Naso-pulmonary Drug Delivery System ....

NASAL DRUG DELIVERY SYSTEM
Department of Pharmaceutics

● In ancient times the Indian Ayurvedic system of medicines used nasal route for
administration of drug and the process is called as “Nasya”
● Intranasal drug delivery is now recognized to be a useful and reliable alternative to
oral and parenteral routes. Undoubtedly, the intranasal administration of medicines
for the symptomatic relief and prevention or treatment of topical nasal conditions has
been widely used for a long period of time.
● However, recently, the nasal mucosa has seriously emerged as a therapeutically viable
route for the systemic drug delivery.
● In general, among the primary targets for intranasal administration are
pharmacologically active compounds with poor stability in gastrointestinal fluids,
poor intestinal absorption and/or extensive hepatic first-pass elimination, such as
peptides, proteins and polar drugs.
Advantages:
● Hepatic first pass metabolism avoided.
● Rapid drug absorption and quick onset of action.
● Bioavailability of larger drug molecules can be improved by means of absorption
enhancer. Department of Pharmaceutics
Nasopulmonary drug delivery system

● Bioavailability for smaller drug molecules is good.
● Convenient for long term therapy, compared to parenteral medication.
● Drugs possessing poor stability in G.I.T fluids can be given by nasal route.
● Easy and convenient.
● Easily administered to unconscious patients.
Disadvantages:
• Pathologic conditions such as cold or allergies may alter significantly the nasal
bioavailability.
• The histological toxicity of absorption enhancers used in nasal drug delivery
system is not yet clearly established.
• Relatively inconvenient to patients when compared to oral delivery systems
since there is a possibility of nasal irritation.
• Nasal cavity provides smaller absorption surface area when compared to GIT.

Cross-sectional view
a – nasal vestibule
b – palate
c – inferior turbinate
d – middle turbinate
e – superior turbinate (olfactory mucosa)
f – nasopharynx

PATHWAYS FOR NASAL ABSORPTION
 Absorption through the olfactory neurons, transneuronal absorption. Olfactory
epithelium is considered as a portal for substances to enter CNS.
 Absorption through the supporting cells & the surrounding capillary bed.
 Venous drainage: a rich venous plexus is found under the mucous membrane
which is drained by veins accompanying the arteries.
 Absorption into the cerebrospinal fluid.
Site of drug spray &
absorption

NOSE BRAIN PATHWAY:
• The olfactory mucosa (smelling area in nose) is in direct contact with the brain
and CSF.
• Medications absorbed across the olfactory mucosa directly enter the brain.
• This area is termed the nose brain pathway and offers a rapid, direct route for drug
delivery to the brain.
Olfactory
mucosa
Highly vascular
nasal mucosa
Brain
CSF

Nasal pH
• Nasal secretion of adult : 5.5-6.5
• Infants and children: 5-6.7
• It becomes alkaline in conditions such as acute rhinitis, acute sinusitis.
• Lysozyme in the nasal secretion helps as antibacterial and its activity is
diminished in alkaline pH.
MECHANISM OF DRUG ABSORPTION:
• The first step in the absorption of drug from the nasal cavity is passage
through the mucus . Small, unchanged particles easily pass through this layer.
However, large or charged particles may find it more difficult to cross.
• Mucin, the principle protein in the mucus, has the potential to bind to solutes,
hindering diffusion.
• Structural changes in the mucus layer are possible as a result of environmental
changes (i.e. pH, température, etc.)subsequent to a drug’s passage through the
mucus.

• There are several mechanisms for absorption through the mucosa. These
include transcellular or simple diffusion across the membrane, paracellular
transport via movement between cell and transcytosis by vesicle carriers.
• Drug absorption are potential metabolism before reaching the systemic
circulation and limited residence time in the cavity.
Following mechanisms have been proposed :
1) The first mechanism involves an aqueous route of transport which is also
known as the paracellular route. This route is slow and passive. There is an
inverse log-log correlation between intranasal absorption and the molecular
weight of water-soluble compounds. Poor bioavailability was observed for
drugs with a molecular weight greater than 1000 Daltons.
2) The second mechanism involves transport through a lipoidal route that is
also known as the transcellular process and is responsible for the transport of
lipophilic drugs that show a rate dependency on their lipophilicity. Drugs
also cross cell membranes by an active transport route via carrier-mediated
means or transport through the opening of tight junctions.

