UNIT 3

NASOPULMONARY DDS

MANSI
DAMANI
CONTENT:

• Introduction to Nasal and Pulmonary routes of drug delivery,

• Formulation of Inhalers (dry powder and metered dose),

• nasal sprays,

• nebulizers.

BOOKS:

• NK Jain-Advances in controlled and novel drug delivery; Introduction to NDDS

• SP Vyas

• Reviews/research papers
INTRODUTION TO NASAL AND PULMONARY ROUTES OF DRUG DELIVERY
 ADVANTAGES

NASAL ROUTE PULMONARY ROUTE

• Non-invasive method for delivering drug into blood
• Non-invasive
stream that require IV injection
• Easy and convenient
• Macromolecules like proteins and peptides can be
• Self administration possible
administered- insulin for diabetes
• Large surface area
• Drug targeting to lungs especially for conditions like
• Rich vasculature
bronchitis, asthma, emphysema
• Rapid onset of action
• Rapid onset better than Oral delivery or SC
• Favourable metabolic environment
• Rapid deposition in lungs, hence high doses cannot
• Rate and extent of drug absorption in plasma similar
be needed
to IV administration
• Helps avoid GI tract problems such as poor solubility,
• No hepatic first pass metabolism
gut irritation, low BA, food effects, variation in doses
• Lesser systemic side effects
• Lower systemic exposure
• Simple formulations can also penetrate nasal mucosa
• Relatively safer in asthmatics and diabetics because
• Macromolecules like proteins and peptides can be
they require longer treatments and hence unwanted
administered
exposure of drug to other organs is prevented
 DISADVANTAGES
• Limited drug absorption because of presence of mucus layer; drug-mucus interaction
• Muco-ciliary clearance
• Short residence time
• Nasal irritation
• Difficulty in delivering accurate dose
• Efficient absorption of slowly absorbed drugs difficult- since lungs remove particles by efflux transport
• Difficult administration in very young or elderly
• Chances of immunologic reaction
• Inadequate availability of toxicity data for penetration enhancers
• Nasal pathology may affect effective absorption
• Physiological variations in individuals- respiratory maneuver; device or formulation variables- such variations unacceptable
for very potent drugs
• Oro-pharyngeal deposition can give local side effects
• Some patients may not be able to use devices correctly
 Optimum aerosol particle size 1-5micron for
deep lung delivery; too small particles exhaled
Low efficiency fast; too large will affect oropharynx and
of inhalation larynx
system

Amount of drug per puff is too less

Problem in device/ need Improper
dosing Less drug mass
for patient education
reproducibility CHALLENGES per puff

Poor
Stability in liquid state; moisture sensitive formulation
stability
 MECHANISM OF NASAL ABSORPTION

AQUEOUS DRUGS
It involves an aqueous route of transport,
which is also known as the paracellular
route but slow and passive. There is an
inverse log-log correlation between
intranasal absorption and the molecular
weight of water-soluble com-pounds. The
molecular weight greater than 1000
Daltons having drugs shows poor
bioavailability.
LIPOPHILIC DRUGS
It involves transport through a lipoidal route
and it is also known as the transcellular
process. It is responsible for the transport of
lipophilic drugs that show a rate dependency
on their lipophilicity. Drug also cross cell
membranes by an active transport route via
carrier-mediated means or transport through
the opening of tight junctions for examples:
chitosan, a natural biopolymer from shellfish,
opens tight junctions between epithelial cells
to facilitate drug transport.
 PATHWAYS FOR NASAL ABSORPTION

 Olfactory epithelium- portal for CNS and PNS circulation of drugs

 Nasopharynx- for viruses that cause common cold, measles
 Nasal mucosa- drugs with poor oral absorption like insulin and those which undergo extensive hepatic first pass
metabolism like propranolol
 Transport through nasal membrane- involves diffusion of drugs

Some examples for potential pathways of nasal absorption:

