Novel drug delivery systems

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Abstract
The pitfalls of needle-based injections are well known. A series of discoveries led to
the development of the hypodermic needle which underwent significant changes. The
first air-powered needle-free injection systems were developed during the 1940s and
1950s. Needle free delivery is done conveniently both for solids and liquids. Needle-
free injection systems are typically made up of three components including an
Injection device, disposable needle free syringe and air cartridge. Various needle free
injectors are available in the market like Biojector, vitajet, iject, cool.click etc. These
formulations are designed for better acceptability and patient convenience. They offer
less pain and no needle phobia. They are ideally suited to chronic injections of
varying doses of insulin, proteins and monoclonal antibodies.1
Keyword: Needle Stick Injuries, Sterility, Propel, Needle Free Devices,
Immunization

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1. Introduction
Needle-free injection systems are novel ways to introduce various medicines into
patients without piercing the skin with a conventional needle. The first hypodermic
syringes were first developed by French surgeon, Charles Gabriel pravaz, in 1853,
although there is a minor development in syringes since then, the technology has been
remained unchanged for last 150 years. Needle-free systems was first described by
Marshall Lockhart in 1936 in his patent jet injection. Then in the early 1940’s Higson
and others developed high pressure “guns” using a fine jet of liquid to pierce the skin
and deposit the drug in underlying tissue. These devices were used extensively to
inoculate against infectious diseases and were later applied more generally in large
scale vaccination program. Today, they are a steadily developing technology that
promises to make the administration of medicine more efficient and less painful.
2
Needle free injection technology (NFIT) encompasses a wide range of drug delivery
systems that drive drugs through the skin using any of the forces as Lorentz, shock
waves, pressure by gas or electrophoresis which propels the drug through the skin,
virtually nullifying the use of hypodermic needle.
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The devices as such are available
in reusable forms. In contrast to the traditional syringes, NFIT not only gives the user
freedom from unnecessary pain but drugs in the form of solid pallets can also be
administered. The future of this technology is promising ensuring virtually painless
and highly efficient drug delivery. The major drawback associated with this
technology is post administration “wetness” of the skin which may, if not taken care
of, harbor dust and other untoward impurities.
4
This technology is being backed by
organizations as World Health Organization, Centers for Disease Control and
Prevention and various groups including Bill and Melinda Gates Foundation. This
technology is not only touted to be beneficial for the pharma industry but developing
world too find it highly useful in mass immunization programs, bypassing the chances
of needle stick injuries and avoiding other complications including those arising due
to multiple uses of single needle.
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Better patient compliance has been observed.

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1.1. STRUCTURE OF HUMAN SKIN :
Knowledge of the structure of skin is essential for successful administration of drugs
through needle free injection systems as these drugs are administered underneath the
skin.
Human skin is generally made of two layers
i.e., epidermis and dermis.
Figure 1. Layer of Skin
Epidermis:
It is the outermost layer of the skin. It forms the waterproof, protective wrap over the
body's surface and is made up of stratified squamous epithelium with an underlying
basal lamina. The epidermis contains no blood vessels, and cells in the deepest layers
are nourished by diffusion from blood capillaries extending to the upper layers of the
dermis. The main type of cells which make up the epidermis are Merkel cells,
keratinocytes, with melanocytes and Langerhans cells also present. The epidermis can
be further subdivided into the following strata (beginning with the outermost layer):

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corneum, lucidum (only in palms of hands and bottoms of feet), granulosum,
spinosum, basale.
Dermis:
The dermis is the layer of skin beneath the epidermis that consists of connective tissue
and cushions the body from stress and strain. The dermis is tightly connected to the
epidermis by a basement membrane. It also harbors many Mechanoreceptors (nerve
endings) that provide the sense of touch and heat. It contains the hair follicles, sweat
glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The
blood vessels in the dermis provide nourishment and waste removal from its own cells
as well as from the Stratum basale of the epidermis.
Hypodermis:
The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to
attach the skin to underlying bone and muscle as well as supplying it with blood
vessels and nerves. It consists of loose connective tissue and elastin. The main cell
types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of
body fat). Fat serves as padding and insulation for the body. Another name for the
hypodermis is the subcutaneous tissue.
2
1.2. Principle :
NFIT uses the energy which is stronger enough to propel a premeasured dose of
medication, loaded in specific unique “cassettes” which can be rigged with the
system.
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These forces can be generated from any of the ways ranging from high-
pressure fluids including gases, electro-magnetic forces, shock waves or any form of
energy that is capable enough to impart a motion to the medicament.
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1.3. Objective
1. To review needle vs. needle-free injection systems and describe the different
types of needle-free injection systems.
2. Less Painful and Potentially Safer.
3. The key benefits of avoiding a needle and ease of use of a liquid jet injector
do not outweigh the overall cost of goods compared with other delivery
technologies.
4. Major advantages of needle-free systems are the elimination of broken
needles, a more constant delivery of vaccines and drugs, and decreased
worker safety risk.
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1.3.1. Needle vs. Needle-free Injection
A) Cost Efficiency: Needle-free injection systems can potentially reduce medical
costs for the pork producer because the chance of injury to an employee from
inadvertent needle sticks is eliminated. Needle-free systems also eliminate the
purchase of needles. Needle breaks, which can damage tissue and cause a decrease
in overall yield and profitability, are also therefore eliminated. However, the start-
up costs associated with needle-free injection systems can be large. Pork
producers should weigh the costs and benefits to these systems before adapting
new technology.
B) Worker Safety: Safety is a key ingredient to any pork operation. Employees
must be properly trained on the use and maintenance of all equipment. Needle
injection can be dangerous due to inadvertent needle sticks or cuts. However,
needle-free injection is not 100% safe. Needle-free systems are designed for a
high force dose to be administered very quickly and should only be used with
proper training. These systems do offer a limited amount of risk to the operator, if
properly trained, and exclude the possibility of needle sticks and cuts.

