Download nasal dosage forms and devices for intranasal drug delivery

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Moharil et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Volume 3, Issue 4, 554-571.
Review Article
ISSN 2278 – 4357
NASAL DOSAGE FORMS AND DEVICES FOR INTRANASAL DRUG
DELIVERY
Sumedh Moharil*, Kamlesh Niranjane, Latika Nasare, Anuradha nagdevte,
Nitin Bhople.
Dadasaheb Balpande College of Pharmacy Besa, Nagpur
Article Received on
25 February 2014,
Revised on 16 March
2014,
Accepted on 05 April 2014
*Correspondence for Author
ABSTRACT
Intranasal delivery devices deliver medications directly to the nasal
cavity , where they can be absorbed directly by the appropriate tissues.
Studies have demonstrated that medications against some CNS
disorders can be more efficacious when delivered by the intranasal
Sumedh N. Moharil
route, particularly if these are the routes of infection. In addition, many
Dadasaheb Balpande College
drugs may be delivered by intranasal routes. Advantages of these
of Pharmacy Besa, Nagpur
routes of delivery include targeting the drug to the site of infection or
disease, rapid absorption into the blood stream, and easier, needle-free
delivery. Nasal delivery has a number of compelling advantages over other routes of
administration; namely its non-invasiveness, rapid attainment of therapeutically relevant
concentrations to the bloodstream, no first-pass metabolism, and ease of administration.
Viable nasal delivery technologies have the potential to enable drug developers in creating
innovative medicines using already approved products by delivering them through new routes
of administration.
Keywords-Nasal dosage form, Nasal devices.
INTRODUCTION
1. Powder dosage forms
Dry powders are used in nasal drug delivery due to major advantages of this dosage form are
the lack of preservatives, administration of larger doses of drugs and the improved stability of
the formulation ,do not support microbial growth, and administration of nasal powders may
increase patient compliance, especially if the smell and taste of the delivered drug is
unacceptable . Compared to solutions, the administration of powders could result in a prolonged contact with the nasal mucosa Powder form is suitable for number of non-peptide
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drugs and is well suited for peptide drugs. Polymer-based powder formulations allows easy
application to the nasal cavity by metered dose in sufflation even if the polymer is highly
mucoadhesive. After getting in contact with the nasal mucosa, polymer-based powders by
absorbing water from the nasal mucus willing to form viscous gel. Then, the free polymer
chains penetrating into the tissue crevices can hold back and the retention time of the drugs in
the nasal cavity increased by cilliary movement.
Structure of nasal mucosa
The types of powder dosage forms are described below:
1. Insufflators
Insufflators are the devices to deliver the drug sub-stance for inhalation; it can be constructed
by using a straw or tube which contains the drug substance and sometimes it contains syringe
also.. Many insufflator systems work with pre-dosed powder doses in capsules.

