Nasal Sprays – (Naso – Pulmonary Drug Delivery Systems)

Nasal
Sprays

(Naso – Pulmonary Drug Delivery Systems)

Intended
learning outcomes

At the end of the
session students will be able to:

1.       Justify
the need for nasal sprays, differentiate nasal sprays with other nasopulmonary
devices

2.       Enlist
the advantages and limitations of nasal sprays

3.       Describe
formulation  aspects of nasal sprays

4.       Recall
marketed formulations of nasal sprays

Nasal Sprays

• Intranasal drug delivery is recognized to be a useful and
reliable alternative to oral and parenteral routes.

• The nasal route of drug delivery can be used for both
local and systemic drug delivery. For instance, localized nasal drug delivery
is usually used to treat conditions related to the nasal cavity, such as
congestion, rhinitis, sinusitis and related allergic conditions.

• A diverse range of drugs including corticosteroids,
anti-histamines, anti-cholinergic and vasoconstrictors can be administered
locally. In recent years, achieving a systemic drug action using the nose as
the entry portal into the body has received more attention.

• Also, the nasal delivery seems to be a favorable way to
circumvent the obstacles for bloodbrain barrier (BBB) allowing the direct drug
delivery in the biophase of central nervous system (CNS)-active compounds.

• It has also been considered to the administration of
vaccines.

• Now a day’s multiple types of formulation are used to
administer drug by nasal rout, which includes nasal spray, nasal drop, nasal
powder, nasal gels & nasal insert etc.

• Administration of drugs through the nose in the spray
dosage form is a noninvasive method that gives rapid onset of drug action.
Because the nasals spray dosage form is cost-effective, easy to use/carry and
self-administrable, it has high patient compliance.

• Therefore, nasal drug delivery has become a popular route
of drug administration and has strong growth opportunity

Advantages
of Nasal Drug Delivery System

1. Intranasal administration offers several practical
advantages from the viewpoint of patients (non-invasiveness, essentially
painless, ease drug delivery and favorable tolerability profile)

2. Rapid drug absorption.

3. Quick onset of action.

4. Hepatic first – pass metabolism is absent.

5. The bioavailability of larger drug molecules can be
improved by means of absorption enhancer or other approach.

6. Better nasal bioavailability for smaller drug molecules.

Limitations:

1. Dose is limited because of relatively small area
available for the absorption of drug.

2. Time available for drug absorption is limited.

3. Diseased condition of nose impairs drug absorption.

4. The absorption enhancers used to improve nasal drug
delivery system may have histological toxicity which is not yet clearly
established.

5. Absorption surface area is less when compared to GIT.

6. Nasal irritation

7. Certain surfactants used as chemical enhancers may
disrupt and even dissolve Membrane in high concentration

Formulation
of Nasal Sprays

• Nasal spray drug products contain therapeutically active
ingredients (drug substances) dissolved or suspended in solutions or mixtures
of excipients (e.g., preservatives, viscosity modifiers, emulsifiers, buffering
agents) in nonpressurized dispensers that deliver a spray containing a metered
dose of the active ingredient.

• The dose can be metered by the spray pump.

• A nasal spray unit can be designed for unit dosing or can
discharge up to several hundred metered sprays of formulation containing the
drug substance.

• Energy is required for dispersion of the formulation as a
spray.

• This is typically accomplished by forcing the formulation
through the nasal actuator and its orifice.

• The formulation and the container closure system
(container, closure, pump, and any protective packaging) collectively
constitute the drug product.

• The design of the container closure system affects the
dosing performance of the drug product.

• Both solution and suspension formulations can be
formulated into nasal sprays.

1) Active
Pharmaceutical Ingredient

An ideal nasal drug candidate should possess the
following attributes:

• Appropriate aqueous solubility to provide the desired dose
in a 25–150 ml volume of formulation.

• Appropriate nasal absorption properties.

• No nasal irritation from the drug.

• A suitable clinical rationale for nasal dosage forms, e.g.
rapid onset of action.

• Low dose. Generally, below 25 mg per dose.

• No toxic nasal metabolites.