• Bacteria like E.coli gain entry : nasal mucosa-lymphatics- blood
• Dopamine: nasal mucosa- CSF and serum
• Progesterone: nasal membrane- olfactory dendrites-nervous system- olfactory mucosa- submucosal blood
vascular system- CSF
• Penicillin: nasal membrane- blood stream
• Vccinia virus: nasal mucosa- submucous lymphatics-cervical lymphatic pathway- CNS
 FACTORS INFLUENCING PK AND BA OF DRUGS FOLLOWING NASAL ABSORPTION
1) Physiological factors
• Speed of mucus flow
• Pathological condition of nasal
cavity/ presence of infection
• Change in physiological state
• Membrane permeability
• Muco-ciliary clearance
• Cold, rhinitis.
• Blood flow
2) Dosage form factors 3) Administration factors
• Concentration of active drug • Volume administered/ size of
• Physicochemical properties of droplet
active drug • Site of deposition
o Molecular size. • Mechanical loss into oesophagus
o Lipophilic-hydrophilic balance. • Mechanical loss to other regions in
o Enzymatic degradation in nasal nose
cavity. • Mechanical loss anteriorly from
o Stability nose
o Solubility
o Physical state of drug
o Chemical state of drug
• Physicochemical properties of
excipients
• Density, pH, viscosity, molarity of
formulation
• Toxicity of dosage form
Particles with size more than
20 µm – directly exhaled out
with the air from nasal cavity
Particles with size 10-20 µm

Particles with size 5 -10 µm

Particles with size 1-5 µm or

less then 1 µm
FORMULATION OF INHALERS (DRY POWDER AND METERED DOSE)
METERED DOSE INHALERS
• Fluticasone propionate (Flexotide mite-
GSK)
• Flunisolide (Nisolid- Master Pharma) .
• Salbutamol (Ventolin- Glaxo Welcome).
• Formoterol (Foradil –Novartis)
• Ipratropium bromide( Atem –Chies).
 METERED DOSE INHALERS
• A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a
short burst of aerosolized medicine that is inhaled by the patient.
• It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and
other respiratory diseases.
• In MDIs, micronized drug is either dissolved/ suspended in liquid propellant with other excipients like surfactants and
filled in pressurized canisters that are fitted with metering valve.
• On actuation of metering valve, a predetermined amount of dose is released.
• When released from canister, the formulation undergoes volume expansion in the passage within the valve and forms
a mix of gas and liquid before discharge from orifice.
 ADVANTAGES OF MDI DISADVANTAGES OF MDI

•Site Specific Drug delivery •Proper Breathing co-ordination is needed

•Metered Dose delivered (Dose accuracy) for proper delivery of contents
• Reduced drug loss •Possible dosing error
• Formulation not in direct contact with •Therapy cannot be terminated
outer environment •Difficult to deliver high dose
•Tamper Proof •Potential source of contamination or
•Easy to use (Patient friendly) infections
•No drug preparation is needed •Accessory devices decreases portability
•Portable
•Usually inexpensive as compared to Dry
Powder inhaler (DPI) and Nebulizer
•Multi dose capacity
•Remaining dose remains intact after each
use
 A typical MDI unit consists of:

FORMULATION SURFACTANT METERING VALVE

PROPELLANT CONTAINER ACTUATOR AND INHALATION AID

FORMULATION
 PROPELLANT

The main purpose of the propellant, is to provide the energy to propel the drug from the valve in the form of droplets,
which rapidly evaporate to leave the drug particles.

Hydrocarbon Propellants
(Most Common)

Advantages-
• Inexpensive
• Minimal ozone depletion
• Negligible “Green house effect”
• Excellent solvent

Disadvantages-
• Flammable
• Aftertaste
• Unknown toxicity data
• Low liquid density
Chlorofluorocarbons
(Used in Inhalation Aerosols)

Advantages:
Low inhalation toxicity
High chemical stability
High Purity
CFC-11 is a good solvent

Disadvantages:
Destructive to atmospheric ozone
Contribute to “Greenhouse effect”
High cost

CFCs are implicated in the destruction of the ozone layer due to a reaction between the ozone and the chlorine radical
(Consequently the production and use of CFCs have been banned
Hydrofluoroalkanes

Advantages:
Low inhalation toxicity
High Chemical Stability
High Purity
No ozone depletion

