Painless and Needle free Supersonic Injection Technologies
Dr. J.K. Patel
Drug delivery is defined as any formulation or device that improves therapeutic
effectiveness of a drug by controlling the rate, time and place of the compound
entering the body. These aspects have been important to pharmaceutical industry,
so, it is an important part of the drug development process.
In the drug delivery by injection to the body Needle phobia affects at least
10% of the general population. Subcutaneous injections are used for many reasons,
including immunizations, administration of medications such as insulin and
heparin, and to provide local anesthesia, both for surgery and for intravenous
Various approaches are employed to alleviate the pain caused
by intravenous cannulation. These include jet injectors use a propelling force,
which can be metal springs, compressed air, carbon dioxide, or helium gas,
to create pressure that is used to literally “shoot” drug, in liquid or powdered
form, in to the skin, provides needle free and pain free delivery of traditional
and biotechnology drugs and vaccines and has application to diagnostics. Appropriately
formulated fine particles of 1 to 70 µm diameter are accelerated to sufficiently
high velocities in a hand held device using the energy of a transiently supersonic
helium gas jet so that they can painlessly enter tissue. So, these devices
cause little to no pain, and are simple to use, convenient, and effective.
As a result, drugs or vaccines delivered by this way could be more efficacious
than those delivered by traditional parenteral routes. In this technique,
the drug particles have suitable physical and chemical properties and are
in a specific size range, these are explaining in later. The technology can
be applied to traditional small molecules, peptides, proteins or DNA, i.e.
any pharmaceutical agent or vaccine that can be formulated in to solid particles
of the appropriate size distribution, mass and strength. This article will
review the complementary approaches to the needle free injection, liquid and
powdered based NFI, systems, powder characteristic, summarize the currently
available NFI technologies by different companies and advantages of the NFI
compare to the other drug delivery system.
The development of a system that allows
medicine to be propelled through the skin into the underlying tissue, without
the use of a needle, could offer an effective alternative to conventional
delivery. It is a high velocity dry
powder injection, a new development in drug delivery, provides needle free and
pain free delivery of traditional and biotechnology drugs and vaccines. For
delivery via skin, the particles must only breach the outermost barrier, the
stratum corneum. So, drugs delivered with powderject’s technology or Needle Free Injection (NFI)
reach the circulatory system faster than those administered by subcutaneous
injection, because it’s an intradermal delivery and
the capillary blood supply is immediately adjacent to where you’re placing the
For delivery via powderject’s
technology the drug particles must have suitable physical and chemical
properties and be in a specific size range but may consist of pure drug or
advanced formulation containing traditional inert ingredients to dilute or
stabilize the drugs or alter their delivery profile. Appropriately formulated
fine particles of 1 to 70 μm diameters are
accelerated to sufficiently high velocities in a hand held device1, 2.
The technology can be applied to traditional small molecules, peptides,
proteins, or DNA, i.e., any pharmaceutical agent or vaccine that can be
formulated into solid particles of the appropriate size distribution, mass and
strength, and it also successfully deliver testosterone, lidocaine
hydrochloride, and macromolecule such as calcitonin
and insulin3, 4.
Complementary approaches to NFI
There are two approaches to NFI: liquid
and powder drug delivery.
(1) Liquid based NFI
The principle of NFI was first
demonstrated in 1936 (Lockhart, 1936). But the second generation of NFI technologies
came during the 1970s and 1980s and focused primarily on the insulin market for
diabetes therapy. And then past few years have seen a resurgence of interest in
third generation NFI technology and new approaches to technology
commercialization 5, 6.
These technologies are used by the same
basic principle to deliver the drug, if a high enough pressure can be generated
by a fluid in intimate contact with the skin, and then the liquid will punch a
hole in to the skin and be delivered in to the tissues in and under the skin.
Although the same principle is applied as
in powder but there is difference in the actual design and operation of the
devices. Device has major influenced by the accuracy of delivery and stress
subjected to the product delivered. The device has sufficient pressure to
puncture the skin.
