Aural And Nasal

Question 1

Advantages of the nasal route

Answer 1

• 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.
• Could achieve better systemic bioavailability than the oral
route:

Question 2

Describe the nasal anatomy

Answer 2

• nasal cavity split in to 2 halves by nasal septum
• Covered with mucous membrane containing
  goblet cells secreting mucus.
• Absorption occurs across turbinates and septum

Question 3

How are lipophilic and polar drugs transported across the nasal epithelium?

Answer 3

1. Lipophilic Drugs: Transported transcellularly via:
   • Passive diffusion (concentration-dependent)
   • Receptor/carrier-mediated transport
   • Vesicular transport mechanisms
2. Polar Drugs: Pass through epithelial tight junctions (paracellular pathway)
   • Limited by molecular size (<1000 Da for effective transport)

Question 4

What are the key functions of the nose in air filtration and drug delivery ?

Answer 4

• Functions of the Nose = passageway for air to the respiratory tract , Humidifies and warms incoming air
• Large particles trapped in nasal filter undergo rapid clearance
• Particles deposited on mucus are moved by ciliated epithelial cells toward the pharynx
• Site of particle deposition and clearance rate are crucial for local and systemic drug delivery

Question 5

What is the function of the clearance system ?

Answer 5

• The function of this clearance system is to remove foreign substances from the nasal cavity, and this includes drugs.

Question 6

What is local drug delivery ?

Answer 6

• Deliver directly at site of action
• rapid relief at lower dose compared to oral
• reduce systemic side effects
• eg. Nasal corticosteroids (reduces nasal mucosa
  inflammation)

Question 7

Why is intranasal delivery useful for systemic drug delivery, and what are some examples?

Answer 7

• Provides rapid onset of action, useful in emergencies.
• Bypasses first-pass metabolism, leading to faster drug absorption.
• eg. Fentanyl: Provides quick pain relief.
• The nasal delivery is effective but has low bioavailability.

Question 8

How does solubility affect systemic absorption ?

Answer 8

• drug must be in solution to be absorbed
  • Only 25-200μl of liquid can be administered intranasally.
  • Drugs with low aqueous solubility and/or those require a high dose pose problems.

Question 9

What is mucociliary clearance, and why is it important in drug delivery ?

Answer 9

• Cilia found on the surface of epithelial cells transport mucus 5 mm per min toward the nasopharynx.
• function = remove foreign substances from the nasal cavity, and this includes drugs

Question 10

How can solubility issues be overcome to improve absorption ?

Answer 10

• formulating as a suspension or powder in micro-size range, requires drug to dissolve in nasal cavity fluid before absorption
• select a different salt form of an ionisable drug
• use appropriate excipients eg.co-solvents
• modifying its molecular form (eg. prodrug )

Question 11

How do lipophilicity and hydrophilicity affect systemic absorption via the nasal route?

Answer 11

• Lipophilic drugs are rapidly absorbed by 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

Question 12

How does molecular size affect absorption ?

Answer 12

• 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.

Question 13

how does degree of ionisation affect absorption ?

Answer 13

• 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 closest to the nasal mucosa minimises local irritation, but pH 3-10 can be tolerated.
• Unionised drug molecules with a higher LogP (lipophilicity )better absorbed than ionized form.

Question 14

how does enzymatic activity affect absorption ?

Answer 14

• enzymes in the nasal cavity are including monooxygenase, cytochrome P450, proteolytic enzymes
• drugs may be metabolised in the lumen or as they pass epithelium by enzymes
• so solution is to include enzyme inhibitors in formulation
• encapsulate drug - limits enzyme access
• use of prodrugs to reduce the affinity of drug for the enzyme

Question 15

how does mucosal contact time affect absorption ?

Answer 15

• Increase residence time of drug in turbinates could potentially increase drug absorption.
• Mucoadhesive polymers (e.g. chitosan) can prolong the drug in contact with the mucosa without being absorbed themselves
• Increase formulation viscosity increases residence time
• increase contact time does not necessarily increase absorption

Question 16

how does nasal epithelium permeability affect absorption ?