Trimel.-a device developed by a Danish company (Direct Haler) . There are two versions
of this device, One version is intended for pulmonary drug delivery where subjects inhale
through the small tubular device and one for nasal drug delivery where subjects blow into one
end of the tube while the other end is inserted into the vestibule of the nostril. This tubular
device includes a middle section with corrugations. The corrugations allow flexion of the
device and create turbulence that de-agglomerates the powder. The subject then exhales
through the device to expel the powder from the tube and into the nostril. By using rhynal
catherater causes the soft palate to automatically elevate to separate the oral cavity and the
nasal passages, preventing lung inhalation during delivery.
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OptiNose has developed a breath-powered Bi-Directional™ nasal delivery technology
for liquid and powder medications which utilizes the exhaled breath to deliver the drug to the
nose, but with additional key different parts that importantly impact drug deposition and
clearance patterns and clinical device performance.
2. Dry powder inhaler
Dry powder inhalers (DPIs) are devices through which a dry powder formulation of an active
drug is delivered for local or systemic effect via the pulmonary route or intranasal route. Dry
powder inhalers are bolus drug delivery devices that contain solid drug, suspended or
dissolved in a non polar volatile propellant or in dry powder inhaler that is fluidized when the
patient inhales. The medication is commonly held either in a capsule for manual loading or a
proprietary form from inside the inhaler. The dose that can be delivered is typically less than
a few tens of milligrams in a single breath since larger powder doses may lead to provocation
of cough .
3. Dry Powder Inhaler Devices Capsule-based
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Main features
Easy to use design developed with emerging human, factors standards in mind Low
Cost Versatile ,Compact
Storage position
Open tray and insert capsule.
ready for inhaiation
Powder emptying can be confirmed through capsule window which remains open
during inhalation.
Characteristics
Dose type
Dose range
Pressure Drop
Lifetime
Componants
Performance
Patent
Uses
# 3 Capsule
From µg to 50 mg
kPa at 35 L/min. Performance substantially
flow-independent 25 L/min.
30 to 60 capsules (one month’s use)
Three, Plastic
Lactose-based, fine particle fraction: 20 –
50%
Particle engineered, FPF: 50 – 80%
Filed in 2010
Chronic or acute uses
4. Dry Powder Inhaler Devices
TwinCaps
It was developed specifically for high dose, acute and chronic treatments .A very simple
inhaler, suitable for emergency treatments or in situations where minimal usage instructions
or medical supervision are available .It is low cost and is disposable.
Main features
Contains two factory-filled doses in pre-formed cavities
Extremely easy to use
Foil-pouched for moisture protection
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Uptake inhaler
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Inhale first dose
Push the buttone in one direction
Push the dose shuttle
Inhaled second dose
Characters
Dose Type
Dose Range
Pressure Drop
Lifetime
Components
Performance
Patent
Use
Status
Two capsule shaped cavities
From µg to 50 mg
4 kPa at 35 L/min.
Performance substantially
flow-independent 25 L/min.
Single use, disposable
Two, plastic
Lactose-based, fine particle fraction:
20 – 50%
Particle engineered, FPF: 50 – 80%
Filed in 2006 in 45 countries, granted
in almost all.
Acute and short chronic treatments
Available for development and
licensing, except for influenza treatment
5. Nasal powder sprayers

Fit-lizer. capsule-based, single-dose powder devices (When inserted into a chamber, the
top and bottom of the capsule is cut off by sharp blades. A plastic chamber is compressed by
hand, compressed air passes through a one-way valve and the capsule during actuation, and
the powder is emitted.
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Unidose-DP™, is similar to the Fit-lizer device. An air-filled compartment is compressed
until a pin ruptures a membrane to release the pressure to emit the plume of powder. Delivery
of powder formulations of a model antibody (human IgG) has been tested in a nasal cast
model based on human MRI images. Approximately 95 % of the dose was delivered to the
nasal cavity, but the majority of it was deposited no further than the nasal vestibule with only
about 30 % deposited into deeper compartments of the nasal cavity. The company report in
their website that they have entered into a collaboration to develop an undisclosed nasal
powder product with this device.

SoluVent™- a powder device where a positive pressure is created with a plunger that
pierces a membrane to expel the powder. A device based on this technology is being tested
with powder vaccines.

Aptar group (Pfeiffer/Valois) offers a powder device (Monopowder) based on the same
principle as the devices above but with a plunger that when pressed creates a positive
pressure that ruptures a membrane to expel the poswder. The device has been used in studies
in rabbits, but no data from human deposition or clinical studies have been published .

Pressurized MDIs
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
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disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is
most commonly a bronchodilator, corticosteroid or a combination of both for thetreatment of
asthma and COPD. Other medications less commonly used but also administered by MDI are
mast cell stabilizers, such as (cromoglicate or nedocromil).The advantages of MDIs are their
portability and small size, availability over a wide do-sage range per actuation, dose
consistency, dose accu-racy, protection of the contents and that they are quickly ready for
use(Newhouse MT., 1991).
To use the inhaler the patient presses down on the top of the canister, with their thumb
supporting the lower portion of the actuator. The propellant provides the force to generate the
aerosol cloud and is also the medium in which the active component must be suspended or
dissolved. Propellants in MDIs typically make up more than 99 % of the delivered dose.
Actuation of the device bring out a metered dose of the formulation which contains the
medication either dissolved or suspended in the propellant. Breakdown of the volatile
propellant into droplets, followed by rapid evaporation of volatile propellant, outcome in the
generation of an aerosol consisting of micrometer-sized medication particles that are inhaled.
2. Liquid nasal formulations

