Lecture 8: nasal delivery I

Question 1

What does the nasal cavity have?

Answer 1

• rich complex and adaptive blood supply with blodo flow of 400mL blood per 100g of tissue
• comprehensive lymphatic system
• sympathetic, parasympathetic and cranial nerve supplies

Question 2

What are the functions of the nose?

Answer 2

-heats and humidifies inspired air before it reaches alveoli
(inhaled air between 20-50 degrees C are warmed to within 10degrees of body temperature and at least 97% relative humidity)
-smell, olfactory membrane (comprises ~5% of nasal area which allows detection of noxious gases)
-Defense system against inhaled particles and pathogens (turbulent air flow allows particles to get stuck on mucous and eventually swallowed)

Question 3

What is the mucociliary clearance?

Answer 3

• the mucus layer is ~5-20mm thick and comprises of a gel and sol layer
• back 2/3 of the nasal cavity is covered with cilia which move in wave like motions to propel mucous and materias trapped in it towards the nasopharynx

-defense system

Question 4

What is the mucous turnover time?

Answer 4

10-15 minutes

Question 5

What are the mechanisms of nasal drug absorption?

Answer 5

Paracellular:

• aqueous route: slow and passive
• transport between cells
• poor bioavailability for drugs with MW > 1000Da

transcellular:

• lipid route is faster than the paracellular route but it is still passive
• transports lipophilic drugs.

tight junction:

• allows exchange of small ions between apical and basolateral sides of cell membranes
• transport of larger molecules is limited

active transport:
-involves receptor mediated or vesicular transport mechanisms

Question 6

What is the aim of intranasal drug delivery?

Answer 6

achieve therapeutic drug levels in systemic circulation in the absence of damage to the nasal mucosa and the mucociliary clearance system

Question 7

what are good drug candidates for nasal delivery?

Answer 7

• drugs which show poor bioavailability e.g. most peptides and proteins
• drugs that undergo extensive FPM
• drugs that display erratic oral absorption e.g. propranolol
• drugs that require rapid therapeutic onset e.g. opiates for pain relief.

Question 8

What are the advantages of the nasal route for systemic drug delivery?

Answer 8

• easily accessible organ which allows simple non distressing self admin of liquid and powder formulations
• relatively large surface area for drug absorption
• avoids FPM
• drugs rapidly absorbed allowing fast onset of drug action
• intimate and comprehensive lymphatic and capillary networks which provide a rich sink area for drugs to pass into
• some drugs absorbed via the olfactory mucosa can pass into the brain

Question 9

What are the disadvantages of using the nasal route for systemic drug delivery?

Answer 9

Mucociliary clearance
-turnover time for mucous is 10-15mins

Mucous barrier:

• physical barrier
• multitiude of receptors to trap bacteria and viruses

Defence mechanism:
-secretory IgA molecules present in mucous may affect some drugs

Enzymatic degradation:
-many enzymes present intracellularly, extracellularly, in the mucous and boud to epithelial membranes

Question 10

What are the physicochemical factors influencing drug absorption?

Answer 10

• molecular size and weight
• pH and partition coefficient
• solubility
• dissolution rate
• particle size and morphology

Question 11

What is the relevance of molecular weight to nasal drug delivery?

Answer 11

• the smaller the MW the faster the absorption up to about 300Da
• nasal absorption decreases significantly when MW > 1000Da (unless an absorption enhancer is used)

Question 12

What is the relevance of pH and partition coefficient to nasal drug delivery?

Answer 12

pH at the surface of mucosal cells is 7.4
pH of the mucous layer is 5.5-6.5

thus the local pH can be modified by a nasal formulation
-absorption is increased with %unionised however a pH 3 will cause structural changes in the epithelial cells of the nasal mucosa so we must be careful

Question 13

What is the relevance of solubility and dissolution rate to nasal drug delivery?

Answer 13

Solubility:
- a small volume (25-200uL) is administered by the nasal route so solubility needs to be really good
Dissolution rate:
-mucociliary clearance also means that for particulate nasal products (suspensions/powders) dissolution rates are important

Question 14

What is the relevance of particle size and shape to nasal drug delivery?

Answer 14

Particle size:
-particles in the 5-10micron range are deposited in the nasal cavity. particles below this are deposited in the lungs.
particles above this cause a gritty sensation and irritate the nasal mucosa.
Particle shape:
-linear molecules absorbed slowly than circular molecules

Question 15

What are the barriers to nasal peptide absorption?

Answer 15

• large molecular size of peptides
• high charge density
• hydrophilicity at physiological pH

Question 16

How can nasal bioavailability be improved?

Answer 16

• modity structure/physicochemical properties of the drug
• improve nasal residence time
• enhance nasal absorption

Question 17

How can the structure or physicochemical properties of a drug be modified?

Answer 17

• can administer synthetic peptide and protein analogues which are more stable, specific, potent and easily absorbed
• e.g. Desmopressin was developed from vasopression. Desmopression shows better bioavailability
• e.g. Synthetic salmon calcitonin is used instead of human calcitonin to treat OP. It has a much longer half life and greater potency

Question 18

What do absorption enhancers do?

Answer 18

• inhibit enzyme activity
• reduce mucous viscosity or elasticity
• decrease mucociliary clearance
• open tight junctions
• solubilise or stabilise drug

Question 19

What are the two types of absorption enhancers?

Answer 19

chemical enhancers

physical enhancers

Question 20

How do chemical enhancers work?

Answer 20

• act by compromising nasal mucosa (often irreversibly

- e.g. chelating agents like EDTA, bile salts like sodium cholate, surfacants like lysophosphatidylcholine

Question 21

how do physical enhancers work?

Answer 21

• affect nasal clearance reversibly by forming a gel

- e.g. chitosan solutions, starch microspheres and nasal gels.

Question 22

What are the properties of an ideal enhancer?

Answer 22

• immediate, predictable, transient and non harmful effect on nasal membrane
• not systemically absorbed and does not allow absorption of opportunistic substances found on nasal epithelium
• compatible with peptides and proteins and other substances likely to be formulated with it

Question 23

do commercial nasal formulations currently use a penetration enhancer?

Answer 23

No, the ideal penetration enhancer has not been found yet, but there is still research going on