01.nasal Dosage Forms

Nasal Dosage Forms
INTRODUCTION
Nasal formulations are aqueous-based systems that are instilled within or sprayed
into the nasal cavity and are predominantly employed for the treatment of
congestion (pseudoephedrine hydrochloride), allergic rhinitis (e.g. beclomethasone
dipropionate) and infection (mupirocin).
It includes transmucosal drug delivery and the administration of locally acting
products.
About 2% of the overall drug delivery is administered via the nasal route.
Advantages:
The onset of action for the systemic drugs is so rapid and in many cases it is
preferred to the invasive methods.
The route avoids the first pass metabolism and the destruction by nasal enzymes
can be neglected.
The amount of drug needed is small
It is a preferable route for peptide drugs
NASAL ANATOMY AND PHYSIOLOGY

The nose has two major functions, which are: the sense of smell (olfaction) and the
respiration or breathing.
The outermost part of the nose is the nasal vestibule, which runs for about 15 mm
from the nostrils to the nasal valve.
Behind the nasal valve is the nasal cavity, with a length of about 60 mm and a
volume of 20 mL, and this passes into the nasopharynx.
The nasal cavity is divided vertically for most of its length by the nasal septum,
and each wall of the cavity contains three folds known as the nasal turbinates.
Hence the nasal cavity has a relatively large surface area for its volume -
approximately 160 cm2
The nasal septum is not very accessible for the penetration of drugs into the human
system since it consists mostly of cartilage and skin.
The most efficient area for drug administration is the lateral walls of the nasal
cavity, which consist of highly vascularized tissue, the mucosa.
Inside the cavity, the mucosa is covered with the ciliary epithelium.
The ciliary activity is the driving force of the secretory transport in the nose.
1
Approximately 1 L of mucus is transported from the anterior part to the posterior
part of the nose per day.
The mucus in the rear of the cavity is removed by swallowing.
The function of the ciliary activity is to remove any particles that are trapped on
the mucus blanket during inhalation.
It takes approximately 20–30 min for the whole mucus layer to be renewed.
The nasal mucosa is a natural site for the perception of environmental influences.
Mucus presents a diffusional barrier to drug absorption, and any formulation must
be able to overcome this, as well as remain in the region long enough to allow drug
release and absorption.
For an effective administration of therapeutic drugs through the nasal mucosa, the
following must be taken into consideration:
The method and technique of administration
The site of drug deposition
The rate of clearance through the ciliary activity
The pathological condition of the nose
PHYSICOCHEMICAL FACTORS INFLUENCING DRUG ABSORPTION

IN THE NASAL CAVITY
1. Molecular size and weight
The molecular weight cut-off, beyond which absorption was negligible, was about
two orders of magnitude better for nasal administration (about 20 000 Da
compared to around 200 Da for peroral delivery).
2. The effect of pH and the partition coefficient

The pH at the surface of the mucosal cells has been reported to be 7.39; the mucus
layer is slightly acidic, at pH 5.5-6.5.
It should be mentioned that the local pH can be modified by a nasal formulation.
The effect of pH on peptide drugs is more complex, as peptides have a large
number of ionizable groups of either charge.
Peptides are characterized by their isoelectric point, the pH at which they have no
net charge and where their solubility is often lowest.
The nasal absorption of insulin (isoelectric point at pH 5.4), was found greatest at a
solution pH of 3.1 (net positive charge on insulin) and lowest at pH 6.1, near its
isoelectric point.
The absorption mechanisms of peptides are however, complex, owing to their size
and structure.
2
3. Other physicochemical factors affecting nasal absorption
The solubility of the drug and its dissolution rate are important, especially if it is
presented as a solid dosage form (e.g. a powder). In addition, powder morphology
and particle size influence the deposition of the drug inside the nasal cavity.
All of these factors must be considered in the design of formulations
IMPROVING DRUG AVAILABILITY IN NASAL ADMINISTRATION

There are three main ways to maximize the systemic bioavailability of drugs
administered nasally:
Improve nasal residence time
Enhance nasal absorption
Modify drug structure to change physicochemical properties.
Increasing nasal residence time

1. Applying the drug to the anterior part of the nasal cavity, (largely determined by
the type of dosage form used).
2. The preparation could be formulated with polymers such as methylcellulose, but
some times it delays absorption. Why?
Enhancing nasal absorption