Solution and Sprays
The drug solutions are nasally administered as nasal drops, sprays, and as metered dose
nebulizer. The dose of the active ingredient administered depends upon the volume of drug
and the concentration of drug in the formulation. The therapeutic levels of nitroglycerine, 3
ng/ml in central venous blood, 1.7 ng/ml in arterial blood, and 0.4 ng/ml in peripheral venous
blood were achieved within 2 minutes following intranasal administration of 0.8 mg/ml of
nitroglycerine in normal saline. The effect of formulation variables such as dose of API, pH
of the solution, and its osmotic properties on nasal absorption had been reported by various
researchers.

Suspensions
Suspensions for nasal administration are prepared by suspending the micronized drug in a
liquid diluent or carrier suitable for application to the nasal mucosa. The formulation of
suspension form enhanced the insulin uptake and reduces blood glucose as compared with
solution form.[
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Devices

Instillation and rhinyle catheter
Catheters are used to deliver the drops to a specified region of nasal cavity conveniently . Put
the formulation in the tube and kept tube one end was positioned in the nose, and the solution
was approached into the nasal cavity by blowing through the other end by mouth. Dosing of
catheters is determined by the filling prior to admin-istration and accuracy of the system and
this is mainly used for experimental studies only.

Compressed air nebulizers
Nebulizer is a device used to administer medication in the form of gases state into the lungs.
The compressed air is filling into the device, recognised as compressed air nebulizers. The
common principal for nebulizers, is to either use oxygen, compressed air or ultrasonic
power, as means to break up medical solutions/ suspensions into minor droplets, for direct
inhalation from the mouthpiece of the device. Nebulizers credited their medicine in the form
of a solution, which is loaded into the device upon use. Corticosteroids and Bronchodilators
such as salbutamol (Albuterol USAN) are often used, and sometimes in combination with
ipratropium . The reason these medication are inhaled instead of ingested in order to target
their effect to the respiratory tract, which speeds up onset of action of the medicine and
minimises side effects, as comparative to other alternative intake routes .This device is not
suitable for the systemic delivery of drug by patient himself.

Aeroneb Solo vibrating mesh nebulizer
Distinct anterior deposition in the valve area with nebulizers is confirmed in another very
recent publication comparing nasal inhalation from a nasal sonic/pulsating jet nebulizer
(Atomisor NL11S® sonic, DTF-Medical, France) and a new nasal mesh nebulizer system
designed to minimize lung inhalation (Aeroneb Solo®, Aerogen, Galway, Ireland; ) with the
equal mean particle size (5.6 ± 0.5 µm). The new system consists of two integrated
components: the nebulizer compressor administering a constant airflow rate transporting the
aerosol into one nostril via a nozzle and a pump simultaneously aspirating from a second
nozzle in the other nostril at the same airflow rate while the subject is instructed to avoid
nasal breathing . The new nasal mesh nebulizer produced more deposition in terms of volume
of liquid (27 % vs. 9 %, i.e., 0.81 vs. 0.27 ml) in the nasal cavity. The much higher
concentration found in the nasal cavity in this present study is probably a result of the shorter
nebulizing time and smaller delivered volume in the study testing the PARI pulsating
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nebulizer (20 s at a rate of 3 mcg/ml/min to each nostril versus delivery of 3 ml for up to 10
min) before assessment of deposition was performed. With much longer delivery time, the
gastrointestinal (GI) tract will be cleared by the fraction dose beyond the nasal valve.