FACTORS INFLUENCING NASAL DRUG ABSORPTION
 Factors Related to Drug
a) Lipophilicity: On increasing lipophilicity, the permeation of the compound
normally increases through nasal mucosa because of high lipophilicity though it has
some hydrophilic character for some drugs.eg: alprenolol and propranolol.
b) Chemical Form: Conversion of the drug into a salt or ester form can alter its
absorption. eg: In-situ nasal absorption of carboxylic acid esters of L-Tyrosine was
significantly greater than that of L-Tyrosine.
c) Polymorphism: Polymorphism is known to affect the dissolution rate and
solubility of drugs and as well as their absorption through biological membranes. It is
therefore advisable to study the polymorphic stability and purity of drugs for nasal
powders or suspensions.
d) Molecular Weight: The permeation of drugs less than 300Da is not significantly
influenced by the physicochemical properties of the drug, which will mostly
permeate through aqueous channels of the membrane. By contrast, the rate of
permeation is highly sensitive to molecular size for compounds with MW = >300 Da.

e) Partition Coefficient and pKa: As per the pH partition theory, unionized species
are absorbed better compared with ionized species and the same holds true in the
case of nasal absorption. The nasal absorption of weak electrolytes such as salicylic
acid and amino-pyrine was found to be highly dependent on their degree of
ionization. Although for amino-pyrine, the absorption rate increased with the increase
in pH.
f) Solubility & Dissolution Rate: Drug solubility and dissolution rates are important
factors in determining nasal absorption from powders and suspensions. The particles
deposited in the nasal cavity need to be dissolved prior to absorption. If a drug
remains as particles, no absorption takes place.
 Factors Related to Formulation
a) pH and Mucosal Irritancy: The pH of the formulation, as well as that of nasal
surface, can affect a drug’s permeation. To avoid nasal irritation, the pH of the nasal
formulation should be adjusted to 4.5–6.5 .

b) Osmolality: Because of the effect of osmolality on the absorption, isotonic
solutions are usually preferred for administration for shrinkage of the nasal epithelial
mucosa.
c) Viscosity: A higher viscosity of the formulation increases contact time between the
drug and the nasal mucosa there by increasing the time for permeation. At the same
time, highly viscous formulations interfere with the normal functions like ciliary
beating or mucociliary clearance and thus alter the permeability of drugs.

PULMONARY DRUG DELIVERY
SYSTEM

 The respiratory tract is one of the oldest routes used for the administration of
drugs. Over the past decades inhalation therapy has established itself as a valuable
tool in the local therapy of pulmonary diseases such as asthma or COPD (Chronic
Obstructive Pulmonary Disease).
 The drug used for asthma and COPD e.g..- β2-agonists such as salbutamol
(albuterol), corticosteroids such as budesonide, beclomethasone and mast-cell
stabilizers such as sodium cromoglycate.
 The latest and probably one of the most promising applications of pulmonary drug
administration is
• Its use to achieve systemic absorption of the administered drug substances.
• Particularly for those drug substances that exhibit a poor bioavailability when
administered by the oral route, as for example peptides or proteins, the
respiratory tract might be a convenient port of entry.

Advantages:
• The dose needed to produce a pharmacological effect can be reduced.
• Low concentrations in the systemic circulation are associated with reduced
systemic side-effects.
• Rapid onset of action.
• Avoidance of gastrointestinal upset.
• Avoidance of intestinal and hepatic first-pass metabolism.
Disadvantages:
• Complex delivery devices are required to target drugs to the airways.
• Aerosol devices can be difficult to use.
• Various factors affect the reproducibility of drug delivery to the lungs, including
physiological (respiratory maneuver) and pharmaceutical (device, formulation)
variables.
• Drug absorption may be limited by the physical barrier of the mucus layer and the
interactions of drugs with mucus.
• Mucociliary clearance reduces the retention time of drugs within the lungs. Efficient
drug delivery of slowly absorbed drugs must overcome the ability of the lung to
remove drug particles by mucociliary transport.

