NASAL AND PULMONARY

DRUG DELIVERY SYSTEM

 NASAL DRUG DELIVERY SYSTEM

Introduction.
• in ancient times the Indian Ayurvedic system of medicine used
nasal route for administration of drug and process is called as
Nasya
• convenient and reliable route, for local and systemic
administration of drugs
• The nasal cavity is an easily accessible
• It offers lower doses, more rapid attainment of therapeutic
blood levels, quicker onset of pharmacological activity fewer
side effects, high total blood flow.
 ADVANTAGES
• Large nasal mucosal surface area for dose absorption
• Rapid drug absorption via highly-vascularized mucosa
• Rapid onset of action
• Ease of administration, non-invasive
• Avoidance of the gastrointestinal tract and first- pass
metabolism
• Improved bioavailability
• Lower dose/ reduced side effects
• improved convenience and compliance
• Self-administration.
 DISADVANTAGES

• Pathologic conditions such as cold or allergies may alter

significantly the nasal bioavailability.
• 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.
 ANATOMY & PHYSIOLOGY OF
NASAL CAVITY
• the nasal cavity consists of passage of a depth of approximately
12-14cm
• The nasal cavity consists three main regions:
1) Nasal vestibule
2) Respiratory region
• major drug absorption.
• 15-20 % of the respiratory cells covered by layer of long cilia size
2-4 μm.
3) Olfactory region
• small area in the roof of the nasal cavity of about 10 cm2
• drug is exposed to neurons thus facilitate it across the cerebro-
spinal fluid.
• Normal pH of the nasal secretions in adult is 5.5- 6.5.
• Infants and young children is 5.0- 6.7.
• Nasal cavity is covered with a mucous membrane. Mucus
secretion is composed of 95%- water,2%-mucin,1%-salts,1%-
of other proteins such as albumin, lysozyme and lactoferrin and
1%-lipids.
MECHANISM OF DRUG ABSORPTION
• Paracellular (intercellular):
Slow and passive absorption of
peptides and proteins associated
with intercellular spaces and
tight junctions.
• Transcellular : Transport of
lipophilic drugs passive
diffusion/active transport.
• Transcytotic: Particle is taken
into a vesicle and transferred to
the cell.
 FACTORS AFFECTING NASAL
ABSORPTION
1. Molecular weight :-
• The nasal absorption of drugs decreases as the molecular
weight increases.
• reported a sharp decline in drug absorption having molecular
weight greater than 1000 daltons.
2. Lipophilicity :-
• Absorption of drug through nasal route is dependent on the
lipophilicity of drugs.
• E.g. Alprenolol and Propranolol which are lipophilic, has
greater absorption than that of hydrophilic Metoprolol.
3. pH of solution :-
• pH should be optimum for maximum absorption.
• Nonionised lipophilic form crosses the nasal epithelial barriers
via transcellular route.
• E.g. Decanoic acid shows maximum absorption at pH 4.5.
Beyond this it decreases as solution becomes more acidic or
basic
4. Drug concentration :-
The absorption of drug through nasal route is increased as
concentration is increased.
E.g. 1-tyrosine shows increased absorption at high concentration
in rate.
 ENHANCEMENT IN ABSORPTION
Following approaches used for absorption enhancement :-
Use of absorption enhancers.
• Absorption enhancers work by increasing the rate at which the
drug pass through the nasal mucosa.
• Various enhancers used are surfactants, bile salts, chelaters, fatty
acid salts, phospholipids, cyclodextrins, glycols etc.
Various mechanisms involved in absorption enhancements are:-
• Increased drug solubility
• Decreased mucosal viscosity
• Decrease enzymatic degradation
• Increased paracellular transport
• Increased transcellular transport
Increase in residence time:-
• By increasing the residence time the increase in the higher local
drug concentration in the mucous lining of the nasal mucosa is
obtained.
• Various mucoadhesive polymers like methylcellulose,
carboxymethylcellulose or polyacrylic acid are used for
increasing the residence time.

Use of physiological modifying agents:-

• These agents are vasoactive agents and exert their action by
increasing the nasal blood flow.
• The example of such agents are histamine, leukotrienene D4,
prostaglandin E1 and β- adrenergic agents like isoprenaline and
terbutaline
 NASAL DELIVERY SYSTEMS
• Liquid formulation :-
• These are usually aqueous solutions of the drug. The simplest
way to give a liquid is by nose drops.
• They are simple to develop and manufacture, compared to
solid dosage forms but have a lower microbiological and
chemical stability, requiring the use of various preservatives
Nasal Powder

• This dosage form may be developed if solution and suspension

dosage forms cannot be developed
• absence of preservative and superior stability of the
formulation.
• Local application of drug is another advantage of this system.
Squeezed bottles :-
• These are used for nasal decongestant and work by spraying a
partially atomized jet of liquid into the nasal cavity.
• They give a better absorption of drug by directing the
formulation into the anterior part of the cavity and covering a
large part of nasal mucosa