Antares Pharma, lnc.
Advantage health services lnc.
National medical products, lnc. (NMP)
Equidyne Systems, lnc.
(2) Powder based NFI
system for particle delivery is the combination of a device with a specially
formulated powdered drug. Unique devices have been configured for injection
into any physically accessible tissue; normal skin or mucosal sites. Some
systems have been designed for single use and are completely disposable and
others, intended for longer courses of therapy, have some reusable elements.
For convenience and economy, reusable systems have only the drug and
pressurized helium energy source in a single cartridge that is replaced for
The principle of
all the devices is the same; i.e. the harnessing of the energy of a transient
gas jet to accelerate a pre measured dose of particulate drug formulation. The
most common orifice size is 0.127mm, compared to a 25-gauge needle, which is
about 1mm. So, process is completely painless, “people feel the tap of the gas
on the skin, it’s like flicking your finger against your skin.” So, device
configuration will satisfy many therapeutic applications.
systems are powered by a manufactured helium gas aluminum microcylider
of ampoule design and use a drug cassette or package to introduce the powder
into the gas flow. In operation, the microcylider tip
can be broken when the device is pressed against the tissue site to be treated.
This releases the compressed helium suddenly to open the drug cassette for
delivery of its payload to the tissue. The gas does not actually penetrate the
skin, instead, it is reflected back in to the device through a silencer. The
silencer is necessary because the flow is transiently supersonic. Instead of
hearing a report, the sound is like a gentle handclap. The other components of
the device are manufactured from medical grade plastics using standard
injection molding techniques15, 16.
injection systems for intermittent use are fully disposable and contain all the
required components within a fully assembled, sealed system. A pre measured
mass of drug powder is heat sealed within a trilaminate
drug cassette that consist of two plastic membranes chosen to tear wide open at
a specific pressure to initiate the supersonic helium flow. The nozzle is
countered to achieve a pre determined gas velocity, and a flow pattern to
deliver a total area up to 2cm‑2 depending upon the
therapeutic requirements. The system is fitted with a silencer to reduce the
sound of the gas flow to a low level, like the “pop” of a cork. Drug or vaccine
penetration will occur through the stratum corneum in
to the epidermis.
Companies involved in powder based NFI
Powderject17 manufactured by Powderject
pharmaceuticals, based in oxford and the
of helium gas to push a dry powder through the skin, leaving no puncture mark.
Sarphie et al., 199718 was delivered inulin to
hairless guinea pigs from a prototype Powderject device. Though
inducing a small but acceptable degree of skin damage. So, advantageous
for the delivery of large macromolecules across the skin, the Powderject system
has also been used for intradermal DNA immunization
against influenza a virus in mice (Degano et al., 1998) 19. Other
therapeutic agents either as particles or as coatings on small gold particles
delivered by jet injectors include hepatitis B DNA, proteins such as B-
interferon as well as small organic conventional therapeutic agents such as lidocaine (lignocaine) for local anaesthesia.
As the concept of
needle less injection of powders has become established, more efforts are being
directed at optimizing delivery by understanding the gas and particle dynamics
within the devices (Quinlan et al., 2001)
The formulation or powders
Powder is an
essential component of the Powderject technology. For powder injection particle
quality and size distribution are uniquely important, not only traditional
shelf life chemical stability but also physical stability is required.
According to information from Powderject, these administered particles must
have suitable properties and fall in a specific size range. They may consist of
pure medicines, or may be novel formulations containing additional inert
ingredients to dilute or stabilize the product. The powder must retain its size
distribution during transport and storage and particles must be sufficiently
robust to survive the highly energetic gas jet within the device as well as
ballistic impact with the skin. The dispersed particles must then dissolve and
the payload diffuses to act locally or be transported by the systemic
circulation to the intended site of action in the body21.