Mechanism of drug absorption:
 Drug diffusion through alveoli.
 Absorption by carrier mediated transport.
 Phagocytosis of insoluble particles allow absorption of compounds with low
lipophilicity &/or high molecular weight.
The human respiratory system is a complicated organ system of very close structure–
function relationships. The system consisted of two regions:
• The conducting airway: The conducting airway is further divided into many
folds: nasal cavity and the associated sinuses, and the nasopharynx, oropharynx,
larynx, trachea, bronchi, and bronchioles.
• The respiratory region: The respiratory region consists of respiratory
bronchioles, alveolar ducts, and alveolar sacs.
The human respiratory tract is a branching system
of air channels with approximately 23 bifurcations from the mouth to the alveoli. The
major task of the lungs is gas exchange, by adding oxygen to, and removing carbon
dioxide from the blood passing the pulmonary capillary bed.

Lung region
1.Nasopharynx region (NP)
2.Tracheobronchial region: (TB)
3.Alveolar region: (AV)
Anatomy and physiology of lungs

MECHANISMS OF PARTICLE DEPOSITION IN THE AIRWAYS
1) Inertial impaction: This is the main deposition mechanism for particles >1 μm in
the upper tracheo-bronchial regions. A particle having a large momentum may
not able to follow the altering direction of the inspired air as it transferred the
bifurcations and it will show result to collide with the airway walls as it continues
on its original course.
2) Sedimentation:- By the settling under gravity the particles may deposited. It
becomes highly important for particles that reach airways where the airstream
velocity is relatively low, e.g. the bronchioles and alveolar region.
3) Brownian diffusion:- This is of minor significance for particles >1 μm. Particles
smaller than this size are displaced by a sequentially bombardment of gas
molecules, which may results in particle collision with the airway walls. The
chances of particle deposition by diffusion increases with the particle size
decreases. Brownian diffusion is also more common in regions where airflow is
very low or absent, e.g. in the alveoli

NASAL SPRAY

 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
non-invasive 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.
 Both solution and suspension formulations can be formulated into nasal sprays.
 Due to the availability of metered dose pumps and actuators, a nasal spray can
deliver an exact dose. The particles size and morphology (for suspensions)of the
drug and viscosity of the formulation determine the choice of pump and actuator
assembly.
Dymista Nasal Spray:

Instruction before use

FORMULATION OF NASAL SPRAY:
 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.
 Nasal sprays are applied to the nasal cavity for local and/or systemic effects.
Although similar in many features to other drug products, some aspects of nasal
sprays may be unique (e.g., formulation, container closure system, manufacturing,
stability, and drug product).
 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 collectively constitute the drug
product.

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.
 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, 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 that serve
as a biocompatible solubilizer and stabilizer in combination with lipophilic
absorption enhancers.
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 increases stability of suspension. Common examples include Polysorbate.
g) Bioadhesive polymers: 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). They improve the contact time of drug on
mucosal surface. Example like chitosan, thiomer.
h) Penetration enhancer: Chemical penetration enhancers are widely used in the
nasal drug delivery. Example like sulphoxides, azones.

INHALERS
Metered Dose Inhalers(MDI) Dry Powder Inhalers (DPI)

Metered Dose Inhalers (MDI)
• Used for treatment of respiratory diseases such as asthma and COPD.
• They can be given in the form of suspension or solution.
• Particle size of less than 5 microns.
• It can be deliver measure amount of medicament accurately.
Advantages:
• It delivers specified amount of dose.
• Small size and convenience.
• Usually inexpensive as compare to dry powder inhalers and
nebulizers.
• Quick to use.
• Multi dose capability more than 100 doses available.
Disadvantages:
• Difficult to deliver high doses.
• There is no information about the number of doses left in the
MDI.
• Accurate co-ordination between actuation of a dose and
inhalation is essential. Department of Pharmaceutics

 These inhalers consist of a canister, actuator and a spacer. The canister is
composed of a metering dose valve with an actuating stem.
 The formulation (API, liquefied gas propellant and a stabilizer) present in the
canister.
 The drug may be suspended or dissolved in the liquefied gas propellant.
 Upon actuating, the metering dose valve is opened which releases a single metered
dose of medication along with the liquefied gas propellant to spray out of a
canister. This process is called ‘Cavitation’.
 The liquefied gas propellant is volatile in
nature, which breaks down into liquid droplets
and evaporates rapidly & the dried micronized
drugs are inhaled to the lung.

