Lecture 8: nasal delivery I Flashcards

1
Q

What does the nasal cavity have?

A
  • 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
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2
Q

What are the functions of the nose?

A

-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)

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3
Q

What is the mucociliary clearance?

A
  • 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

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4
Q

What is the mucous turnover time?

A

10-15 minutes

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5
Q

What are the mechanisms of nasal drug absorption?

A

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

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6
Q

What is the aim of intranasal drug delivery?

A

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

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7
Q

what are good drug candidates for nasal delivery?

A
  • 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.
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8
Q

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

A
  • 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
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9
Q

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

A

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

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10
Q

What are the physicochemical factors influencing drug absorption?

A
  • molecular size and weight
  • pH and partition coefficient
  • solubility
  • dissolution rate
  • particle size and morphology
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11
Q

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

A
  • 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)
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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

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

A

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

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15
Q

What are the barriers to nasal peptide absorption?

A
  • large molecular size of peptides
  • high charge density
  • hydrophilicity at physiological pH
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16
Q

How can nasal bioavailability be improved?

A
  • modity structure/physicochemical properties of the drug
  • improve nasal residence time
  • enhance nasal absorption
17
Q

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

A
  • 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
18
Q

What do absorption enhancers do?

A
  • inhibit enzyme activity
  • reduce mucous viscosity or elasticity
  • decrease mucociliary clearance
  • open tight junctions
  • solubilise or stabilise drug
19
Q

What are the two types of absorption enhancers?

A

chemical enhancers

physical enhancers

20
Q

How do chemical enhancers work?

A
  • act by compromising nasal mucosa (often irreversibly

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

21
Q

how do physical enhancers work?

A
  • affect nasal clearance reversibly by forming a gel

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

22
Q

What are the properties of an ideal enhancer?

A
  • 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
23
Q

do commercial nasal formulations currently use a penetration enhancer?

A

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