also must be strong because they hit the skin at high velocities. The particles
have been clocked as fast as 900 meters per second, with 400 to 600 meters per
second being more typical range. For powders having particle densities around
1g/cc, mean diameters of greater than about 20 μm
are required for skin penetration for typical velocities. At particle size
ranges above 100-μm local skin tolerability limits the delivery. In a
special case, the injections of DNA vaccines, gold particles of 1-3 μm diameter coated with a nucleic acid, typically
plasmid DNA, are used. Such particles take advantage of the high density of
gold to provide sufficient momentum to penetrate tissue. Such coated gold
particles are small enough to enter living cells without damaging them. Inside
the cell plasmid DNA dissolves and natural transcription and translation
process in the cell produce the encoded proteins. The proteins, when processed
by the cell into antigen peptides and presented by the major histocompatibility complex (MHC) evoke both cellular and humoral immune responses. The response to a DNA vaccine is
similar to that provoked by a natural infection but without the risks of a
replacing infectious agent16.
In The Powderject
system process to make powders particles is powder compression, milling and sieving.
Other more readily scalable methods include spray drying, spray freeze drying,
fluid bed drying, spray coating of seed particles, solution filling and drying
pre formed hydrogel beads and emulsion techniques to form erodible micro
particles, with ideal particle size distribution, shape, strength, and
dissolution characteristics demonstrate significant improvements in preclinical
studies of bioavailability and consistency.
In the Powderject
system ideal particle formulations and processes for each application are as
Table: 2. Ideal characteristic of particle
Ideal characteristic of particle
Particle size range:
Organics: 10-70 μm
Gold / DNA: 1-3 μm
High process yields
Drug stability (during processing and storage)
Capability of aseptic operation
Scale (up and down)
Reproducible particle size range narrow is desired
By using the drug in powder form rather than dissolved in liquid, a much
smaller volume of material is shot through the skin, so the injection is become
painless22. Development of specific powder composition for each
drug is based upon need for long-term chemical and physical stability as well
as compatibility with a scalable process. A decision on drug content is made
to achieve an automated high-speed dispensable dose mass deliverable by the
Powderject powder injection system. Specific traits such as moisture tolerability,
flowability, etc. and the need for buffers, sugars, cryo-protectants, process
shear-protectants, antioxidants, densifiers and binders, etc.to stabilize
biomolecules are considered. Bioerodible carriers, slowly dissolving excipients
or specific, less soluble salts or dissolution aids can provide sustained
release or otherwise altered pharmacokinetics to improve drug performance.
For ease of regulatory approval, selection of excipient is generally directed
to those already used in approved parenteral products16.
Determination of crystallanity or glass transition temperature and water
vapor sorption analysis is valuable in certain cases. A practical functional
test is in vitro skin penetration using full thickness human cadaver skin.
Injected skin can be mounted in Franz type diffusion cells to assess drug
delivery, dissolution and transport. Measurement of transepidermal
water loss (TEWL) can also determine the physical effect of the powders on the
Most Protein and
peptide drug are only be delivered currently by needle and syringe or with less
invasive pulmonary or nasal approaches. Protein drugs are very potent so it
fits powderject systems perfectly. Drugs of this
class required increased stability during storage and delivery as a dry solid
avoids costly chilled supply lines to maintain their activity in a liquid form.
Advantages of NFI technology
As such, the
potential applicability of this delivery technology is huge. The technology
allows patients to self-administer, reduces tissue damage and distributes
medicine more effectively and widely in the subcutaneous tissue without
penetration in to deeper layers23. Delivery by this means could
consequently stimulate langerhans cell activity and,
as such, induce mucosal as well as humoral immunity.
As a result, vaccines delivered in this way could be more efficacious than
those delivered by traditional parenteral routes. The
therapeutic applications are diverse and limited only by the mass of drug
formulation that can be delivered and inherent local compatibility with the
tissue at the site of application. Powder presentation of drugs or vaccines by
this system offers, important therapeutic and / or prophylactic advantages over
the other drug delivery techniques are following:
· Avoid real as well as needle phobia based pain
· Obviate needle stick hazard and sharps disposal
· Enhance stability by ambient storage and delivery as a dry
· Eliminate complexity of reconstitution and any effects of shear
· Provide rapid delivery and reproducibility comparable with
needle and syringe
· Improve bioavailability over other non- or less invasive drug
· Improve immune response to DNA and conventional vaccines
· Provide the capability to alter the pharmacokinetics of
· Jet injectors are used to deliver mass immunization of
influenza, tetanus, typhoid, diphtheria, pertussis,
and hepatitis A vaccines24.