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C) Sterility: Sterility is a key factor to proper vaccination and drug delivery.
Sterility can be affected by human error. For example, the same needle may be
used on multiple animals. Workers may forget to change needles when drawing
vaccine from a bottle. Needle-free injection takes the needle out of the equation,
and due to the high powered dosing mechanism, there is a little to no chance of
cross contamination.
D) Pork Safety: The use of needles, along with human error, may also cause pork
carcass defects. If needles are disposed of correctly or dropped after use there is
always of a possibility of an animal ingesting the needle or being stuck in an
unassuming place. Needle-free injection systems eliminate residual needles and
needle fragments from pork carcasses. The Pork Quality Assurance (PQA) Plus
program recommends that all producers have a broken needle policy in place.
E) Proper Dosage: Injection site is a crucial element in making sure that a proper
dosage is received by the animal. A needle injection provides many unknown
variables that can prevent proper dosing and in turn create havoc in your
vaccination program. Proper dosing is highly dependent on many factors. Among
these factors are the size and age of the pig and the recommended route of
administration. Different methods of administration such as subcutaneous (SQ) or
intramuscular (IM) are very important in guaranteeing quality vaccination. If a
vaccine or drug is not administered accordingly the effectiveness of the drug and
the withdrawal time are altered. Incorrect injection sites in both needle and
needle-free injection can impair pork safety.
F) Injection Methods: Subcutaneous injections in small pigs should be given by
pulling loose skin in the elbow or flank area. This technique is called tenting. In
sows, the area just behind the ear is an acceptable sight for SQ injection.
Intramuscular injection is conventionally administered in the neck just behind the
ear. IM injection anywhere else is not acceptable because it will compromise pork
safety and it should never be injected in the loin or ham muscles.
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1.4. Needle although effective has several draw backs
1. Needles are expensive. The cost results in a lower vaccination rate,
especially for children in developing countries.
2. Lack of reusability, if a needle syringe is not sterilized reusing it can lead to
the spread of disease.
3. Many people have a fear of needles (often called Trypanophobia,
Belonephobia or Aichmophobia) which causes them to avoid treatment.
Needle pho-bia affects at least 10% of the general population.
4. Accidental needle sticks lead to injuries and possible infections.
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1.5.Advantages of using Needle Free Injection Technology
Advantages galore as one delve into Needle Free Injection Technology. The
biggest proof of its credibility and effectivity is its acceptance among the patients and
wide practice by medical professionals and organizations. Though this is a pretty new
concept in India, but in developed nations this technology is listed below:
1) Painless Procedure : The word “Needle free” itself psychologically
suggests a painless procedure and certainly it does live up to his name and
intriguing nature. Be it Nano-patch or Jet Pressure or Gas Powered Needle
free Injection all of these provide pain less inoculation of drug into the body.
Thus, causing a relief to millions, irrespective of age, gender or geography
who are needle-phobic.
2) Relief to patients who have to be administered with Transdermal
Inoculation many times a day : These are mainly people suffering from
acute Diabetes. Such patient has to be administered with insulin at regular
intervals to keep a check on their blood sugar levels. This is an extreme
painful procedure as the patient has to undergo numerous injection pierces a

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day and for the entire duration of his/her stay in the hospital. Needle Free
Injection Technology thus comes as a blessing to such people.
3) Efficient use of vaccine : Researchers have found that the amount of drug
that is introduced inside our body through conventional injections do not
cause the right magnitude of effect which actually that amount of drug
should do. This means that considerable amounts of drug do get wasted. As
evident from above diagrams some portion of the drug do get trapped inside
the muscle and are eventually excreted from our body. Such a thing never
occurs in Needle free injections. A specific amount of drug is administered
which gets totally used by our body as there is no entrapment and immediate
dispersion upon introduction.
4) Pandemic effective : During pandemics such as Cholera, diarrhea,
dysentery availability of drug and medical professionals are not in
abundance which leads to incomplete administration of drug among the
patients thus leading to death of many. Such a mishap can be easily averted
if a mass amount of such Needle Free Injections can be delivered to families
where they themselves can administered under minimum medical
supervision.
5) Self administrable: As previously mentioned, needle free injection can be
administered without any medical supervision or expertise; there is no need
for patients to visits clinics or hospitals.
6) Less expensive : In developed nations the cost of Needle free injections are
less than conventional needle injections. Though this is not a reality is
developing countries, effort are being made to realize such a project.
7) Zero Contamination : This is due to the fact that the needle free injections
are for one time use only. Even if one tries to reuse it ( as it happens in case
of conventional injections ) one can’t because the drug can’t be refilled into

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the device. Thus making the device absolutely fool proof from sabotage by
unscrupulous agents, thereby rendering cent percent safety and
contamination free inoculation.
8) Better drug diffusion : Conventional injections deliver drug into our
muscles where it gets trapped for a period of time before getting diffused
into our body, thereby causing a delay in action of the drug. Moreover there
is also a possibility of the drug being trapped inside the muscles thus
resulting in wastage of the drug. Such thing never happens in Needle free
injections because drugs are instantaneously transported into our system,
thanks to the Langerhans cells and Lymph nodes in our body which supports
such a brilliant mechanism.
9) Zero disposals Hazard : Conventional needle injections have mainly two
types of disposal hazards. Firstly, injury caused to the person handling the
sharps which might lead to devastating effect as contamination is inevitable.
Secondary there is a fear of reusability of the used sharps. Though the
second factor has been stopped but still unscrupulous activities thrives where
used needle injection are washed, rinsed packed and again sold into the
market. Such possibilities would never occur if needle free injection is used.
10) Ideal for Developing countries : This is the one of the most propelling
motives which has culminated in design of this technology. Developing
countries have a huge population but lacks proper medical facilities and
scarcity of trained medical personnel. Thus during any vaccination drive or
treatment during pandemics most of the mass are left untreated, thereby
causing permanent impairment or even death. To eradicate such an
undesirable happening this technology gives the best possible solution.
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1.6. Limitation of Needle Free Injection Technology
1) High pressure delivery of drugs by the Jet pressured needle free injection can
damages fragile molecules beneath our skin surface, especially Monoclonal
antibodies.
 This can be resolved if a specialized device is employed to control
the exact pressure of drug delivery.
 Though this problem is faced only by patients who undergo
multiple inoculations within a short period of time thus is not of a
major concern for the generally ill patients or patients for
vaccination.
2) Unreliable penetration of the skin due to the shape of the diffusive jets used
with these devices.Unreliable injection amount when using small volumes.
3) Higher start-up costs
4) Higher requirement for training and maintenance
5) It’s not applicable for Intravenous route.
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1.7. Application
1. Intramuscular, subcutaneous and intradermal administration of Vaccines.
E.g. smallpox, polio, measles
2. Intradermal administration of hormones. E.g. growth hormone
3. Intradermal administration of anesthetics. E.g. lidocaine
4. Subcutaneous administration of insulin.
5. Used in the treatment of migraine. E.g. sumatriptan
6. Animal Pharmaceuticals. E.g. MS Pulse250 system is used
7. Used to deliver drugs (Weston medical) Which consist of proteins, peptides,
monoclonal antibodies, small molecules and vaccines.
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2. Methodology of Released Medicines from NFIT:
Needle-free injection devices, first called “jet injectors,” were developed in the 1930s
and used extensively for over 50 years in mass human vaccination programs for
smallpox, polio, and measles (Dr. Charles potter, Henry, C).However, only recently
they are being promoted as devices for the self-administration of parenteral drugs.
When administered vaccine through the skin mechanical compression to force
fluid through a small orifice (force generated by a compressed gas typically air,
CO2 or nitrogen), an ultrafine stream of fluid penetrates the skin, delivering the
vaccine in a fraction of a second to the skin, (these devices produced a high-pressure
stream 76 to 360 µm in diameter, compared to 810 µm for a 21-gauge needle)
Injection event requires less than 0.5 seconds. All require a power source that
provides a very high peak pressure behind the liquid in order that it can drill a hole in
the skin, without the use of a needle, followed by a reduced pressure profile to force
the rest of the liquid into the skin. This requires careful control over the power source
to ensure accurate and reliable delivery of the drug to different skin locations on the
same person (Needle free insulin devices, 2004).13
2.1. Components for Needle less Injection Shown in the
Picture Below:
Figure 2. Components for Needle Less Injection
 Nozzle: The nozzle has two critical functions; it acts as the passage for the
drug and as the surface which contacts the skin. The nozzle contains a flat