Disadvantages:
Poor solvent
Minor “Green house effect”
High Cost

HFA 227 and HFA 134a are very poor solvents; hence the existing CFC surfactants/valve lubricants are not soluble in the
HFAs. If any new surfactant is to be used it should have e adequate drug safety data.
Compressed gases

Advantages:
Low inhalation toxicity
High Chemical Stability
High Purity
Inexpensive
No environmental problem

Disadvantages:
Require use of non-volatile co-solvent
Produce coarse droplet spray
Pressure falls during use
 SURFACTANT

Cationic Zwitterionic
Anionic Nonionic
eg. Cetylpyridinum eg.
eg. Oleic acid Phosphatidylcholine eg. Sorbitan trioleate
chloride

Function of surfactant
• Valve lubrication
• Aid homogeneous distribution
• Maintain stability of “foaming” aerosols
• Emulsify propellant & aqueous phase
• Enhance dissolution of medicament in propellant or solvent system.
 CONTAINER

• Chemically inert with good mechanical strength

• Should be able to withstand internal pressure

• Aluminum /plastic-coated glass (experimental work where direct observation of the contents is required).

• Stainless steel (expensive for production).

• Drug particles in HFA suspensions have a much greater tendency to stick to the can walls than in CFC systems

• In that case Al aluminum to be coated with a polymer, usually a fluoropolymer / Teflon / Silicon can be used
 METERING VALVE
The primary function- reproducible delivery of a fraction of liquid phase of
formulation.
Forms a seal over canister; thus acts as barrier to external environment and
also prevents loss of pressurized contents
Generally the amount of dose dispensed per actuator- 25 to 100 ul
Typically a valve can be actuated 200 times during product lifetime
The metering valve in MDI is in inverted position as compared to other
conventional aerosolized products

How does it work?

Depression of valve----contents of metering chamber discharged through

orifice----stem valve----patient

What are its part made up of?

Valve body- acetal, polyester

Valve stem- acetal, stainless steel
Ferrule- anodised aluminium
Seals and gasket- butyl, nitrile or neoprene
Actuator- polyethylene or polypropylene
 ACTUATOR AND INHALATION AID

Actuators:
The actuator is the means by which the valve stem in the metering chamber is depressed and the subject can inhale the
dose by cupping their lips around the mouthpiece.
It permits actuation off the valve, provides an orifice through which the spray is discharged

The depression of valve generates an aerosol cloud that is dependent on various parameters like:
• Geometric size of active drug especially in case of suspension type
• Volume of metering chamber
• Diameter of jet orifice in mouth piece
• Vapour pressure ( propellant ratio) of formulation

Large orifices with large volume metering valves permit administration of concentrated suspensions with reduced
tendency of blockage
Inhalation aids/ Spacers:

Children have difficulty synchronising the actuation and inhalation for effective use of MDI
Therefore spacers are used which is kept in between the mouthpiece of MDI and patient mouth. It assists patient in co-
ordination by allowing them to actuate in the reservoir and subsequently the resulting cloud can be inhaled.

Spacers operate through various mechanism:

• Provide delay before inhalation so that propellant evaporates thus permitting particles to reach minimum size
• Slow done particle velocity; hence the impact to oropharynx is reduced
• Helps increase inhalation time by the patient
DRY POWDER INHALERS
 DRY POWDER INHALERS
 Dispenses powder in a stream of inspired air/as aerosol.
 Drug is inhaled as mist of fine particles
 Drug is preloaded in device or in soft gelatin capsules or blister discs
 Environmentally friendly because no CFC/propellants
 Versatile because they are patient-breath actuated (passive DPI) or by component in DPI device like impeller or vibrator
(active DPI) and no co-ordination between actuation and inhalation required

Advantages over MDI:

• No propellant
• No other excipient except carrier
• Useful for children
• Can deliver larger dose of drug