Aerosol distribution deposition showed a distinct maximum value at 2 cm from the nostril
for both nebulizers corresponding to deposition in the nasal valve region [72]. Furthermore,
aerosol distribution deposition in the vertical plane showed a similar profile for both
nebulizers with a distinct maximum close to the floor of the nose. Importantly, the delivery
strength for nebulizers and delivery techniques appear very low with only 27 % vs. 9 %, i.e.,
0.81 vs. 0.27 ml, possibly due to the long delivery time and resulting differences in
mucociliary and other mechanisms of clearance. In other words, a study assessing deposition
after several minutes of delivery is likely to underestimate the actual exposure to the posterior
ciliated part of the nose compared to the study assessing deposition after a short period of
delivery of less than 1 min (20 s × 2) .

Squeezed bottle
Squeezed nasal bottles are mainly used as delivery de-vice for decongestants. They include a
smooth plastic bottle with a simple jet outlet. While pressing the plas-tic bottle the air inside
the container is pressed out of the small nozzle, thereby atomizing a certain volume. By
releasing the pressure again air is drawn inside the bottle. This procedure often results in
contamination of the liquid by microorganisms and nasal secretion sucked inside. Dose
accuracy and deposition of liquids delivered via squeezed nasal bottles are strongly dependent on the mode of administration. The differences between vigorously and smoothly
pressed applica-tion influence the dose as well as the droplet size of the formulation. Thus the
dose is hard to control. Therefore squeezed bottles with vasoconstrictors are not
recommended to be used by children.

Metered-dose pump sprays
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 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 Metered- dose
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pump sprays include the container, the pump with the valve and the actuator. The dose
accuracy of metered-dose 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

Drops delivered with pipette
Drops and vapour delivery are probably the oldest forms of nasal delivery. Dripping breast
milk has been used to treat nasal congestion in infants, vapours of menthol or similar
substances were used to wake people that have fainted, and both drops and vapours still exist
on the market .Drops were originally administered by sucking liquid into a glass dropper,
inserting the dropper into the nostril with an extended neck before squeezing the rubber top to
emit the drops. For multi-use purposes, drops have to a large extent been replaced by
metered-dose spray pumps, but inexpensive single-dose pipettes produced by “blow-fill-seal”
technique are still common for OTC products like decongestants and saline. An advantage is
that preservatives are not required. In addition, due to inadequate clinical efficacy of spray
pumps in patients with nasal polyps, a nasal drop formulation of fluticasone in single-dose
pipettes was introduced in the EU for the treatment of nasal polyps. The rationale for this
form of delivery is to improve drug deposition to the middle meat us where the polyps
emerge. However, although drops work well for some, their popularity is limited by the need
for head-down body positions and/or extreme neck extension required for the desired gravitydriven deposition of drops . Compliance is often poor as patients with rhino sinusitis often
experience increased headache and discomfort in head-down positions.

Mucosal Atomizer Device (MAD
 Single-use,Disposable
 Fits on standard syringe
 Manufactured by Wolfe-Tory Medical, Inc, Salt Lake City, UT
 Devices donated for study
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 Device designed to allow emergency personnel to delivery nasal medications as an
atomized spray.
 Broad 30-micron spray ensure excellent mucosal coverage.
 Atomized nasal medi and CSF via olfactory mucosa to nose-brain pathway
 Achieves medication levels comparable to injection
Reduce Pain and Bleeding Associated with:
Nasal and oral instrumentation
Nasogastric tube placemen
Controlled Administration

Exact dosing, exact volume

Titratable to effect (repeat if needed)

Atomizes in any position

Atomized particles are optimal size for deposition across broad area of mucos
Minimal Resource Utilization

