routes of administration (aural and nasal) Flashcards
advantages of the nasal route
- Easy to administer.
- Non-invasive, painless.
- Avoids first-pass effect
- Low enzymatic activity
- Direct route to brain is possible
- Potential to elicit a rapid onset of action.
- Newer formulations potentially allow for peptide delivery
nasal anatomy
nasal cavity is divided by a septum
covered with mucous membrane containing goblet cells secreting mucus
absorption occurs across turbinates and septum
nose brain pathway
- The olfactory mucosa is in direct contact with the brain and cerebral spinal fluid.
- Drug could potentially absorbed across the olfactory mucosa and enter the CNS.
- Potentially offer a rapid, direct route for drug delivery to the brain, bypassing the blood brain barrier.
- Beneficial for treatment of e.g. Parkinson’s disease, Alzheimer’s disease or pain
nasal physiology
- The nose functions both as a passageway for the movement of air into the respiratory tract, and also as an ‘air-conditioner’ to humidify and warm the air.
- Large particles trapped in the nasal filter undergo rapid clearance.
- Particles impact onto mucus layer on top of ciliated epithelial cells would get moved towards the pharynx.
- The site of particle deposition and the rate of clearance are of primary importance for local and systemic delivery
drug delivery- locally
treating conditions affecting the nose - deliver directly at the site of action
permit rapid relief at a much lower dose vs oral
reducing systemic side side effects
drug delivery- systematically
- Intranasal delivery can be useful in emergencies where rapid onset of action is required, e.g:
– Sumatriptan for migraine
– Fentanyl for pain relief - Nasal delivery of peptides has been successful although with low bioavailability, e.g.
– Desmopressin acetate: a pituitary hormone for diabetes insipidus.
how does solubility affect systematic absorption and how can it be overcome
drug must be in solution to be absorbed
drugs with low aqueous solubility and/or those require a high dose problems
- Solubility can potentially overcome by:
– formulating as suspension or powder in the micro-size range, but requiring drug to first dissolve in nasal cavity fluid before absorption.
– Selection of a different salt form of an ionizable drug
– The use of appropriate excipients, e.g. co solvents.
– Modification of its molecular form (including the use of a prodrug)
how does lipophilicity/ hydrophilicity affect systemic absorption
- Lipophilic drugs are rapidly absorbed from the nasal cavity by the transcellular route with bioavailability similar to that of
IV. – E.g. fentanyl, progesterone, propranolol. - Hydrophilic drugs are absorbed via the paracellular route (between cells) and this route provided a much smaller area for absorption.
how does molecular size affect systemic absorption
- The rate and extent of absorption is inversely proportional to the molecular weight of drug.
- Drugs with molecular mass <1 kDa have relatively efficient absorption.
- Particle size of 10-50 microns adheres best to the nasal mucosa.
– Smaller particles pass on to the lungs.
– Larger particles impacted on the anterior section and run-out of the nose
how does the degree of ionization affect systemic absorption
- Nasal mucosa surface has pH of 7.4, whilst mucus has a pH pf 5.5-6.5.
- Local pH becomes alkaline in certain nasal conditions e.g. acute rhinitis and acute sinusitis.
- Formulation pH closes to the nasal mucosa minimises local irritation, but pH 3-10 can be tolerated.
- Unionised drug molecules with a higher LogP is better absorbed than ionized form
how does enzymatic activity affect systemic absorption and solution
- A broad range of enzymes are present in the nasal cavity including monooxygenase, cytochrome P450, proteolytic enzymes.
- Drugs may be metabolised in the lumen or as they pass across the epithelium.
– Metabolic activity is still less than that of the GIT. - Possible solution:
– To include enzyme inhibitors in the formulation
– Use of prodrugs to reduce affinity of drug for the enzyme.
– Encapsulate the drug to limit enzyme access to it
how does nasal epithelium permeability affect systemic absorption
The mucus layer is a diffusion barrier.
* Permeability of small, uncharged molecules are less affected compared to larger, cationic molecules or small relatively hydrophobic molecules.
* Penetration enhancers can be added to alter the epithelium structure temporarily to increase permeability.
– However, no agent has proven to be tolerated or non- toxic to the nasal mucosa
nasal devices- dropper/squeezed plastic bottle
advantage
cheap and simple system for nasal delivery
disadvantages
require considerable skill, dexterity and flexibility to apply the liquid uniformity across mucosa
if the liquid is delivered too quickly causes the formulation to drip from the nostril to throat, causing a cough
volume administered is subject yo patient technique. only suitable for drug with large therapeutic window
nasal devices- nasal spray
both solutions and suspensions can be formulated in metered-dose pump or pre- filled syringe
spray nozzle produces fine droplets
deliver exact dose and spread across nasal mucosa
available in multi-dose in reservoir or unit dose
easier and faster to administer than drops, but require priming
nasal devices- nasal tube
for creams, gels, ointments for local effect
messy to apply, applied with finger or cotton bud
uncontrolled dose