Answer 16

• The mucus layer is a diffusion barrier.
• permeability of small, uncharged molecules less affected by mucus layer compared to large, cationic, hydrophobic molecules.
• Penetration enhancers can be added to alter the epithelium structure temporarily to increase permeability.

Question 17

what does the typical nasal liquid formation contain ?

Answer 17

– API
– Antimicrobial preservatives (e.g. benzalkonium chloride)
– Antioxidants (e.g. butylated hydroxytoluene)
– Solubilising agents or co-solvents (e.g. glycol derivatives)
– Salts for adjusting pH and tonicity
– Humectants, to minimize irritation to the nose (e.g. glycerol)
– Viscosity-enhancing agents (e.g. methylcellulose)
– Absorption enhancers (if necessary)

Question 18

what are the advantages and disadvantages of nasal dropper/squeezed plastic bottle ?

Answer 18

• adv = cheap and simple systems for nasal delivery.
  disadvantages:
• Require considerable skill, dexterity and flexibility to apply the liquid uniformly across the mucosa.
  – Require semi-recumbent or other unusual position.
• The liquid delivered too quickly causes formulation to drip
  from the nostril to throat, causing cough.
• Volume administered is subject to patient technique. Only suitable for drugs with
  large therapeutic window.

Question 19

What are the key features and characteristics of nasal spray devices?

Answer 19

• solution and suspension can be formulated, in metered-dose pump or pre-filled syringe
• deliver exact dose from 25-200μl and spread across nasal mucosa.
• Easier and faster to administer than drops,
  but requires priming.

Question 20

What are the key characteristics and limitations of nasal tube devices for drug delivery?

Answer 20

• For creams, gels and ointments for local effects.
  limitations:
• Messy to apply, applied with finger or cotton bud.
• Uncontrolled dose.

Question 21

what are the key characteristics + considerations for ear drops ?

Answer 21

• Used topically
• drug either in solution or suspension with a suitable vehicle (water, glycerol)
  considerations:
• Some vehicles (e.g. alcohol) may cause mild stinging
• Avoid products with nut oils (e.g., almond, peanut) in patients with nut allergies
• Oil-based preparations may need pre-warming with minimial heat to be more effective

Question 22

what is ear wax + its composition + when does it need to be removed ?

Answer 22

• ear wax is normal bodily secretion which provides a protective film on the meatal skin.
• needs only be removed if it causes deafness or interferes with a proper view of the ear drum
• Composition of ear wax is mostly lipophilic substances ( keratin, lipids, peptides, fatty acids, cholesterol )

Question 23

What are cerumenolytics, how do they work, and what are some common examples?

Answer 23

• agents that soften cerumen (ear wax) and lubricate the ear canal, so disintergrate or remove ear wax
• Common cerumenolytics: eg. olive or almond oil ear drops, waxsol, exterol

Question 24

What is otitis externa, its causes, and treatment options?

Answer 24

• Inflammatory reaction of the meatal skin
• Mostly caused by bacteria or fungus.
• Many cases recover after thorough cleansing of the external ear canal by suction or dry mopping.
• Corticosteroid ear drops, astringent solution or acetic acid solution can be used.

Question 25

What are astringent preparations, and example of how they’re used in ear treatments?

Answer 25

• substance that causes shrinking or
  constriction of body tissues, usually locally after topical medicinal application
• eg. Aluminium acetate ear drops (13 %)

Question 26

What are the key components of corticosteroid ear preparations, and what is an example?

Answer 26

• formulated in combination with anti-infective drugs
• eg. Otomize® ear spray:
  – Dexamethasone 0.1 % (corticosteroid)
  – Nyomicin sulphate 0.6 % (antibiotic)
  – Acetic acid 2 % (bactericide & fungicide)
  – Water (solvent)
  – Methyl hydroxybenzoate (preservative)
  – Propyl hydroxybenzoate (preservative)
  – Stearyl alcohol (viscosity enhancer)

Question 27

acetic acid use + preparations + shelf life ?

Answer 27

• Acetic acid 2% can be used locally to treat mild otitis externa
• Possess antibacterial and antifungal activities, active against: Haemophilus and Pseudomonas species, Candida and Trichomonas
• Shelf life 18 months, then one month after first use.