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surface and an orifice. The nozzle provides the surface which comes in contact
with the skin and the orifice which the drug passes through when injected.
 Drug reservoir: The drug volume holds the injection fluid inside the device.
 Pressure source: The energy source provides the necessary driving energy
to the drug for injection. Many of the devices on the market use either
mechanical or stored pressure as energy storage elements. The mechanical
method stores energy in a spring which is released pushing a plunger to
provide the necessary pressure. The pressure storage method uses com-pressed
gas in a vessel which is released at the time of injection (Reddy M. S, 2011)
2.2. Mechanism of Working :
Figure 3. Visualizing the Process of Transdermal Injection
a. Impact of a piston on a liquid reservoir in the nozzle increases the pressure,
which shoots the jet out of the nozzle at high velocity (velocity > 100 m/s).
b. Impact of the jet on the skin surface initiates formation of a hole in the skin
through erosion, fracture, or other skin failure modes.
c. Continued impingement of the jet increases the depth of the hole in the skin.
If the volumetric rate of hole formation is less than the volumetric rate of jet
impinging the skin, then some of the liquid splashes back towards the injector.
d. As the hole in the skin becomes deeper, the liquid that has accumulated in the
hole slows down the incoming jet, and the progression of the hole in to the
skin is stopped. The dimensions of the hole are established very early in the
process (a few tens of microseconds) from the time of impact.
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2.3. Stages of Needle free drug delivery (Dr. Bruce G., August
2005):
There are three stages in the needle free drug delivery:
1. The peak pressure phase-optimal pressure used to penetrate the skin (<0.025
sec)
2. Delivery or dispersion phase (up to 0.2 sec)
3. Drop off phase (<0.05 sec)
The total amount of time required to deliver the vaccine is up to 0.5 seconds
2.4. Design
The air-forced needle-free injection systems are typically made up of three
components including an:
 Injection device
 Disposable needle free syringe
 Air cartridge
The injection device is made of a durable plastic. It is designed to be easy to hold for
self-administration of medicine. The needle-free syringe is also plastic. It is sterilized
and is the only piece of the device that must touch the skin. The syringe is made to be
disposed after every use. For portable units, pressurized metal air cartridges are
included. Less mobile devices have air hook-ups that attach to larger containers of
compressed air. Some air-forced systems use a reusable spring to generate the pushing
force instead of pressurized air cartridge.
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3. Classification of Needle Free Injection Technology
3.1. On the basis of working
3.1.1. Spring systems.
3.1.2. Laser powered.
3.1.3. Energy propelled systems.
3.1.3.1. Lorentz force.
3.1.3.2. Gas propelled / air forced.
3.1.3.3. Shock waves.
3.2. On the basis of type of load
3.2.1. Liquid.
3.2.2. Powder.
3.2.3. Projectile / Depot.
3.3. On the basis of mechanism of drug delivery
3.3.1. Nano-patches
3.3.1.1. Sandpaper assisted delivery.
3.3.1.2. Iontophoresis enabled.
3.3.1.3. Micro-needles.
3.3.2. Jet pressure needle free injection
3.4. On the basis of site of delivery
3.4.1. Intra dermal injectors.
3.4.2. Intramuscular injectors.
3.4.3. Subcutaneous injectors.

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Mode of Action of Needle Free Injection Technology
3.1. On the Basis of Working
3.1.1. Spring system : Springs have been used to harbor energy and have been
proven to be quite effective in powering NFIT devices. For NFITs, energy storage and
further transmittance via spring is one of the easiest and simplest. However, the
design of the spring must follow the standard protocols and the storage conditions
must be simple or the spring will take a “set” over time deteriorating the performance
of the device. The basic issue with respect to the design of the spring is that the force
provided by the spring will reduce in proportion to the distance over which the load
has been applied as according to the Hook's law.
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In simple words, in spring assisted
NFIT, the pressure shall gradually decreases throughout the injection.
Figure 4. Mechanism of Working

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Figure 5. Size comparison of a human hair, 24 gauge needle and drug
stream
3.1.2. Laser powered: A newer dimension of NFIT developed by Prof Jack Yoh and
his team (Department of Mechanical and Aerospace Engineering, Seol National
University, South Korea) uses laser based system that blasts microscopic jets of drugs
into the skin.
The technology uses an erbium-doped yttrium garnet laser (the one used in the care of
laser resurfacing of the skin) to drive a very fine and precise stream of drug or
medicament with the right amount of force.
The laser is integrated with an adapter which holds the drug to be administered. The
device also contains a chamber for water which is used to drive the medicine;
however, the arrangement is so done that the drug is separated from the driving fluid
(water) with the help of a membrane.
 Working
The laser pulse of a wavelength of about 2940 nm is emitted,which has a life span of
about 250 millionth of a second. It attacks the driving fluid generating a vapor inside
the fluid.
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The bubble formed impacts on the membrane, applying a pressure to it

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causing a strain on it leading the drug to be forcefully ejected from a minute nozzle of
about 150 millionth of a meter in diameter with very great impact on the skin,
sufficient enough to smoothly penetrate into the skin, without any damage to the
tissues and no drug splash back happen.
The research team in association with a major company is still working on the
technology to develop better and more advanced variants of this technology.
3.1.3. Energy propelled system
Commercial spring powered jet injectors offer little to no control over the pressure
applied to the drug during the time of the injection; also these devices are often loud
and sometimes painful. The force required to propel the drug so as to have a
penetrating effect can also be generated by energy in various forms.
3.1.3.1 Lorentz force
Researchers at MIT have engineered an NFIT device which uses Lorentz force to
push a piston forward ejecting the drug at very high pressure and velocity (almost
equal to that of sound in air). The main component of the device is the Lorentz force
actuator which facilitates the entire process.
 Working
The design of the device is built around a Lorentz force actuator which consists of a
small and powerful magnet which is surrounded by a wire coil that remains attached
to a piston which is inside a drug ampoule. When current is applied, it interacts with
the magnetic field so as to produce a force, which pushes the attached piston forward,
while the stream of the formulation from the device is forced out as thin as the
mosquito's proboscis.
The amount of current supplied can be very well regulated enabling the speed of the
coil to come under our regulation. This would finally control the velocity with which

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the drug is ejected. The research team has even demonstrated the device to act in a
high pressure phase when the drug penetrates deeper into the skin at desired strength
and in a low pressure phase where the drug is delivered in a lower stream so as to be
absorbed by the surrounding tissues. This capability of the device has made it be a
versatile NFIT system suitable for corneal drug application and also fit for pediatric
use.
3.1.3.2. Gas propelled/air forced
Figure 6. Gas Propellant
Gas, as a power source will be less suitable for reusable devices unless special
arrangement and design alterations or component modifications may be made such
that the pressure is not lost, and the spring is reset for each injection, still, gas
powered NFITs have greater scope since compressed gas offer higher energy density
than a metal spring. Gas powered devices tend to be either single use or need a

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periodic replacement of the gas cartridge. Some devices employs gas as a simple
spring where the stored gas accelerates the piston there are portable and compact,
however, developing a gas spring which retain a specific proportion of the gas to
work at the lapse of its shelf life is a major challenge.
To overcome such challenges, an alternate method has been developed which uses
carbon dioxide liquefied at the storage temperature and pressure. This approach has
been proven beneficial as a minimal loss of gas from the container inflicts virtually
“no” or “zero” reduction in pressure. However, the pressure in such containers is
highly sensitive to temperature with the pressure doubling between 0° and 40°. This
may affect the performance of the device if a broader operating temperature range is
desired. This problem can be sorted out by using a pressure regulator.
Further research has led to the evolution of reusable, sophisticated and comparatively
more portable gas powered NFITs as in such systems (one developed by Team
Consulting Ltd., Cambridge, UK) simple Butane combustion engine is used to power
the device. The complete efficacy of this system is yet to be established, and data
published.
Figure 7. Cross -Ject