Absorption enhancers work by increasing the rate at which drugs pass through the
nasal mucosa, by altering the structure of the epithelial cells in some way.
General requirements of an ideal absorption enhancer at its concentration in use
are:
It should give an effective increase in the absorption of the drug.
It should not cause permanent damage or alteration to the tissues.
It should not otherwise be irritant or toxic, either to the local tissues or to the rest
of the body.
It should be effective in small quantities.
The enhancing effect should occur when absorption is required (i.e. there should
not be a lag in its effect).
The effect should be temporary and reversible.
The enhancer should fulfill all other expectations of formulation excipients (e.g.
stability and compatibility).
Substances tried as enhancers include, surfactants and bile salts.
Surfactants investigated include non-ionic ethers and esters, and anionic
surfactants, and found to be particularly effective enhancers. But, unfortunately,
their enhancement usually correlates with mucosal damage, as the surfactants
associate with cellular components such as membrane lipids and proteins.
Surfactants are therefore unsuitable for therapeutic use as enhancers.
3
Bile salts appear to possess much of the enhancing activity but less of the damage
potential of surfactants.
Commonly studied bile salts include sodium cholate, sodium deoxycholate, and …
all of which can cause enhancement at low concentrations.
Several mechanisms have been proposed for the enhancing action of bile salts:
Increasing cell membrane permeability by forming temporary channels through the
lipid structure;
Forming intercellular aqueous pores by opening the tight junctions between cells
(most likely);
Increasing the lipophilicity of charged drugs by forming ion pairs;
Inhibition of proteolytic enzymes.
Although bile salts are claimed to be safer than surfactants they can still cause
damage to epithelial cells.
Other substances include phosphatidylcholines and Cyclodextrins
Modifying drug structure

Cyclodextrins can perform some of these functions, although they do not actually
change the drug's structure.
Some structural changes will be permanent, either by altering substituent groups on
the molecule or by using different salt forms. However, they have the risk of
changing the drug's therapeutic and toxicological profile and thus require
regulatory approval.
An alternative is to use prodrugs, whereby the prodrug has favourable properties
for absorption but is changed to the active drug on passing through the nasal
epithelium.
NASAL DELIVERY SYSTEMS AND THEIR FORMULATION

Nasal dosage forms must fulfill the following:
Must be effective
Must be safe and stable, both chemically and microbiologically
Must be acceptable to the patient to ensure compliance.
If the formulation is a liquid it may commonly contain:

antimicrobial preservatives (e.g. Benzalkonium chloride)
antioxidants (e.g. butylated hydroxytoluene)
solubilizing agents or cosolvents (e.g. glycol derivatives)
salts for adjusting pH and tonicity
humectants, to minimize irritation to the nose (e.g. glycerol)
viscosity-increasing agents (e.g. methylcellulose), and
absorption enhancers.
4
Deposition mechanisms
The mechanisms of depositing inhaled particles on the nasal lining include:
impaction, sedimentation and diffusion.
Impaction: this occurs when there is a change in direction of the airflow - as
happens when inspired air passes through the nasal valve - and the inertia of large
or fast-moving particles carries them in their original direction.
This is usually the main way of depositing particles in the turbulence caused by
fast flow rates, or with particles larger than 0.5-1 μm
Varying the rate of flow from the device or the aero- dynamic particle size the
formulator can influence this type of deposition.
Sedimentation: this happens when the air is moving slowly and the particles settle
slowly under the force of gravity. (Stokes' equation).
The control over this is to ensure a slow flow rate by modifying the drug particle
size or formulation droplet size.
Diffusion: This occurs by Brownian motion and is thus limited to very small
particles (< 0.5 μm).
Normally diffusion is not important, as the inspired particles are too large.
Nasal dosage forms
Nasal dosage forms usually contain the drug in a liquid or powder formulation
delivered by a pressurized or pump system.
Liquid formulation
Are usually aqueous solutions having the general benefits and drawbacks of
pharmaceutical solutions.
They are relatively simple to develop and manufacture compared to solid dosage
forms, but have a lower microbiological and chemical stability.
The liquid form can be soothing to the nasal lining but this may be countered by
the excipients, such as the antimicrobial preservatives, which can be irritant or
ciliotoxic.
Giving liquids as drops is cheap and simple but the dose is not accurate and easily
removed
Squeezed bottles: these are often used for nasal decongestants.

They give a better absorption of drug by directing the formulation into the anterior
part of the cavity and covering a large part of the nasal mucosa.
Deposition and volume are subject to the technique of the user.
Since the formulation is expelled through a plain orifice without any type of valve
system, it is subject to contamination by 'suck-back‘.
Metered-dose pump systems: these offer greater control over dosing than any of
the previous systems.
5
They can deliver solutions, suspensions or emulsions, with a predetermined
volume between 25 and 200 μL, thus offering deposition over a large area.
The size and localization of the dose are controlled by changing factors such as the
rheological and surface tension characteristics of the formulation and the design
and geometry of the pump.

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Nasal Dosage Forms

NASAL ANATOMY AND PHYSIOLOGY

PHYSICOCHEMICAL FACTORS INFLUENCING DRUG ABSORPTION

2. The effect of pH and the partition coefficient

IMPROVING DRUG AVAILABILITY IN NASAL ADMINISTRATION

Increasing nasal residence time

Enhancing nasal absorption

Modifying drug structure

NASAL DELIVERY SYSTEMS AND THEIR FORMULATION

If the formulation is a liquid it may commonly contain:

Squeezed bottles: these are often used for nasal decongestants.

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