Challenges:
• Powder should be effectively be deaggregated; if inspiratory flow rate is too high; higher impaction with oropharynx
• High inspiratory flow rate which is difficult in asthmatics/infants; cumbersome to load capsule in device under attack
• Coughing may occur with certain compounds
• Unpleasant taste of bronchodilators
• Efficacy of passive DPI depend on inspiratory flow rate of patient
• Elevated humidity-powder particles may clump
• Less efficient than MDI since twice dose is required for delivery from DPI as compared to MDI
All DPIs have 4 basic features:
• Dose metering mechanism
• Aerosolization mechanism
• Deaggregation mechanism
• Adaptor to direct aerosol to patients mouth

To introduce the drug particle inside the lungs, the aerodynamic diameter of particles should be less than 5 microns
But small particles are difficult to dispense.
One approach is to take lactose as carrier. Particle size of lactose is 60-80 microns.
Drug particles are theoretically stripped from the surface of lactose particles, to which they are loosely attached during
generation process.
Two types: SINGLE DOSE/UNIT DOSE and MULTI DOSE

SINGLE DOSE DPI

Marketed: Spinhaler®, Rotahaler®, Aerhaler®, Cyclohaler® and Chiesi®

These basically require patient to put a dose manually into apparatus prior inhalation

In Spinhaler®, drug+carrier (to facilitate pwder flow) mix –loaded in hard gelatin capsule—device—on activation—capsule
is pierced—drug dispensed—inhaled by patient

Rotahaler®-drug in HGC- device-broken open- powder inhaled through tube

Spinhaler® Rotahaler®
MULTI DOSE DPI

1) Diskhaler®, Diskus®- contain multi-dose blister packs coiled inside inhaler that are to be punctured immediately before
inhalation

Diskhaler®-circular disk with 8 powder charges in separate Aluminium blisters- when the device is primed, blisters are
pierced and all contents dispensed in dosing chambers

2) Turbohaler®, Easyhaler®, Pulvinal®, Clickhaler®- all doses in bulk powder reservoir from which dose is made available by
adjusting the device prior to inhalation

Turbohaler®- drug is in the storage reservoir- drug dispensed in dosing chamber by simple back and forth twisting of base
of the device.
No need of carrier; can deliver particles at low flow rate
 FORMULATION CONSIDERATIONS FOR DPI
The performance of DPI is dependent on three things:
• Drug
• Carrier
• Design of device

Desirable properties of drug for DPI:

• micronized or microcrystalline;
• small particle size less than 5 microns,
• good aerodynamic properties,
• good flow

But interparticle forces make the powder to deaggregated and hence carrier is needed. Lactose is generally used.
Carrier also used as bulking agents since potent drugs are required in very small amount
Typically used ratio is 100:1 (lactose: drug)

These powders (drug+carrier) are incorporated in HGC- but these capsules tend to absorb moisture; hence add dessicant

Spray dried particles show better aerodynamic properties

How to work with hygroscopic powders?

Coat the hygroscopic powder with layer of hydrophobic material like caproic acid or lauric acid
But care should be taken- particle adhesion may take place
Pulmospheres for DPI
• Recent development
• Readily deaggregated with little energy, they have low density hence easily remain airborne and maintain their velocity
as compared to similar sized particles of higher density-better aerodynamics- better lung penetration
• These particles also have less interparticulate force-hence no carrier required
• Good flowability- hence larger doses can be delivered per actuation

PulmoSphere particles are manufactured by an emulsion-based spray-drying process, designed to create porous
particles with a sponge-like morphology

Scanning electron microscope images of: (a) typical micronized drug

particles, (b) TIP particles, and (c) TIP particle (closeup).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146747/
 NEBULIZER
• Devices that convert aqueous solutions or micronized suspensions of
drug into aerosol for inhalation.
• Can be used to deliver relatively larger amount of drug solution and
suspension; for larger therapeutic dose
• Can deliver drugs that cannot be formulated conveniently into MDI/DPI
• Advantage over DPI/MDI is that drug can be inhaled during normal tidal
breathing through a face mask or mouthpiece and hence can be used for
children, elderly and patients with arthritis.
• Can be used for patients having problems with co-ordination or dexterity
• Traditional nebulizers are not very portable.
 FORMULATION CONSIDERATIONS FOR NEBULIZERS