Nasal drug administration is quick and easy

No sterile technique required

Eliminate IV set-up time
Using the MAD
 1st: Draw up practice solutions:
 Saline or water.
 Be aware of volume and what dose that would equal.
 2nd: Expel air from syringe.
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 3rd: Attach the MAD device via luer lock.
 4th: Briskly compress the syringe plunger.
 Brisk brief compression results in controlled atomization.
 Gently pushing the plunger will not result in atomization.
With practice you can give an exact volume down to 1/10 of a milliliter.
3. New Spin on Nasal Drug Delivery
Differentiate your drug products with an intranasal delivery system thatimproves treatment
efficacy and facilitates patient compliance.ViaNase™ is an advanced nasal drug delivery
device with the ability tooptimally saturate the entire nasal cavity, including the olfactory
regionand paranasal sinuses. ViaNase offers effective and efficient deliveryof a wide range of
topical, systemic, and nose-to-brain drug therapies.Its pocket–size and patient-friendly
operation facilitate compliance
Controlled Particle Dispersion™ Technology
ViaNase with Controlled Particle Dispersion (CPD)™technology allows formulations to
negotiate the complicated structure and varied airflows of the nasal cavity. Using the
principle of vertical flow, CPD effectively disrupts inherent nasal cavity airflows to deliver
formulations to the entire nasal cavity including the olfactory region and paranasal sinuses.
By optimizing droplet size and trajectory, CPD saturates the nasal cavity, lengthens
formulation residence time, and minimizes peripheral deposition to the lungs and stomach.
Advantages
1-Consistent dosing
2-Superior efficacy
3-Preservative-free, unit
4-dose ampoules
5-Patient-friendly operation,-Pocket-sized portability

ViaNase atomizr
A handheld battery-driven atomizer intended for nasal drug delivery has been introduced
(ViaNase by Kurve Technology Inc., Lynnwood, WA, USA). This device atomizes liquids by
producing a vertical flow on the droplets as they exit the device. The induced vertical flow
characteristics can be altered in circular velocity and direction to achieve different droplet
trajectories. As discussed above, it is not clear that vortex flow is desirable for penetration
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past the nasal valve; however, it has been suggested that this technology is capable of
targeting the sinuses, and some gamma-deposition images suggesting delivery to the sinuses
have been published. However, no information related to impact of prior surgery or
numerical quantification of nasal or sinus deposition verifying the claimed improved
deposition to the upper parts of the nose has been published. The ViaNase device has been
used to deliver nasal insulin in patients with early Alzheimer’s disease (AD), and clinical
benefit has been demonstrated. In these studies, delivery of insulin was performed over a 2min period by nasal inhalation. However, when insulin is delivered with this device, lung
deposition is likely to occur, and some concerns related to airway irritation and reduction in
pulmonary function have been raised in relation to long-term exposure to inhaled insulin
when Exubera was marketed for a short period as a treatment for diabetes. This example
highlights the issue of unintended lung delivery, one important potential clinical problem
associated with using nebulizers and atomizers producing respirable particles for nasal drug
delivery.

ViaNase Electronic atomize

Accuspray Nasal Atomiz
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4. Semi-solid dosage forms
A gel is a soft, solid or solid-like material consisting of two or more components, one of
which is a liquid, present in substantial quantity. A gel should, on a time scale of seconds, not
flow under the influence of its own weight. The solid-like characteristics of gels can be
defined in terms of two dynamic mechanical properties: An elastic modulus, G’(ù), which
exhibits a pronounced plateau extending to time at least of the order of second; and a viscous
modulus, G”(ù), which is considerably smaller than G’(ù). The first biological uses of gels
(polymerized methyl methacrylate) were presented by the institute for Macromolecular
Chemistry in Prague in 1960 and involved the manufacturing of contact lenses, arteries, etc.
Gelation occurs through the cross-linking of polymer chains, something that can be achieved
by (i) covalent bond formation (chemical cross-linking) or (ii) non-covalent bond formation
(physical crosslinking). Gels have been used for the delivery of drugs for both systemic and
local actions . Many different methods using gels have been reported, including subcutaneous
delivery for sustained release, buccal delivery, deliveries to the stomach, colon, rectum,
vagina, and nasal.
Gel formulations with suitable rheological properties increase the contact time with the
mucosa at the site of absorption. The increased contact time is caused by the mucoadhesive
properties of the polymer in the gel and by the rheological properties of the formulation
reducing the clearance by the nasal and ocular protective mechanisms.
5. Liposomes: These are phospholipid vesicles composed by bilayer enclosingone or more
aqueous compartments, in these compartments drug can be entrapped or adsorbed.
6. Microspheres: Microsphere has important role in nasal drug delivery with enhance
absorption, sustained release, and also has great importance because it protects drug from
enzymatic degradation.
7.Nanaparticulate Systems;
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