Nasal drug delivery

Why is the nasal cavity used as a drug delivery option?

• easily accessible

• Rich vascular plexus = topically administered drugs can rapidly achieve effective blood levels whilst avoiding IV

How is a good nasal drug delivery most effectively accomplished?

Accomplished by distributing drugs solutions as a mist of small droplets 

Why are large droplets not favoured in nasal drug delivery?

Can aggregate and run off instead of being absorbed

Why is the nasal route a promising method of systemic delivery?

Easily accessed vascular bed

Why is nasal favoured in comparison to buccal/oral administration?

• Nasal has a faster onset e.g., in pain, migraine and ED treatment

• Drug won’t be destroyed by gastric acid + avoids first pass metabolism

• Paediatric patients may refuse oral treatment but nasal may be enter

• Buccal medicines require retention of dosage form on buccal areas and may not stay in contact/lower patient compliance

Why may children be more likely to prefer nasal administration?

Ease of access, non-invasive and lack of pain

What are the advantage of nasal drug delivery?

• rapid onset of action

• Simple administration - painless, convenient, easy

• Reduced systemic side effects

• Avoids first pass metabolism

• Comparable to IV administration and better than Subcut/IM

What are the disadvantages of nasal drug delivery?

• local metabolism

• Limited number of medications that can be delivered via this route 

• Many formulations not adequately concentrated to achieve ideal dosing volumes - drug conc or frequency of dosing 

• Mucosal health impacts absorption - diseases can affect 

What is the volume of the nasal cavity?

Around 20ml 

How does the nasal septum divide?

vertically

What is a nasal concha?

A long, narrow and curled bone shelf with protrudes into the breathing passage of the nose

What is a diagram showing the anatomy of the nasal cavity?

WATCH THE VIDEO 

What does the anterior section in the nasal mucosa comprised of?

Squamous epithelium from vestibule to turbinates

What is the key role of the nasal mucosa?

Forms a layer covering the cells, Does not allow materials to penetrate and captures bacteria and large molecules and prevents from entering

What is the average pH of the nasal mucosa?

5.5-6 but higher in children 

What is a diagram highlighting nasal mucosa?

What fraction of nasal mucosa cells are non ciliated?

1/3

What are the characteristics of nasal mucosa?

300 cilia per cell, size 5-100mm x0.1-0.3mm, 10Hz clearance and moves at 5-6mm/min 

What are some examples of uses of nasal drug delivery for the local route?

Antihistamines, decongestants, corticosteroids, nasal infections

What is an example of a decongestant in local nasal drug delivery?

Ephedrine to relieve congestion of mucous membranes in acute sinusitis and hayfever 

Why are corticosteroids used in local nasal drug delivery?

Reduce inflammation and suppress immune system

What is an example of a drug used for nasal infections?

Betnesol-N (betamethasone sodium 0.105% w/v + Neomycin sulphate 0.5% w/v) - colourless pale yellow liquid

How is betnesol-N administered?

2-3 drops instilled into each nostril 2 or 3 times daily 

What can the side effects of Betnesol-N be?

Sneezing, changes in sense of smell and taste

What is an example of a systemic drug administered nasally?

Desmopressin to treat nocturnal enuresis/bedwetting

Why can nocturnal enuresis occur?

Deficiency in secretion of ADH during sleep 

How does desmopressin work?

Raises night time levels of ADH and decreases urine production 

Why is nasal administration favoured for desmopressin?

Faster absorption and onset of action faster than oral tablets

Why is Buserelin used for as a systemic nasal drug?

Treating prostate cancer and endometriosis

Why is buserelin administered nasally?

Ineffective via oral administration due to first pass metabolism in GIT 

How is buserelin administered?

Nasal spray 3x per day

Whyat is galantamine used to treat?

Dementia

Why does galantamine use nasal route of administration?

Causes sickness when administered orally 

mucociliary clearance slides

Mucociliary clearance

What local metabolism occurs in the nose?

Cytochrome P450s, dehydrogenases, hydroxylases, carboxylesterases, carbonic anhydrase and glutathione transferase 

What enzymes may affect peptide drugs administered nasally?

Proteolytic enzymes

What can poor nasal absorption of a drug be attributed to?