 Largely solutions; suspensions can also be used. But concentration of suspension is a major concern.
 Generally water is used as vehicle.
 But co-solvents can be used- ethanol, glycerine, PG
 Osmotic agents- to prevent bronchoconstriction due to hyper/hypo-osmosis
 pH of nebulizer solution should be more than 5
 If drug is in powder form, saline is added for reconstitution
 In US, nebulization solution are made in sterile conditions; hence, no preservatives
 If needed preservatives can be added after checking toxicity; BKC is used
 Important physicochemical considerations:
• Solubility- wrt to pH, ionic strength, buffer level, co-solvent level.
• Isoelectric pH for proteins and peptides
• Log P
• pKa
Nebulizers are specialized atomizers.
General aerosols by :
1) High velocity air steam dispersion/jet nebulizers

2) Ultrasonic energy dispersion

 AIR JET NEBULIZER
The operation of air jet nebulizer requires external gas supply of compressed gas or oxygen. This gas supply is driving force for
atomization.
Respiratory solution and suspensions are placed in reservoir
Dose is generally 1-3 ml; dead volume of 0.5-2ml have been reported.

Working:
Compressed gas is expelled through an orifice with high velocity generating negative pressure. This low pressure along with
capillary action causes solution to travel up and get entrained with compressed gas and forms a liquid film
Since the film is unstable; it forms droplets
Larger droplets are impacted by baffles and return back to reservoir to be recirculated.
Smaller droplets (1-10 microns) escape the baffles into the mouthpiece.
The major operating variable is the rate of air flow.
Air jets are single use and multi-use types.
• Single use- convenient
• Multi use- cost effective but require thorough cleaning
 ULTRASONIC NEBULIZER
No supply of external gas required; battery or electricity operated
Respiratory solution or suspension is atomized by means of piezoelectric crystal transducer
An alternating current causes crystal to shrink and expand causing a vibration that is amplified by stainless steel shim
Two mechanisms to explain how oscillating waves travelling through bulk liquid forms aerosol cloud:
1) Formation of cavitation bubbles at low frequency
2) Capillary wave formation at high frequency
 NASAL SPRAY
• Most of the pharmaceutical nasal preparations on the market containing solutions,
emulsions or suspensions are delivered by metered-dose pump sprays.
• Nasal sprays, or nasal mists, are used for the nasal delivery of a drug or drugs, either
locally to generally alleviate 25 cold or allergy symptoms such as nasal congestion or
systemically, see nasal administration.
• Although delivery methods vary, most nasal sprays function by instilling a fine mist into
the nostril by action of a hand-operated pump mechanism.
• The three main types available for local effect are: antihistamines, corticosteroids, and
topical decongestants
• Nasal sprays include the container, the pump with the valve and the actuator.
• The dose accuracy of pump sprays is dependent on the surface tension and viscosity of
the formulation.
• For solutions with higher viscosity, special pump and valve combinations are on the
market.
 Excipients Used in Nasal Spray Formulations

BUFFERS SOLUBILISERS PRESERVATIVES ANTI-OXIDANTS SURFACTANT HUMECTANT BIOADHESIVE PENETRATION

POLYMERS ENHANCERS
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 and citric acid.

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-ß-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.

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.
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.

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.

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 (tweens) and Sorbitans (Spans)
Bio adhesive polymers:
• Compound that is capable of interacting with biological material through interfacial forces and being retained on such
material for prolonged periods 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.

Penetration enhancer:
Chemical penetration enhancers are widely used in the nasal drug delivery.
 Characterization of Nasal Spray
pH
Viscosity

Osmolality
Impurities and Degradation Products Assay
Pump Delivery and Spray Content Uniformity (SCU) Droplet Size Distribution

Spray Pattern and Plume Geometry Particle Size Distribution

How to Use a Metered-Dose Inhaler
https://www.youtube.com/watch?v=gFGM-8X98zs

How to Use a Metered Dose Inhaler with a Spacer

https://www.youtube.com/watch?v=cjyf7lWnEBI

Asthma how-to: How to use a Dry Powder Inhaler

https://www.youtube.com/watch?v=bxC48vQEfZI

How to Properly Use a Nebulizer

https://www.youtube.com/watch?v=pEKFKZiLNaA