Nasal Gels
• High-viscosity thickened solutions or suspensions
Advantages:
• reduction of post-nasal drip due to high viscosity
• reduction of taste impact due to reduced swallowing.
• Reduction of irritation by using emollient excipients.
Metered-dose pump system :-
• They can deliver solutions, suspensions or emulsions with a
predetermined volume between 25 to 200 μL, thus offering
deposition over a large area.
• Particle size and dose volume are two important factors for
controlling delivery from metered-dose systems.
• The optimum particle size for deposition in the nasal cavity is
10μm.
• Better absorption is achieved by administering two doses, one
in each nostril, rather than a single large dose
 IN SITU GEL SYSTEM
• In situ gel formation of drug delivery systems can be defined
as a liquid Formulation generating a solid or semisolid
depot after administration.
Importance of in situ gelling system
• The major importance is that the possibility of administering
accurate and reproducible quantities compared to already
formed gel.
• It increases the exposure time of drugs with that of mucus at
the site of absorption
• better bioavailability,
• Increases patient compliance
Applications of nasal drug delivery.
A. Nasal delivery of organic based pharmaceuticals :-
• Various organic based pharmaceuticals have been investigated
for nasal delivery which includes drug with extensive
presystemic metabolism.
• E.g. Progesterone, Estradiol, Nitroglycerin, Propranolol, etc.

B. Nasal delivery of peptide based drugs :-

• Nasal delivery of peptides and proteins is depend on –
• The structure and size of the molecule.
• Nasal residence time
• E.g. calcitonin, secretin, albumins, insulin, glucagon
PULMONARY DRUG
DELIVERY SYSTEM.
 DELIVERY SYSTEMS

• Aerosols are used for the delivery of the drug by this route of
administration.
• The aerosols are defined as pressurized dosage from
containing one or more active ingredients, which upon
actuation emit a fine dispersion of liquid or solid materials in
gaseous medium.
• There are three commonly used clinical aerosols:
1. Metered–dose Inhaler (MDI)
2. dry-powder inhaler (DPI)
3. Jet or ultrasonic nebulizers,

• The basic function of these three completely different devices

is to generate a drug-containing aerosol cloud that contains the
highest possible fraction of particles in the desired size range.
 PRESSURIZED METERED DOSE
INHALERS
• Drug is either dissolved or suspended in liquid propellants
together with other excipients and presented in pressurized
container fitted with metering valve.
• The predetermined dose is released as a spray on actuation of the
metering valve.
Containers:-
• Aerosol container must withstand pressure as high as 140-180
psig at 130°F.
• Pharmaceutical aerosols are packaged in tin- plated steel, plastic
coated glass or aluminum containers.
• Aluminum is relatively inert and used uncoated where there is no
chemical instability between containers and contents.
Propellants:-
• These are liquefied gases like chlorofluorocarbons and
hydrofluoroalkanes.
• These develop proper pressure within the container & it expels
the product when valve is opened.
• At room temperature and pressure, these are gases but they are
readily liquefied by decreasing the temperature or increasing
pressure.
Metering valves:-
• It permits the reproducible delivery of small volumes of
product.
• Depression of the valve stem allows the contents of the
metering chamber to be discharged through the orifice in the
valve stem and made available to the patient.
• After actuation the metering chamber refills with liquid from
the bulk and is ready to dispense the next dose.
Advantages of MDI
• 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 of MDI
• 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
 DRY POWDER INHALERS(DPI)
• DPIs are drug delivery devices that contain solid drug in a dry
powder mix (DPI) that is fluidized when the patient inhales.
• 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 formulation problems.

Single dose powder inhalers

• These are devices in which a powder containing capsule is placed
in a holder. The capsule is opened within the device and the
powder is inhaled.
• Ex: rotahaler.
Multidose Devices
• This device is truly a metered-dose powder delivery system. The
drug is contained within a storage reservoir and can be dispensed
into the dosing chamber by a simple back and forth twisting
action on the base of the unit.
• Ex: turbohaler.
 NEBULIZERS

• It delivers relatively large volume of drug solutions and

suspensions.
• They are used for drugs that cannot be formulated into pMDI’s
or DPI’s.
• There are three categories :-
• Jet nebulizers.
• Ultrasonic nebulizers.
• Vibrating-mesh nebulizers
1. jet nebulizers:-
• They are also called as air-jet or air-blast nebulizers using
compressed gas.
• The jet of high velocity gas is passed tangentially through a
narrow venture nozzle typically 0.3 to 0.7 mm in diameter.
• e.g. Pari LC nebulizer.

[Link] nebulizers:-
• In this the energy necessary to atomize liquids come from the
piezoelectric crystal vibrating at high frequency.

[Link]-mesh nebulizers:-
• In this device aerosols are generated by passing liquids through a
vibrating mesh or plate with multiple apertures.
 APPLICATIONS
• Asthma ex: ephinephrine.
• Pulmonary infections. Ex: ribavarin.
• COPD. Ex: salbutamol
• Cardiovascular diseases. Ex: furosemide
• Lung cancer ex: interferon
• Cystic fibrosis. Ex: ivacaftor
• Diabetes. Ex: insulin
• Vaccine delivery. Ex: para-influenza type 2 vaccine
• Diagnostic ex: 99m Tc-DTPA
Advantages
• Smaller doses can be administered locally.
• Reduce the potential incidence of adverse systemic effect.
• It used when a drug is poorly absorbed orally, e.g. Na
cromoglicate.
• It is used when drug is rapidly metabolized orally, e.g.
isoprenaline