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Major industries (Cross-Ject and BioValve) working for the development of NFIT
systems have employed a technique of gas generation chemically in which the gas is
produced at a reproducible and predictable rate to power the device. The reaction is
initiated either mechanically or electrically, where the chemical “burns” generating
gas.
The major drawbacks associated with this technology include:
1. Complicated validation protocols.
2. Foul odor due to combustion of reactants.
3. Large volume manufacture of reactants.
3.1.3.3. Shock waves
Shock waves are generated by any sudden release of energy. These disturbances carry
energy and can be propagated through a medium. Researcher at the “Indian Institute
of Science” (IISc) Bengaluru have developed a needless noninvasive drug delivery
system employing this energy at supersonic levels.
The prototype of this device consists of following major parts:
a. Ignition system to ignite the “charge.”
b. Polymer tube which contains the explosive material which is suitably coated.
c. Drug holding chamber to load the drug.
d. The system also contains the cavity holder and metal foils.
A micro-blast is induced through a tiny “controlled” explosion which is propagated at
supersonic speeds, yielding high pressure and temperature. The pressure generated via
this “explosion” technique is strong and potent enough to eject the drug (a vaccine as
in the case of system developed by IISc) filled in a miniature model device. The drug
is forced into the skin while the integrity of the skin remains intact. If the technology
developed by IISc proves to be successful, the institute will offer cheaper,

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noninvasive technologies which will not only arrest the incandescence needle stick
injuries but would also limit infections at healthcare centers.
3.2 On the Basis of Type of Load
3.2.1. Liquid
Figure 8. DoseProTM
: An Easy-To-Use Three –Step Process
Liquid NFIT is the first variant of the NFIT systems and still, major players in the
pharma industry are working on it.
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The entire mechanism of achieving a successful
injection with a needle free system depends upon the ability of a liquid jet, stronger
enough to penetrate the skin and the underlying fat layer without harming the skin or
the integrity of the drug molecule. The mechanics involved in liquid NFITs is so
complex that the recent studies have been carried out to understand the complete
procedure of it.
Delivering fluid from NFIT involves a thorough application of fluid mechanics. The
steps involved are:
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I. “Registration”: The orifice of the device is placed exactly over the pores of
the skin.

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II. Exact pressure: The fluid must be forced at an optimum pressure, stronger
enough that it keeps the holes in the skin open and consistent enough that it
avoids the resealing of the holes.
III. Channel drilling: The initial pulse of the fluid drill a channel into the fat
layer deep enough that the dose is drifted from the hole into the skin.
IV. Quicker pressure fall: The pressure drops quickly and sufficiently so that
the fluid may not penetrate the muscles underlying the skin.
3.2.2. Powder
Figure 9. NFIT – Powdered Based
Powder needle free injection depends on being able to formulate the particles of
sufficient density and accelerating them to sufficient velocity strong enough to
penetrate the skin and in a quantity sufficient enough to reach the therapeutic dose
levels. This was made successful by using helium as a power source assisted by
modifications in the ways of formulation of the drug as:

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 Conversion of the drug either pure or along with excipients into hard particles
of 10-50 nm in diameter, with a density approximately the same as a
crystalline drug.
 Coating the drug onto gold spheres which may act as a vector of few
micrometers in diameter, this method is mostly applicable to DNA vaccines.
 Working
The drug is stored in a “cassette” designed so as to house the drug in the center, while
the cassette is capped with a polymeric lid, upon activation a gust of helium gas
ruptures the lid, forcing the drug forward due to specially designed convergent-
divergent type nozzles the drug particles attain the speed near about to that of sound,
hence penetrating the skin.
Drug delivery through this system is limited only to those candidates with an effective
dose of about 1 mg max. Since in powder drug delivery through NFIT systems, it is
difficult to predict the proportion of dose that is difficult to determine the proportion
of dose that is to be delivered to the epidermis, also the maximum payload for a 20
mm diameter target area of skin is about 2-3 mg.
This technology is highly suitable for DNA vaccines and the delivery of local
anesthetic to the skin and oral mucosa.
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3.2.3. Projectile/depot
Highly advanced compared to the prior developed into this variants of the NFITs, the
drug is processed into a long thin depot having sufficient mechanical strength strong
enough to transmit a driving force to a pointed tip which may be formed either of an
inert material or medicament itself.
Generally, a depot is in the form of the cylinder measuring around 1mm in diameter
and few millimeters in length. This dimension may be small enough to limit the
payload, but the quantity of the payload is sufficient enough for many new therapeutic
proteins, antibodies, and other smaller molecules. The depot is strong enough to
puncture the skin when punched with the sharp tipped punch by applying a pressure of

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the order of 3-8 Mega Pascal (MPa). For a depot preparation of around 1 mm, only a
few Newton's of force are required. The delivery device, therefore, would employ the
transfer of energy from a suitable “spring” upon the depot.
3.3. On the Basis of Mechanism of Drug Delivery
3.3.1. Nano-patches
The working of nano-patch or micro-projection depends on the use of an applicator to
deliver the drug through the skin. Nano-patch projections are invisible to the naked
eye and thereof are not anticipated to inflict fear into the people. Drug delivery using
nano-patches have been highly efficient with respect to vaccines. Nano-patches
enable the vaccine to reach the key immune cells located below the skin surface while
the entire process is pain free.
Application Method:-
3.3.1.1. Sandpaper assisted delivery
Figure 10. Sand Paper Aided Delivery
Mostly, a 220 grit “sandpaper” kind of agent is rubbed onto the skin the skin so as to
result in micro-derma abrasion a phenomena where the superficial layer of the skin is
removed; thereby facilitating the entire drug delivery process.
18
Microdermabrasion
has been widely accepted for cosmetic purposes. Sandpaper aided drug delivery has
been successful in increasing the skin permeability, for several vaccines and other
methods of Microdermabrasion have been used to facilitate the movement of drugs

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such as lidocaine, 5-flurouracil.
19
Till now, vaccinations for traveler's diarrhea and
influenza have been developed using this technique (Clinical trials in progress).
3.3.1.2. Iontophoresis enabled
Figure 11. Mechanism of operation
The lipophilic nature of skin debars several salts and other molecules from entering
the skin. By iontophoresis, a small electric current of about 0.5 mA/cm2
is used to
force several drug molecules across the skin.
20
The working of this method involve
the use of two electrodes as patches, where one acts as a drug reservoir, which can
either be positively or negatively charged depending upon the nature of the drug,
another patch is placed somewhere else on the body to complete the circuit.
For successful drug delivery by iontophoresis, both the quantum of charge (positive
and negative) and type of the drug must be compatible with the process. Excipients in
the drug and condition of the skin need to be considered too. Iontophoresis have
shown excellent results as means of drug delivery system for peptides, therapeutic
proteins or vaccines, and oligonucleotides.
Iontophoresis has also been modified so as to remove molecules from the blood
circulation. GlucoWatch, a needless procedure involves a reverse iontophoresis
technique to monitor blood glucose level.