• No offensive odors/aroma associated with the drug.

• Suitable stability characteristics.

2) Excipients used in
nasal spray formulations

There are various types of excipients used in nasal
formulations. Commonly used and frequently added excipients are as follows:

a) Buffers:

Nasal secretions may alter the pH of the administrated dose
which can affect the concentration of un-ionized drug available for absorption.

Therefore, an adequate formulation buffer capacity may be
required to maintain the pH in-situ.

Examples of buffer used in nasal spray sodium phosphate,
Sodium citrate, citric acid.

b) Solubilizers:

Aqueous solubility of drug is always a limitation for nasal drug
delivery in solution.

Conventional solvents or co-solvents such as glycols, small
quantities of alcohol, Transcutol (diethylene glycol monoethyl ether), medium
chain glycerides and Labrasol (saturated polyglycolyzed C8- C10 glyceride) can
be used to enhance the solubility of drugs.

Other compounds can be used like, the use of surfactants or
cyclodextrins such as HP–s Cyclodextrin that serve as a biocompatible
solubilizer and stabilizer in combination with lipophilic absorption enhancers.

In these cases, their impact on nasal irritancy should be
considered.

c) Preservatives:

Most nasal formulations are aqueous based so needs
preservatives to prevent microbial growth.

Parabens, phenyl ethyl alcohol, benzalkonium chloride, EDTA
and benzoyl alcohol are some of the commonly used preservatives in nasal
formulations

d) Antioxidants:

A small quantity of
antioxidants may be required to prevent drug oxidation. Commonly used antioxidants
are sodium bisulfite, butylated hydroxytoluene, sodium metabisulfite and
tocopherol.

Usually,
antioxidants do not affect drug absorption or cause nasal irritation.

e) Humectants

Because of allergic and chronic diseases there can be crusts
and drying of mucous membrane.

Certain preservatives/ antioxidants are also likely to cause
nasal irritation especially when used in higher quantities.

Adequate intranasal moisture is essential for preventing
dehydration. Therefore, humectants can be added especially in gel-based nasal
products.

 Humectants avoid
nasal irritation and do not affect drug absorption.

Common examples include glycerin, sorbitol and mannitol

f) Surfactants

Surfactant incorporation into nasal dosage forms can modify
the permeability of nasal membranes, which may facilitate the nasal absorption
of drug.

It also increase stability of suspension.

Common examples include Polysorbates.

g) Bioadhesive polymers

 Compound that
is capable of interacting with biological material through interfacial forces
and being retained on such material for prolonged periods of time is called as
bioadhesive polymer. They are also called as mucoadhesive if biological
material is mucus membrane.

The bioadhesive force of a polymer material is dependent on
the nature of the polymer, the surrounding medium (pH), swelling and
physiological factors (mucin turnover, disease state).

From a safety (nasal irritancy) point of view use of a
combination of carriers is often recommended.

h) Penetration enhancer

Chemical penetration enhancers are widely used in the nasal
drug delivery.

Sr	Category	Role	Example
1	Isotonicity adjustment	Used to adjust the tonicity of the formulation	Sodium chloride, Dextrose
2	pH adjustment	Used to adjust pH same to physiological conditions and maximize drug stability	Sodium hydroxide, hydrochloric acid sulphuric acid
3	Purging	Purging used to reduce oxidation	Nitrogen
4.	Antimicrobial preservative	To avoid the microbial growth in the formulation	Benzalkonium chloride, ethanol, propylene glycol, Beczoyl Alcohol, chlorobutanol, Methyl paraben
5.	Buffer component	It gives the buffer capacity to formulation at desire Ph	Sodium citrate, Sodium Phosphate
6.	Surfactant	Increases suspendability and stability of suspension	Polysorbate 80,20
7.	Cation chelating agent Forms	chelate with ions present in the formulation and increases the stability	Disodium EDTA
8.	Suspending Agents	Increases viscosity and suspendability of suspension	CMC, Na CMC
9.	Co-Solvent	Helps to improve solubility	Alcohol, PEG 400, Propylene Glycol
10.	umactant	Used to maintain humidification in the formulation	Glycerin