Formulation
1. Active Pharmaceutical Ingredient:
• Active pharmaceutical ingredient first checked for preformulation studies and
particle size should be below 10 µm in case of suspension formulation.
2. Propellant:
• The propellant is used to provide the energy to generate a fine aerosol of drug
particles and to expel the concentrate from the container and deliver to lung. The
liquefied compressed gases are mainly used because discharge of aerosol
undergoes evaporation of propellant to give aerosol of very small particles. A
compressed liquefied gas gives consistent pressure throughout the use of content.
• The traditional pMDI propellant has been chlorofluorocarbon (CFC). However,
nowadays CFC has been replaced by hydrofluoroalkane (HFA) due to concern
about the environmental effects of CFCs on the ozone layer which filters
ultraviolet (UV) radiation posing an increased risk of skin disease and global
warming. HFAs do not contain chlorine and thus have no ozone-depleting
potential.

Ideal Properties of Propellant:
• Boiling point should be between -100°C to 30°C.
• Density should be in between 1.2 to 1.5 g/cm2
.
• Vapour pressure 40 to 80 psig.
• Non-flammable, nontoxic, inert and not reactive in formulation.
• It should have acceptable taste, odor and also should be low cost.
• It should be compatible with primary packaging material.
3. Stabilizing Agent:
Surfactants are used to stabilize the suspension formulation. It also helps in
solubilising drug and prevents crystal growth during the storage period. It improves
valve lubrication. Surfactants such as oleic acid, sorbitan trioleate are highly soluble
in CFC but are not soluble in HFAs, therefore co-solvent are used to dissolve these
surfactants in the HFA propellants.

4. Co-solvent:
Surfactants are highly soluble in CFC but are not soluble in HFA, therefore co-solvent
is used to dissolve the surfactants in the HFA propellants. Ethanol is one of the most
commonly used co-solvents in pMDI formulation. It lowers the vapour pressure of
HFA propellants which produce smaller particle and more respirable drug fractions. It
can even increase the solubility of certain APIs which lead to an increased problem of
crystal growth. Also increase in ethanol causes decrease in volatility and vapour
pressure of the formulation inside the container.

Dry powder inhalers (DPI)
• DPIs are typically formulated as one-phase, solid particle blends. The drug with
particle sizes of less than 5µm is used.
• Dry powder formulations either contain the active drug alone or have a carrier
powder (e.g. lactose) mixed with the drug to increase flow properties of drug.
Advantages:
 Propellant-free.
 Less need for patient co-ordination.
 Less formulation problems.
 Dry powders are at a lower energy state, which reduces the rate
of chemical degradation.
Disadvantages:
 Dependency on patient’s inspiratory flow rate and profile.
 Device resistance and other design issues.
 More expensive than pressurized metered dose inhalers.

DPI Formulation Considerations:
• Consist of the API or carrier powder mixed with drug (API).
• Particle size of drug should be < 5 μm.
• The micronization of drug is done by milling, spray drying, and supercritical fluid
extraction.
• Micronized drug particle achieve good aerodynamic properties of the dispersed
powder.
• Improvement in formulation performance by development of tertiary excipients
like magnesium stearate and leucine.
Carriers used in DPIs
 To improve drug particle flow ability, improving dosing accuracy, minimizing the
dose variability.
 To facilitate the easy emission of drug particles from capsules and devices, thereby
increasing the inhalation efficiency.
• Characteristics of carrier particles include physico-chemical stability,
biocompatibility and biodegradability.

• Should be compatible with the drug substance and must be inert, available and
economical.
• Examples of carriers: Lactose, mannitol, glucose, sorbitol, maltitol, and xylitol.
• The addition of large particle sized Lactose monohydrate reduces the cohesive
force of micronized drug particles and form loose agglomerate with micronized
drug particles.
• Upon inhalation the agglomerates get broken down into its constituent particles,
with the help of mechanical device such as screens, on which the particles
agglomerates impact.
• It releases the smaller sized powdered drug particles into the air to be inhaled to
the lung.
• Here the larger sized lactose monohydrate particles are retain or let behind in the
device and in the mouth & throat.

Naso-pulmonary Drug Delivery System ....

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