Nasal drug delivery, what it is and how it can be used and improved in pharmacy practice.

1. Nasal Drug Delivery
SOM2 – Semester 2

2. Choosing Nasal Delivery
• Historically, nasal administration has been well accepted due to the familiarity of the route.
• The nasal mucosa are thin and highly vascularised, which means that absorption and onset can
be quick, which is beneficial for the relief of short-term symptoms like rhinitis and hayfever.
• The nasal cavity is easily accessible and less invasive than parenteral routes of administration,
which is an advantage in terms of patient compliance.
• Treating local symptoms in the nose and nasal cavity can be achieved through nasal delivery, i.e.
in the case of congestion, allergic rhinitis etc.
• A consideration of nasal delivery is that the drug needs to be absorbed quickly and effectively,
which can be an issue for some drugs.
• Some drugs can also cause irritation and other adverse effects such as bleeding, rebound
congestion and rhinitis.
• The entire dose must also be given in 150μL per nostril, which can be an issue.
• Enzymes such as proteases, peptidases, proteinases and cytochrome P450 enzymes also
present an issue as some drugs, such as proteins and peptides may be degraded before
absorption. However, this could also be used to the medicinal chemist’s advantage in terms of
creating a prodrug that is transformed into the active drug via the action of nasal enzymes.

3. Nasal Delivery
• Nasal delivery devices are used commonly to delivery drugs topically to the nasal mucosa, and
include; drops (solution), sprays (solution), suspensions, gels, powders and ointments.
• Drugs delivered nasally are typically used for a local effect and so are limited to a few therapeutic
classes, such as antihistamines, decongestants and antibiotics. In the case of antibiotics,
Bactroban is an example of a nasal cream or ointment that can be used to treat MRSA, and may
be given to patients, carers and workers in a hospital during times of MRSA outbreak.

4. The Nasal Cavity
• The nasal cavity has a surprisingly large surface area of approximately 160cm2, formed by the
nasal valve, superior turbinate, middle turbinate, inferior turbinate and general nasal mucosa.
• Some limited preparations such as those containing menthol may be delivered to the nasal vale,
but generally it is the back of the nose that is targeted.
• At the superior-most surface of the nose lies the olfactory mucosa, which is an important
consideration in formulation. This region is sensitive and so medicines should be formulated to
avoid damage to this area. Also, the surface is capable to detecting taste which makes it important
that formulations are not foul tasting, which would cause issues with patient compliance.
• The nose itself has several functions, which include; taste, smell, filtering of air, humidifying of
inhaled air, warming of inhaled air and generating turbulent flow. These functions can be
subdivided broadly into two groups of functions; a sensory function and a protective function.

5. Nasal Deposition
• Deposition within the nasal cavity will occur at various locations dependent on particle size and
density, however it is generally desirable that drug is deposited anteriorly as opposed to
posteriorly. If the drug is deposited at the back of the nose, it will quickly be cleared and swallowed
which is an issue for drugs which are intended for a local effect. Similarly, if deposition occurs too
close to the front then the drug will be expelled in runny secretions.
• When a medicine is inhaled into the nose, the first barrier causing deposition will be the nasal
hairs, which are natural filters. The turbulent flow created by turbinates will then cause further
inertial impaction.
• Whereas in pulmonary drug delivery, particles larger than 10μm were mainly deposited via inertial
impaction, in the case of the nose, particles must be larger than 1μm due to the extent of turbulent
flow.
• The ideal size range is 5 - 10μm, any larger and the drug could be swallowed or drip out the front
of the nose. Any smaller, and the drug could be inhaled straight into the lungs.

6. Factors Affecting Absorption
• The respiratory epithelium in the nose must be crossed in order for a drug to be absorbed. This is
coated with a mucus layer 5 - 20μm thick, which is composed 95% of water and other substances
such as glycoproteins, enzymes, proteins, ions and Ig molecules. The composition of this mucus
and composition of the epithelium will affect absorption.
• The mucus is produced by goblet cells and is moved from the front of the nose to the back via
beating cilia on ciliated epithelium. This mucociliary clearance takes approximately 20 minutes
and so drugs must be absorbed quickly once deposited to avoid being swallowed and lost.
• The presence of peptidases, proteases, proteinases and cytochrome P450s with high
monooxygenase activity constitutes the nasal metabolism pathway by which some drugs, i.e.
proteins can be degraded and lost.