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3.3.1.3. Micro-needle
Figure 12. Micro-needle
Micro-needle patches, as the name suggest, employs the use of thousands of tiny
spikes all around 750 μ long. These patches are pressed onto a person's skin while the
spikes pierce the outer most layer of the skin so as to deliver the drug, while the
piercing is not deep enough to hit the blood vessels or even the pain receptors so as to
cause pain. Different types of micro-needles have been developed from the
sophisticated metallic to plastic ones. While some are just “coated” with the drug,
others are hollow having a liquid vaccine or the formulation filled inside.
In some cases, the spikes are made of the formulation itself, in many cases,
dissolvable patches are used which are made of cellulose and/or sugar molecules.
Researchers have revealed the drug delivery (mainly vaccines) have been more
efficient when administered via micro-needle patch than the traditional intra-muscular
injection, since larger number of dendritic cells (which are more susceptible to
vaccines) are located in the skin.
Even micrograms level of drugs can be delivered using micro-needle based drug
delivery system. This makes it the most suitable choice for highly potent and small
molecules or peptides.

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Micro-needle patches have not only proven to be highly effective but have even
shown better patient compliance. However, certain limitations are associated with the
use of micro-needle patches.
21
 Larger doses require bigger patch size.
 The formulation must be able to “coat” or “stick” on to the spikes on needle
surface.
 In cases, if the needle itself is made of the drug, the formulation must have
required physico-chemical property to maintain a sharp tip for adequate skin
penetration.
 The depth of penetration of the micro-needle may differ from person to
person, based on thickness, toughness of the skin and reproducibility of the
application.
 Movements of the body or the body part upon which the patch is applied may
lead to dislodging of the needle.
22
3.3.2. Jet pressure needle free injection
Figure 13. Jet Pressure Injector

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Needle-free injectors use jet pressure to inject the drug rapidly into the correct depth.
The jet is achieved by forcing the drug through a specially designed nozzle, which is
completed in only 300 milliseconds. The drug delivery involved involved is
Transcutaneous type as the jet penetrates the tissue depositing the drug in the
subcutaneous layer.
23
The air- forced needle-free injection systems are typically made up of three
components including an injection device, a disposable needle free syringe and an air
cartridge. The injection device is made of a durable plastic. It’s designed to be easy to
hold for self-administration of medicine. The needle-free syringe is also plastic. It’s
sterilized and is the only piece of the device that must touch the skin. The syringe is
made to be disposed after every use and pressurized metal air cartridges are included.
Some devices have air hook-ups that attach to larger containers of compressed air.
Some air-forced system use a re-usable spring to generate the pushing force instead of
pressurized air cartridges.
Figure 14. MS Pulse 250 System
The diagram above shows the mechanism of drug delivery of a Needle and a Jet
pressured Needle Free Injection. Diagram on the left shows the needle based delivery
where there is a distinct puncture of the skin surface and the drug after delivery gets
trapped for a while without being diffused immediately. On the other hand, there is no

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puncture when the Jet Pressured Needle Free Injection is used, due to the specially
developed nozzle the drug penetrates through a skin pore and is immediately
dispersed into the epidermis, thus enabling a faster transport to the body.
3.4. On the Basis of Site of Delivery
Figure 15. Types of Parenteral Route
3.4.1. Intradermal injector
These systems have been employed to deliver comparatively newer, DNA-based
vaccines to the intradermal layer. The system delivers the drug at a very shallow
depth that is, between the layer of the skin.
3.4.2. Intramuscular injector
One of the most developed NFIT systems employed for intramuscular drug
administration. Drug delivery via this system is the deepest among all. Drug delivery
through NFIT devices has been most successful for vaccination.
3.4.3. Subcutaneous injector
Certain therapeutic proteins including the human growth hormones have been
administered by this system. The medicament is delivered to the adipose layer just
below the skin.
5,10,14

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4. Manufacturing of Needle Free Injection Technology
There are a number of ways for manufacturing the NFIT devices; however, the
following discussion gives an insight over the production of an air forced system as
shown in figure:
Figure 16. NFIT manufacturing process
A) Raw material
As the device is in direct contact with the skin, so it needs to be made from materials
that are pharmacologically inert in nature. Polycarbonates including thermoplastics,
those which are synthetically produced and are easier to mold and light in weight are

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the most suitable raw material for making the outer compartment or the body of the
device. If needed, and in most cases, colorants are added. Gas powered systems use
helium or CO2 as a source of propulsion, even newer designs use butane for such
operations. The body of the device must be made of material like such that, it does not
react with the gas or the other adjutants including the colorants.
The raw materials are utilized through a step by step procedure so as to yield a final
product. Pieces are produced off site, and the manufacture assembles them while all
the assembling process is alone under sterile conditions.
B) Making the pieces
An extremely versatile process used in the plastic manufacturing industry is used for
manufacturing of the devices, called, injection molding process. In this process, the
suitable raw materials in the form of pellets are fed into the hopper either manually or
mechanically.
The hopper directs the pellets into the cylindrical body of the machine with the help
of a rotating screw. The rotating screw pushes the pellets to its nozzle, while the
dimension of the screw decreases, causing the pellets to melt due to the frictional
forces generated due to gliding of the pellets one over the other also, the tube may be
heated externally to increase the temperature which may aid in melting the pellets and
increasing the flowability.
Figure 17. Parts of NFI

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The melt is injected into the mold through the nozzle by the help of screw. When the
plastic enters into the mold, it is kept for some time under increased pressure, allowed
to cool and harden.
The mold parts are opened or separated to eject the formed “design.” The design
formed, or the device made is inspected manually to ensure that no defects or
structural deformity and the process repeat.
C) Assembling and labeling
The formed design is then transported to an assembly line where sophisticated and
highly precise machines apply markings on the design or on the parts. Their markings
may be for dose levels etc., during this stage, workers are employed to insert various
separate compartments so as to form a complete device. Any attachment if needed
such as buttons etc., are fixed at this stage.
D) Packaging
After the device is completely assembled, and attachments fixed, the next step
includes packaging. The device is first wrapped in sterile films and then put into
cardboard or plastic boxes. All the required manuals or insects are put into those
boxes. The boxes are then stacked on pallets and shipped.
6
4.1 Quality control
The entire process is thoroughly supervised for any visual defects or structural
deformity by line inspectors throughout the manufacturing process. The equipment is
also checked for accuracy and precession along with the dimensions and thickness of
the device. Inspectors also go through the labeling and calibration.
24
These devices can have various safety issues, so they are manufactured under strict
control of Food and Drug Administration’s (FDA). FDA conducts an inspection of the
manufacturing units at regular intervals.

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4.2 How does it work?
Figure 18. Injecting Medicament through Skin by Needle Free Injection
a. Medication is driven at high speed through a tiny orifice
b. A fine stream of medication penetrates the tissue
c. Injection event requires less than 0.5 seconds
d. Injections can be IM, SC or ID
 Drug administration through conventional needle system and needle free
injection technology. A spherical bolus is formed in case of conventional
needle system where the surface area/volume ratio is very less when compared
to needle free injected devices. Drug is dispersed as a spider web in case of
needle free injected systems.
2
4.3 Problems It Solves:
1. Avoids needle stick hazard.
2. No sharps disposal problems.
3. Eliminates the concern for the re-use of needles.
4. Injection pain is reduced in most cases.
5. Speeds the injection cycle.

