal mucosa
- decongestants, antihistamines, antibiotics
- solution form as drops and sprays (squeezed bottles and metered-dose pumps)
- suspensions, gels, ointments, creams and dry powders
What are the limitations to nasal delivery?
- many drugs not absorbed
- lack of aqeuous solubility = problem
- limited fluid available - entire dose must be given in max 150mL p.n
- nasal irritation
- nasal metabolism possible
Where is the nasal cavity and what are its features?
- past the nostril and nasal valve
- before nasopharynx region
- large SA
- large volume - 20mL
- highly vascularised
- olfactory region on top of cavity
- divided vertically by nasal septum, has three folds on each wall
- superior, middle and inferior turbinates
What are functions of the nose?
- sensory organ - olfactory stimuli
- chemical sensor for environmental irritants
- filter against airborne particles - drug has to overcome this
- heater and humidifier of inspired air
- generates turbulent flow
- sharp change in direction at nasal valve - can cause impaction
- presence of turbinates
Describe nasal deposition.
- anything that impacts cavity is deposited
- initial removal via nasal hair
- further deposition via inertial impaction (> 1mm, due to turbulence)
- optimum size 10mcm - big enough and enough momentum to get past hairs
What happens to particles smaller or larger than 10mcm?
smaller - deposited further in airways
larger - form droplets and run out nose and may be stopped via nasal hairs
What factors affect nasal absorption?
- primary site of deposition (and absorption) is respiratory epithelium
- columnar cells - ciliated
- goblet and basal cells - secrete mucus
- mucus layer normally 5-20mcm thick, foreign materials trapped in viscous mucus
- moved from cavity to nasopharynx via mucociliary transport and swallowed
- rapid mucociliary clearance half life approx 20 mins
- mucus has enzymatic action (peptidases, proteases, proteinases, CYP450 enzymes)
- epithelium is an addition barrier
What physiochemical factors of a drug would affect absorption?
- effect of MW and weight
- absorption via non-specific diffusion through aqueous channels between cells
- important method of absorption for small hydrophilic drugs
- effect of pH and logP
- lipophilic, unionised form of drug is absorbed by passive diffusion
- increasing lipophilicity = increasing absorption
How can you improve nasal absorption?
- increase nasal residence time
- enhance nasal absorption
- modify drug structure to change physiochemical properties
How can you increase residence time of nasal drugs?
- apply drug to anterior part of nasal cavity
- drops associated with inaccuracise and rapid clearance
- squeezed bottles give better direction of dose, but subject to patient variation
- metered dose pumps have greatest control
- reduce rate of clearance
- use gel fomrulation to increase viscosity eg methylcellulose
- but may decrease diffusion
- microsphere technology
- use gel fomrulation to increase viscosity eg methylcellulose
How can you enhance nasal absorption?
-
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 - but cause mucosal damage
- bile salts are less damaging
- phosphatidylcholines are similar to cell membrane components - enhance absorption and no damage
How can you modify drug structure to enhance nasal absorption?
- alter drug solubility of partition coefficient
- salt formation, change substituent groups
- use cyclodextrins
- drug hides in centre of this, increasing bioavailability by increased aqueous solubility
- use pro drug tech
- add bio-cleavable group
- better absorption properties
- metabolised to active drug by enzymes
Why may the nasal route be advantageous for systemic therapy?
good for drugs that are
- subject to signifcant gut wall and FPM
- possess poor stability in GI tract fluids
- polar compounds exhibit poor oral absorption
rapid systemic effect
What is the problem with nasal administration of proteins and peptides?
low bioavailability
peptides are hydrophobic with a high charge density and large MW; > 10 a.a long = bioavailability <1%
aqueous solubility lowest at isoelectric point
undergo hydrolysis by peptidases in nasal epithelial membrane