7. Physicochemical Properties
• Perhaps the most important physicochemical factor affecting absorption through the nasal mucosa
is molecular weight and particle size. Absorption is inversely proportional to particle size, which
makes smaller, hydrophilic molecules more likely to be able to pass through small aqueous pores
between cells via passive diffusion.
• The partition coefficient and pH also have an effect, as less ionised, more lipophilic drugs can
show some better absorption. These molecules are also absorbed via passive diffusion, but will
simply pass though the plasma membrane and not aqueous pores.
• A balance between lipophilicity and hydrophilicity must exist as making a hydrophilic drug more
lipophilic by increasing molecular weight will decrease absorption.

8. Improving Nasal Absorption
• Broadly speaking nasal absorption can be improved via three routes; changing the
physicochemical properties of the drug, enhancing absorption at the epithelium or by increasing
nasal residence time.
• The residence time can be increased by delivering the drug to the front of the nose, thus avoiding
rapid clearance via mucociliary action. This is dependent on the drug delivery system; nasal drops
are associated with poor reproducibility, quick clearance and patients seem to find them difficult to
administer quickly. Nasal sprays are slightly more accurate better-directed but again show patient
variability as people squeeze the bottle to differing extents.
• The gold standard for nasal delivery devices are metered-dose pumps, which give better control
but are more costly to manufacture and therefore buy.
• Increased residence time may also be achieved through increasing the viscosity of the
preparation; i.e. using a gel product containing methylcellulose, however this may reduce drug
diffusion. Another option would to formulate the product to contain chitosan microspheres, which
have proved useful in improving absorption of insulin. However, this requires ethical consideration
for the patient as chitosan is derived from fish bones.

9. Improving Nasal Absorption
• Enhancing the absorption can also be achieved through disrupting the epithelium and making it
easier for drug moles to cross into the interstitium. There are three classes of absorption-
enhancing surfactants; those that open tight junction, those that disrupt cell membranes, and
those that inhibit enzymes.
• The problem with surfactants is that although their disruption should be temporary, there is no
guarantee of this and so they can lead to damage to the nasal mucosa, which could lead to
bleeding, loss of smell, which itself can result in reduced appetite and a host of issues.
• Bile salts are endogenous and so slightly better in terms of causing damage to the mucosa,
though this can still occur.
• The best excipient to use in terms of causing least damage to the epithelium is a natural
membrane-like component like phosphatidylcholines (i.e. lecithin), which is obtained from eggs.
However, their absorption enhancing effect is inferior to the aforementioned substances.
Method of Action Substance
Opening of tight junction EDTA, sodium deoxycholate
Disruption of cell membranes SDS, sodium deoxycholate
Inhibition of enzymes Amastatin, sodium deoxycholate

10. Improving Nasal Absorption
• The final means of improving absorption is to modify the structure of the drug.
• Modifications can be made by altering chemical groups that affect solubility, or by formulating the
drug inside cyclodextrins. In the latter option, the drug fits inside glucose polymer rings, increasing
aqueous solubility.
• Prodrugs can also be used, as mentioned before. The agent is administered as a prodrug, which
is enzymatically cleaved (i.e. via esterification of OH or COO groups) by nasal enzymes, which
causes the active drug to be released. However, this needs to occur fairly quickly as the drug has
only 20 minutes before it will be carried to the back of the nose and lost (IF it was deposited
optimally at the front of the nose).

11. Nasal Route for Systemic Effect
• The nasal route can be desirable for drugs that are exposed to extensive hepatic first pass
metabolism or gut wall metabolism. It can also be used for polar compounds which are poorly
absorbed in the gut, or at least those that are unstable in the gastric pH.
• The onset is rapid, the route is non-invasive and bioavailability is similar to IV and IM routes in
some cases, i.e. in the case of butorphanol (an opioid analgesic).
• There is ongoing investigation into the use of nasal delivery in the administration of proteins and
peptides, for all the aforementioned benefits. However, the bioavailability can be poor due to
proteolytic activity and metabolism (in addition to large molecular weight opposing uptake).
• Peptides containing more than 10 AAs will have a bioavailability of less than 1%, due to large
molecular weight and polarity. The isoelectric point of drugs is the point of lowest solubility but
best absorption due to no charge being found on the molecule. The molecule cannot be absorbed
when charges are present.
• The absorption of peptides and proteins intended for systemic effect can be improved by
coadminstering protease inhibitors, using a mucoadherent to increase resident time or by
including an absorption enhancer like bile salts. The combination of all three would be most
effective.

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