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6. Improved bio-availability of vaccines.
7. Reduces the system cost of injection.
8. Key Needle Free Manufacturers Of The World.
25
4.4 Needle Free Delivery of Solids
As well as the obvious advantages for liquid formulations, such is needle phobia
etc. described above, delivering the drug or vaccine in a solid dosage form has the
additional advantages that the therapeutic agent will typically be more stable and may
not require cold chain storage. In addition, a solid formulation presents the
opportunity to combine fast-acting and delayed-release forms such as for vaccines so
that the ‘prime’ and ‘boosts’ shots can be given together in a single administration.
1
4.5 Needle Free Delivery of Liquids
Needle-free injectors have the obvious advantages that they avoid issues relating to
needle phobia, needle disposal and the potential for cross contamination of blood-
borne diseases. Probably the most well-known needle-free technologies involve liquid
jet injection. Liquid jet injector technology was first developed many decades ago and
yet it is still not widely used although there are products based on some of these
technologies on the market. One of the main attributes of the liquid jet injectors is that
these use the drug in a liquid form which therefore does not typically require re-
formulation from standard needle and syringe formats. The jet injectors have been
developed as both single-use devices and multi-use systems. All require a power
source that provides a very high peak pressure behind the liquid in order that it can
‘drill’ a hole in the skin, without the use of a needle, followed by a reduced pressure
profile to force the rest of the liquid into the skin. This requires careful control over
the power source to ensure accurate and reliable delivery of the drug to different skin
locations on the same person.
A variety of power sources has been developed for these liquid jet injectors,
including: Springs , Compressed gas, Controlled chemical reactions

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5. Key Needle Free Injection System Manufacture
5.1. Mhi-500:
Mhi-500 is the novel needles free insulin delivery system which offers benefits for all
those involved in diabetes care and also for those involved in the management of
clinical waste. It is a real alternative to needle-based delivery systems.
Compared with a needle injection system, the mhi-500’s needle-free insulin delivery
technology improves the dispersion of the insulin throughout the tissue. This
technology achieved the Food and Drug Administration (FDA) approval in 1996 for
the subcutaneous delivery of insulin and is CE marked for sale throughout the Europe.
This system has been used to give thousands of successful injections without the use
of a needle. The mhi-500 injects insulin by using a fine, high pressure jet of insulin.
This jet then penetrates the tissue, depositing the insulin in the subcutaneous layer.
The jet is created by forcing the insulin through a precisely designed nozzle that is
held in contact with the tissue during the injection.
5.2. Recojet:
Shreya Life Sciences has recently launched its recombinant human insulin under the
brand name Recosulin and a needle-free insulin delivery device, Recojet. According
to the company sources, Recojet is India’s first needle-free insulin delivery device and
poised to revolutionise the insulin therapy.
The new device is expected to give a boost to the therapy, as needle phobia was one
of the reasons preventing insulin use on a wider scale. In general, needle-free
injection technology works by forcing liquid medication at high speed through a tiny
orifice that is held against the skin. This creates an ultra-fine stream of high-pressure
fluid that penetrates the skin without the use of a needle.
5.3. Bioject’s needle free injection technology:
Bioject’s needle-free injection technology works by forcing liquid medication at high
speed through a tiny orifice that is held against the skin. The diameter of the orifice is
smaller than the diameter of a human hair. This creates an ultrafine stream of high-

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pressure fluid that penetrates the skin without using a needle. Bioject’s technology is
unique because it delivers injections to a number of injection depths and supports a
wide range of injection volumes. For instance, the Biojector 2000 can deliver
intramuscular or subcutaneous injections up to one ml in volume.
In addition, Bioject is developing a syringe for the Biojector 2000 that delivers
intradermal injections that is currently in clinical trials. Bioject has a portfolio of
needle-free injection products to meet the varied needs of today’s healthcare
environment. Each product is unique in its power source.
5.4. Biojector 2000:
The Biojector 2000 is a durable, professional grade injection system designed for
healthcare providers. The Biojector 2000 is the only needle free system in the world
cleared by the FDA to deliver intramuscular injections. The system can also deliver
subcutaneous injections, and is being used for intradermal injections in clinical trials.
Figure 19. Biojector 2000
The Biojector 2000 uses sterile, single-use syringes for individual injections, which
prevent the cross-contamination that has been reported with fixed-nozzle jet injection
systems.
More than 10 million injections have been administered successfully using the
Biojector 2000, with no reports of major complications. Because there is no needle,
the Biojector provides healthcare workers with an unparalleled level of protection

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against accidental needle stick injuries. In high-risk situations, such as delivering
injections to patients known to be infected with HIV or hepatitis, the Biojector is an
ideal injection system.
5.5. Vitajet 3:
The Vitajet 3 is an easy-to-use, economical needle-free injection system for delivering
insulin. The system requires no maintenance or re-assembly. With disposable nozzles
that are replaced once-a-week, the Vitajet 3 offers the quality of a reusable medical
product, with the convenience and safety of a sterile disposable. The exclusive, easy-
to-read Crystal Check disposable transparent nozzle allows inspecting the dosage
prior to injection and visually confirming loading and full discharge of your insulin
after each use.
Figure 20. Vitajet 3
The Vitajet 3 received the FDA marketing clearance for delivering subcutaneous
injections of insulin in 1996. Since then, the system has been used to deliver hundreds
of thousands of injections, safely, economically, and without the use of a needle.
5.6. Cool.click:
Bioject developed the cool.click needle-free injection system for delivering Saizen
recombinant human growth hormone. In some children, naturally occurring growth
hormone is absent or is produced in inadequate amounts. In these cases, Saizen or
growth hormone replacement must be injected to maintain normal growth.

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Figure 21. Cool click
Cool.click is a customized version of Bioject’s Vitajet 3 needle-free injection system.
The system includes customized dosage features to accurately deliver variable doses
of Saizen and was designed with bright colors to make the injector attractive and non-
threatening to children. The cool.click received FDA market clearance for delivering
subcutaneous injections of Saizen in June, 2000.
5.7. SeroJet:
The SeroJet is a needle-free injection system for delivering Serostim recombinant
human growth hormone for treatment of HIV-associated wasting in adults. HIV-
associated wasting is a metabolic condition in which people infected with HIV lose
body weight. If not treated, this could result in increased morbidity and mortality.
Serono developed Serostim to treat this condition by utilizing the natural properties of
growth hormone in increasing lean body mass. SeroJet is a customized version of
Bioject’s Vitajet needle free injection system. The system includes customized dosage
features to accurately deliver variable doses of Serostim.