The cost of a
single use dermal powderject system to powderject’s pharmaceutical clients is comparable to needle
and syringe kits. A multiple use dermal powderject
system can reduce the cost per treatment even further, however, each powderject system is expected to offer further significant
economics benefits in the areas of safety, storage, self or home administration
not requiring special skills or training and avoidance of disposal of hazardous
used materials. Follow up medical costs of non compliance with a beneficial
treatment regimen are expected to be reduced, because patients with an aversion
to needle injection are more likely to comply with their course of treatment if
it is administered by means of a powderject system.
As with Powderject, its greatest advantage is the elimination of contaminated
sharps. Although there are not enough data to advocate its use now, this
technology is targeted for pediatric populations25.
issue with the use of jet injectors is the more frequent appearance of
localized soreness, erythema, and hematoma
at the injection site. Injection sites from needle free jet injectors may also
tend to bleed more than those at a needle injection site.
1. Sarphie, D.F. J.
Controlled Release. 1997; 47:61-65.
2. Hickey, P.L. AAPS Conference, November, 1998;
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Reviews in Therapeutic Drug Carrier Systems, 16(4): 331-384, begell house, lnc.,
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5. Baichal A, Neville DA.
Drug Delivery Technology. 2001; 1: 60-62.
6. Hingson RA,
historical development of jet injection and envisioned uses in mass
immunization and therapy based upon two decades’ experience. Military Medicine,
7. Weston Medical.
Weston Medical.com FAQs. Available at:
15. Sarphie, D.F. Gas
Propulsion of Microprojectiles for the Transformation
of Biological Cells, D. Phill. Thesis, university of
16. Haynes, J.R. J. Biotechnology. 1995; 44: 37-42 and
Advanced Drug Delivery Reviews.1996; 21: 3-18.
17. Powderject Pharmaceuticals Plc. Powder Injection. Available at:
18. Sarphie et al., 1997. Transdermal
& Topical Drug Delivery, Adrian C Williams, 2003, 136-137.
19. Degano et al., 1998. Transdermal &
Topical Drug Delivery, Adrian C Williams, 2003, 137.
20. Quinlan et al., 2001. Transdermal
& Topical Drug Delivery, Adrian C Williams, 2003, 137- 138.
21. Pharmatimes. Volume-33, June
22. Bellhouse; B.J., Sarphie; D.F. and Greenford; J.C. (1994-9).
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23. Parent du Chatelet I, Lang J,
Schlumberger M, Vidor E, Soula G, Genet A, Standaert SM, Saliou P. Clinical immunogenicity and tolerance studies of liquid vaccines
delivered by jet injector and a new single use cartridge (Imule):
comparison with standard syringe injection. Imule Investigators
Group. Vaccine. 1997; 15: 449-458.
24. Illum, L and Davis, S.S.
Nasal vaccination: a non invasive vaccine delivery method that holds great
promise for the future, Advanced Drug Delivery Reviews. 2001; 51: 1-3.
Vaccines. Advanced Drug Delivery Reviews. 2001; 51:21-42.
J.K. Patel and H.P. Patel
*Dr. J.K. Patel is Assistant
Professor in Pharmaceutics at Shree S.K.Patel College of Pharmaceutical
Education and Research,
with 10 years of teaching and research experience. He has supervised 9 M. Pharm.
thesis and has 45 publications in international and national journals of
repute. His area of research includes novel drug delivery systems and bioadhesive
technology. He presented research papers and delivered a lecturer at
Email address: firstname.lastname@example.org
Mr. H.P.Patel is presently M.Pharm
III student at Shree S.K.Patel College of Pharmaceutical Education and