• Physiochemical properties of the drug limiting transport across nasal membrane

• Reduced retention time in nasal cavity due to mucociliary clearance

• Biotransformation by the enzymes in the nasal mucosa

What should you use in terms of concentration and volume to maximise bioavailability?

Most concentrated form/lowest volume of medication available - ideal volume is 0,25-0.30mL per nostril 

What does a low volume allow for bioavailability?

Reduces runoff but allows maximum mucosal coverage

How can you double the absorptive surface area in nasal drug delivery?

Use both nostrils

Which drug formulation can you use to maximise surface average coverage in nasal administration?

Atomized spray 

What patient factors should you beware of in nasal administration?

Localised issues in the nose e.g., bleeding, high mucous production

What physiochemical factors can affect nasal absorption?

• lipophilicity/hydrophilicity, molecular weight

• PH and ionisation

• Solubility

• Rate of dissolution

• Particle/droplet size

How can local pH be controlled in the nose?

Formulation 

Why do you need to consider pH when considering physiochemical factors affect nasal absorption?

Disturb integrity of mucous layer and can change ionisation of molecules

What is the pH at the mucosal surface in the nose?

7.39

What is the pH of mucus in the nose?

5.5-6.5

What factors can affect solubility in nasal absorption?

Prodrugs, choice of salt form, use of appropriate excipients

What affects how far the drug particle goes in the nasal cavities as well as what it does when deposited?

Size, shape and density of particulate material 

What is the ideal particle size to ensure particles are deposited in the nasal mucosa?

10-20um

What particle size can pass through the nasal cavity and are deposited in the lungs?

2um or smaller

What will drugs do if introduced as soluble particles in nasal absorption?

Readily pass into nasal lining secretions and absorbed into blood 

What formulation considerations should be thought about when improving nasal administration?

• control of nasal pH

• Maintain toxicity

• Choice of vehicle/viscosity

• Inclusion of antioxidants and preservatives/shelf life

Why may you want to increase viscosity in nasal administration?

Increases retention/nasal residence time by applying polymers 

Why may glycerol be added to improve nasal administration?

Reduces or minimises irritation to the nasal mucosa

What are the requirements of an ideal absorption enhancer?

• rapidly-acting with a transient and reversible effect on nasal epithelium

• Not absorbed systemically

• Non-toxic, non-irritant and non-allergenic

• Doesn’t permit entry of dangerous environmental material

• Compatible with drugs and other excipients in the formulation

• Safe for chronic use - dependant on condition being treated

What are some examples of absorption enhancers?

Surfactants, phosphatidylcholines, cyclodextrins

What are the negative effects of using surfactants as absorption enhancers?

Cause permanent damage and loss of cells

What are the negative effects of phosphatidylcholines?

Disrupts cell membranes as they are similar to naturally occurring cell membrane compounds 

What are the properties of cyclodextrins?

Polar outer surfaces and less polar inner surfaces

What is interception in drug deposition?

When the drug travels so close to a surface of the airway passages

What is impaction in drug deposition?

Fast-moving turbulent flow of large particles/droplets of size 0.5-1um and change direction of air flow 

Where do particles larger than 10um in diameter get deposited?

In nose and throat and cannot penetrate the lower tissues of respiratory tract

What does particle sedimentation depend on?

Air flow velocity, gravitational forces and air resistance

What is the Stokes law equation?

Smaller the particle = more vigorous the movement 

interception and electrostatic precipitation slide

What are some examples of nasal formulations?

Liquids/nasal drops, squeezed bottles/atomised fluids and metered dose pumps

What are some properties of liquid formulations in nasal drug delivery?

Aqueous drug solutions generally, simple and cheap to develop, may require preservatives, can be soothing to nasal mucosa, usually given as nasal drops or unit dose packs 

What can be irritating to nasal mucosa in liquid formulations in the nose?

Preservatives

Why can nasal drops be disadvantageous?

Can be inaccurate and lose liquid

What are squeezed bottles for nasal administration?

Partially atomised spray of liquid, sprayed directly into anterior part of cavity 

What is an advantage of a squeezed bottles as a nasal drug delivery route?

Large surface coverage of nasal mucosa

What is a disadvantage of squeezed bottles as a route of nasal administration?

technique dependant

What are some advantages of metered dose pumps?

Offer greater control, pre-determined volume of 25-200ul, formulator has larger degree of control over deposition 

What can metered dose pumps deliver?

Solutions, suspensions and emulsions