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Figure 22. SeroJet
The SeroJet received FDA market clearance for delivering subcutaneous injections of
Serostim in March 2001.
5.8. Iject:
Bioject has developed a second-generation gas powered injector known as the Iject,
which is based on the design and performance of the B2000 and is intended to serve
as a single-use pre-filled device. The pressure profile of the Iject has been
documented by in vitro testing to be virtually the same as that of the B2000, and
injection performance of the two devices is therefore predicted to be equivalent. The
Iject is a pre-filled single-use disposable injection device configured to administer 0.5
to 1.00 ml subcutaneous or intramuscular injections. The device is distributed “ready
to use.” Thus, it requires no additional parts or modifications for function.
Figure 23. Iject

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The device is primed by rotating the trigger sleeve 180 degrees, and an injection is
administered by advancing the trigger sleeve while the nozzle is held against the
injection site (Figure 21) The Iject needle-free injection system is an investigational
device, subject to the US Food and Drug Administration clearance for commercial
distribution.
5.9. Non-invasive DDS: Untapped potential:
Aradigm Corporation has recently acquired the Intraject technology, initially
developed in the UK by Weston Medical. It is the only pre-filled and disposable
needle-free device in late-stage development, with commercial scale-up in process.
Aradigm’s Intraject collaborators include Roche for the delivery of pegylated
interferon alpha (Pegasys) and GlaxoSmithKline for Imitrex.
The Intraject device is about the size of a fountain pen. The drug capsule is glass, a
material that has demonstrated excellent stability profiles for liquid protein
formulations. The energy to drive the actuator forward to deliver the 0.5-ml
formulation is provided by compressed nitrogen. The delivery process is completed in
less than 60 milliseconds with less bruising and discomfort than may be encountered
with syringes, pens or other devices.
5.10. Biovalve’s Mini-Ject technology:
The Mini-Ject represents the next generation in needle-free injection systems by
combining the features of accuracy reliability, a variety of prefilled options,
comfortable administration, and full disposability, all within a patient friendly easy-
to-use design. The Mini-Ject can deliver a wide range of drugs, ranging from small
molecules to large proteins, fragile antibodies, and vaccines. Delivery can be targeted
to intradermal, subcutaneous or intramuscular depending on the clinical need. No
other single use needle-free delivery technology provides the same level of
performance as the Mini-Ject technology with the ability to target specific tissue
layers over such a broad range of drug volumes (0.1 mL to 1.3 mL) and viscosities.

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5.11. Antares’ Medi-Jector Vision technology:
Antares Pharma, one of the pioneers in the field of needle-free injection technology
has developed Medi-Jector Vision technology which is used to deliver insulin to
diabetes sufferers. It is a newest marketed version of the reusable, variable dose,
spring-powered device for insulin delivery. This technology is also being used to
deliver human growth hormone. Its plastic, disposable needle free syringe allows the
patient to see the dose prior to injection. It is marketed in US and Europe for insulin
administration since 1999.
25,26,27
TABLE 1. SUMMARY OF MARKETED PRODUCT8,28
Product
Name
Compa
ny
Type of
system
Actuation
mechanis
m
Department
of penetration
Drug
Types
Drug
volume
(ml)
Comments
Medi-
jector
vision
Antares
Pharma
Inc.
Liquid
based
needle
free
injection
Spring Subcutaneous Insulin _ Compatible
with all
types of
U-100
insulin
Biojector
2000
Bioject Liquid
based
needle
free
injection
Compress
ed gas
Subcutaneous,
Intramuscular
Liquid 1 Used to
deliver
vaccines
Vitajet3 Bioject Liquid
based
needle
free
injection
Spring Subcutaneous Insulin 0.02 -
0.5
Can be
used for
self-admi
nistration

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Iject Bioject Liquid
based
needle
free
injection
Compresse
d gas
Intramuscular,
Subcutaneous,
Intradermal
Liquid Variabl
e
Available for
single use
or multiple
uses
Intraject Weston
medical
Liquid
based
needle
free
injection
Compresse
d gas
Subcutaneous Liquid 0.5 Delivers
drug in
less than
60 milli sec
Penjet Penjet
Corporat
ion
Liquid
based
needle
free
injection
Compresse
d gas
Intramuscular,
Subcutaneous,
Intradermal
Liquid 0.1 -0.5 Low cost,
easy to
operate
Injex30 Injex Liquid
based
needle
free
injection
Spring Subcutaneous Insulin 0.05-
0.3
Dual safety
system is
present.
Injex150 Injex Liquid
based
needle
free
injection
Spring Subcutaneous Insulin 0.8-1.5 Deliver
largest
dose among
injex
products
Crossject Crossjec
t
Liquid
based
needle
free
injection
Spring Intramuscular,
Subcutaneous,
Intradermal
Liquid 0.2 - 1 Operating
Is based on
Novel gas
tech.
Depixol
Depo
injection
Lundbec
k
Limited
Depot
based
needle
Compresse
d gas
Intramuscular Liquid 2 - 3 Operates by
using

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free
injection
compressed
gas
Powderjec
t system
Powderj
ect
Pharmac
eutical
Powder
based
needle
free
injection
Compresse
d gas
Intradermal Powder
_
Uses helium g
for delivery o
drug
particles
Miniject Bio
valve
Liquid
based
needle
free
injection
Compresse
d gas
Intramuscular,
Subcutaneous,
Intradermal
Liquid 0.1 -0.3 Can deliver
wide range
of drugs

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6. Advances in Needle Free Injection Technology
6.1 Needle free, Auto and pen injectors25,29
An auto injector (or auto-injector) is a medical device designed to deliver a single
dose of a particular (typically life-saving) drug. Most auto injectors are spring-loaded
syringes. By design, auto injectors are easy to use and are intended for self-
administration by patients, or administration by untrained personnel. The site of
injection depends on the drug loaded, but it typically is administered into the thigh or
the buttocks. The injectors were initially designed to overcome the hesitation
associated with self administration of the needle-based drug delivery devices.
Advances in auto injector design and in needle free injectors are helping
pharmaceutical companies to market their drugs and to compete more effectively by
providing gains in market share, allowing greater penetration of markets, helping
patients to comply with dosage regimes and providing safer injections. Indeed,
injection devices were once considered as an afterthought but now in some product
categories they are becoming an entry ticket; an essential part of the drug’s
presentation to the market, without which they would fail to attract patients.
Pharmaceutical companies are developing injectors in parallel with their new drugs, in
the knowledge that a device will be needed at product launch.
Auto injectors are advancing both commercially and technically with the recent
launch of a second pre-filled single-use device, containing a standard pre-filled
syringe, which automates needle insertion, drug delivery and automatically covers the
needle after use. Drugs to treat RA, Anemia and Neutropenia are now available in
such prefilled convenient patient-friendly presentations. In parallel to auto injector
development there have been significant advances in needle-free and powder delivery
which are increasingly showing that they offer an alternative to the needle.
6.1.1. Design
The auto injector keeps the needle tip shielded prior to injection and also has a
passive safety mechanism to prevent accidental firing (injection). Injection depth can

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be adjustable or fixed and a function for needle shield removal may be incorporated.
Just by pressing a button, the syringe needle is automatically inserted and the drug is
delivered. Once the injection is completed some auto injectors have visual indication
to confirm that the full dose has been delivered. Auto injectors contain glass syringes,
this can make them fragile and contamination can occur. More recently, companies
have been looking into making auto injectors syringes out of plastic to prevent this
issue.
Examples
a. Anapen, Epipens, or the recently introduced Twinjects, which is often
prescribed to people who are at risk for anaphylaxis.
b. Rebiject and Rebiject II auto injectors for Rebif, the drug for interferon beta-la
used to treat Multiple sclerosis. An auto injector for the Avonex version of this
same medication is also on the market.
c. Sure click auto injector is a combination product for drugs Enbrel or Aranesp
to treat Rheumatoid arthritis and anemia, respectively.
6.1.2. Military use
a. Auto injectors are often used in the military to protect personnel from
Chemical warfare agents. In the U.S.military, atropine and 2-PAM-Cl
(pralidoxime chloride) are used for first aid ("buddy aid" or "self-aid") against
nerve agents. An issue item, the Mark I NAAK, provides these drugs in the
form of two separate auto injectors. A newer model, the ATNAA (Antidote
Treatment Nerve Agent Auto Injector), has both drugs in one syringe,
allowing for the simplification of administration procedures. In the Gulf War,
accidental and unnecessary use of atropine auto injectors supplied to Israeli
civilians proved to be a major medical problem.
b. In concert with the Mark I NAAK, diazepam (Valium) auto injectors, known
as CANA, are carried by US service members.

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6.1.3. Variants
A newer variant of the auto injector is the gas jet auto injector, which contains a
cylinder of pressurized gas and propels a fine jet of liquid through the skin without the
use of a needle. This has the advantage that the auto injector can be reloaded, and a
variety of different doses or different drugs can be used, although the only widespread
application to date has been for the administration of insulin in the treatment of
diabetes.
6.1.4. Using pens like vials
a. In response to the rising costs of medications, some healthcare providers have
replaced insulin vials on nursing units with insulin pen injectors (or just the
pen cartridges) from which they routinely withdraw a patient’s prescribed dose
using an insulin syringe and needle. In some cases, the pens or cartridges are
used as multiple-dose vials for a single patient, and each dose is removed with
a sterile needle and syringe; in other cases, the pens or cartridges are used as
floor stock “vials” from which to obtain insulin doses for multiple patients
using a new sterile needle and insulin syringe for each puncture into the
cartridge membrane. The manufacturers do not recommend the withdrawal of
medication from the pen, except in an emergency with a malfunctioning pen.
In these instances, the pen should then be discarded, even if insulin remains in
the pen. Similar to withdrawing medication from a vial, these practices may
also result in unlabeled syringes of insulin.
b. Large pockets of “air” have been observed in cartridges of insulin pen
injectors after aspirating some of the drug with a needle. If the pen injector or
cartridge is not discarded, and the air is not eliminated before delivering a
subsequent dose, the patient could receive less than the desired dose of insulin
as well as a subcutaneous injection of air.

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6.2 Intraject Systems
Figure 24. Intrajet device comprises two parts: an
Aquator and pre- filled glass capsule
Intraject system is the world’s first disposable, needle free injection device for the
delivery of liquid medicaments. Invented by terry wetson. Intraject is specially
designed to meet the patient needs; being pre-filled and disposable the system is
designed for unobtrusive, contamination free self-injection. With minimal training a
practitioner, patient or a care can deliver are liable, virtually pain free injection. It is
replacing pre-filled syringes and auto injectors in many commercial product areas.
Intraject offers pharmaceutical companies opportunity to extend the product lifestyle
and manage patent expiry. The system is designed for simple manufacture and, as a
prefilled device, provides pharmaceutical licensees with exclusivity which is critical
for successful product differentiation at low cost.
6.3 Bioject®Zetajet
The Bioject®ZetaJet™, Bioject’s latest advance in needle-free delivery systems,
consists of two components, the portable injector and an auto disabling disposable
syringe. It is intended to deliver vaccines and injectable medications either
subcutaneously or intramuscularly and is indicated for both professional use and
home use for patients who self-inject. The syringe assembly has a unique “auto-
disable” feature that prevents re-use of the syringe.

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The Bioject®ZetaJet™ has FDA clearance for delivering subcutaneous or
intramuscular injections of liquid medication, including vaccines and other injected
medications.
Figure 25. Bioject system
6.4 Injex. Needle-Free Injections for Infiltration Anaesthesia
INJEX Pharma now offers a solution for previous local anesthesia problems, a needle-
free injection system. The INJEX System uses an injection ampoule with a micro
orifice of only ø 0.18 mm through which the anesthetic is administered under dosed
pressure to the sub mucosa – virtually painless and exactly where it is needed.
6.4.1 Areas of application:
The ampoule has to be placed on the attached gingival at an angle of 90° directly
above the tooth to be anaesthetized. This defines a determined area of application

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(anesthesia is possible with the following teeth1: 15-25, 33-43, all teeth of the primary
dentition 55-85).
Figure 26. Injex
6.4.2.Pediatric patients:
Children are especially difficult dental patients because they are so very much afraid
and cannot understand the purpose of the treatment. Experienced dentists are able to
use INJEX to administer anesthetic to all deciduous teeth (KÖRPERICH, 2002). The
shorter onset time (SALEH et al., 2002) also reduces the treatment induced stress for
children. Since only 0.3 ml of local anesthetic is administered, the maximum dose is
hardly ever used. Even very young children can be treated with INJEX
(KÖRPERICH, 2002) who are especially pleased with the needle-free injection. The
stress for accompanying parents is also reduced significantly due to the shorter
treatment time. Small children are frequently less willing to cooperate with the
dentist. This is where INJEX reduces the stress of administering a local anesthetic due
to the lower risk of injury. Patients usually continue to request anesthesia with this
system the next time they visit their dentist (MUNSHI et al., 2001; GRAU et.al.,
1997; SARAVIA et al., 1991).
6.5 Madajet xl Podiatry Needle Free Injector
Easy to use and virtually painless compared to needles. Provides instant local
anesthesia or regional blocking for most podiatric procedures. Minimizes tissue
trauma and facilitates suturing as there is no tissue distention around the injection site.
Provides adequate anesthesia for deep needle insertion. May be used with anesthetics,
steroids and other medicaments. Has interchangeable Extend Tips for easy
sterilization between patients. Can be used on all age groups. Consistent depth of

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penetration of 4- 5.5mm below the epithelium and makes a wheal at the base of the
injection of 5-6mm in diameter. Consistent volume of 0.1cc per injection
intradermally. Permits approximately 38 injections with single loading (to 4.0cc).
May be sterilized by autoclaving or your usual sterilization process - do not use dry
heat.
30
Figure 27. Madajet

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7. The Future
Many of these needle-free alternative technologies are in the development stage.
Companies are still working on producing devices that are safer and easier to use.
They are also working on alternatives which can deliver even more types of
medicines. Inhalers are being improved as are nasal sprays, forced air injectors and
patches. In the future, other foods may be genetically enhanced to deliver vaccines
and other drugs. These include foods like bananas and tomatoes.
In fact, bananas are being looked at as carriers for a vaccine to protect against the
Norwalk virus. Tomatoes that protect against hepatitis B are also being developed. In
addition to new delivery systems, scientists are also investigating methods for
producing longer lasting drugs that will reduce the number of needle injections.
2

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8. Conclusion
Needle-free injection systems have potential to improve efficiencies. Major
advantages of needle-free systems are the elimination of broken needles, a more
constant delivery of vaccines and drugs, and decreased worker safety risk. Needle free
injection systems are customizable to each operation and can be modified to optimize
productivity.
Needle free injection technology offers effective injectors for a wide range of drugs &
bioequivalent to needles and syringes. Needle free devices have demonstrated
consistent delivery to the epidermis, the dermis, the subcutaneous and the
intramuscular space. They offer less pain, avoid needle stick injuries and
contamination, allows self administration and results in no needle phobia and are thus
strongly preferred by the patients. Some of them are ideally suited to chronic
injections of varying doses of insulin, proteins and monoclonal antibodies.
These devices are very easy to be used, don't require any expert supervision or
handling, easy to store, and dispose.
These devices are suitable for delivery of drugs to some of the most sensitive parts of
the body like cornea.
8,25

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