hypodermic injections have been the standard for the cutaneous drug
administration 1. These vaccinations usually called as “shots” are used to control
the infectious diseases in children and adults. However, the pain and needle
phobia associated with the traditional vaccination results in poor patient
compliance. Apart from the poor compliance the needle assisted vaccination
possesses the safety risks for patients, healthcare providers and the
community. The primary concern is the transmission of the infectious diseases
between patients or between patients and the healthcare provider 2. Improper
handling of the syringes will lead to the syringe struck injuries and increased
in the risk of blood-borne diseases.
The needle-free vaccine delivery
system focuses mainly on three different surfaces: under the skin via jet
injectors, via the external surface or transcutaneous delivery or via mucosal
surfaces. The main aim of the vaccine delivery system is to stimulate immune
system of the body. The traditional syringes have been successful in
stimulating immune responses and the new needle-free systems should show
equally potential results in immunological responses.
The jet injectors are used to
deliver liquid medication based on the principal that the high pressure jets
are capable of penetrating deep into the human skin without the causing the
pain at the vaccination site. Here the drug can be delivered to intradermal,
subcutaneous or intramuscular tissues depending on the mechanical properties of
the fluid stream used. The jet injectors are handheld devices contains the
calibrated high tension spring. The drug is delivered through the nozzle where
the nozzle is held against the skin of the patient and when the trigger is
pressed, the spring is released against rubber plunge and this forces the
vaccine with high pressure ranging from 2300 to 3500 pounds per square inch 3
into the skin. The penetration of drug occurs in three different steps:
erosion, stagnation and the dispersion 4.
First the cylindrical hole is formed during the erosion which creates a
pathway for the drug penetrate into the tissue.
The drug follows the path and reaches a point of stagnation from where
the drug is dispersed into the tissue. Different types of jet injectors are
used for vaccination. The multi-use nozzle jet injectors were the first
generation of jet injectors followed by disposable-cartridge jet injectors and
2.1 Multi-use nozzle injectors
The multi-use nozzle injectors were the first
generation of jet injectors used in mass immunization campaign for delivering
vaccines during bioterrorism emergency, natural pandemic or military emergencies.
These injectors provide 50 doses per vial and used for vaccinating 1000
subjects per hour 5. The multi-use injectors are vulnerable to contamination
by body fluids and transmission of blood borne diseases.
2.2 Disposable-cartridge jet injectors
These are single use nozzles used to eliminate the
risk of cross contamination with the multi-use nozzle injectors. Here, the
liquid vaccine is delivered within a disposable cartridge. Currently single
dose cartridge is used to avoid the risk of contamination. But the studies have
shown that, the researchers are working on developing multiuse cartridges that
could for up to 600 injections per hour.
2.3 Powder Injection
The powdered injection in the enhancement of the disposable
cartridge injectors where dry powder is used instead of liquid vaccine. The
studies have shown that these vaccinations have produced both antibody and
immunization responses. The dose required in less as compared to the
traditional syringe method because powder injections deliver the antigens to
Langerhans cells of the epidermis 6.
2.4 Advantages of needle-free injectors
The important advantage of et injectors is that it has
shown similar immunological response as that of traditional syringe method. Due
to the high pressure of the fluid stream, the drug is diffused quickly into the
tissue. This allows for the greater contact
volume between antigen and the immune cells that is increased bioavailability
of the drug. The multiuse nozzle injectors have proven speed of vaccine
delivery thus this could be used in natural pandemics or emergencies. Jet
injectors are easy to use and possesses no occupational risk and reduced cross
contamination compared to the hypodermic injections.
The jet injectors have shown better results than the
hypodermic injection, but it has few limitations which cannot be ignored. The reliability
of the dose and the depth of the drug penetration is dependent on the jet
parameters. Penetration of drug into the tissue is dependent on jet velocity,
orifice diameter, viscosity, fluid volume, porosity and the material stiffness.
The skin’s mechanical properties vary among the individuals thus the efficacy
of the delivery varies from subject to subject. The devices size and cost is
limited by the high pressure requirement (>20MPa) which is required to
penetrate deep into the skin.
of transcutaneous immunization is to penetrate the vaccine antigen or adjuvant
into immune cells through the skin layer 7. The skin is multilayered
structure consisting of outer layer i.e., stratum corneum which is composed
cornified keratinocytes followed by epidermis which is rich with the immune
cells and keratinocytes and lastly the epidermis is supported with the
underlying dermis. Here the drugs are targeted into the Langerhans cells that
stimulates inflammatory cytokine responses.
Stratum corneum has been the greatest barrier for the
permeation of drugs into the skin. Therefore, the transcutaneous immunization
looks for penetrating into the corneum by variety of means such as hydration,
abrasion and electroporation. In hydration, the skin surface is occluded using
wet gauze which causes the keratinocytes to swell and pass the fluid vaccine
into the intercellular spaces. The
corneum can be made permeable by creating mechanical disruption sing adhesive
tapes. In electroporation, aqueous pores are created in the lipid bilayers of
the stratum corneum by the application of the short electric pulses 8.
3.1 Transdermal Patches
Transdermal patches are the first generation system
for transcutaneous immunization. These patches are non-invasive and could be self-administered.
The transdermal patches can provide drug release for the long duration of time
and are safer compared to the hypodermic injections.
Microneedles are pointed projections that are
fabricated into the arrays to provide pathways for the vaccine delivery through
the skin. Studies have shown that the combination of microneedles and the
transdermal patches enhances the skin permeability allowing for the delivery of
larger molecules. The microneedles rage from 25µm to 1000µm depending on the
depth of the epidermis. Solid microneedles painlessly pierce into the skin to
increase the permeability of the skin for the various molecules, proteins and
nanoparticles. The drug formulations are coated within the microneedles which
provides fast and controlled release of peptides and drug into the skin.
3.3 Advantages of transdermal immunization
Transdermal delivery of vaccines provides improved administration
of vaccines. The vaccine delivery targets
the potent Langerhans and the dermal dendritic cells that stimulates the immune
response at the much lower doses than the hypodermic injections. The
transdermal patches are safer and it does not need much training prior to the
application and is cost effective.
Even though the transdermal patches are easy to use, rigorous
clinical studies need to be carried out to prove the results. In case of
microneedles the skin penetrating force is depended on the type, physical
properties and the dose of vaccine antigen loaded into the microneedles. The
patches need additional adjuvants to stimulate the immune responses.
Mucosal vaccine delivery has been the promising drug
delivery system. The mucosal surfaces are rich with immunological cells and
acts as the barrier for the foreign body material. All the mucosal routes such
as oral, nasal, lung, rectal and vaginal are considered as the potential site
for the drug delivery as they provide better bioavailability of the drugs. These
drugs interact with the mucus layer which consists of mucosal epithelial
surface and mucin molecules increases the drug retention time. The mucoadhesive
drugs have shown to increases the drug plasma concentration and therapeutic
activity of the drug 9.
4.1 Nasal vaccines
The intranasal delivery of vaccine provides better
vascularized surface area via which the drug metabolism could be avoided as the
blood is entered directly to the systemic circulation. The vaccine could be
delivered in the form of solutions, powders, micro-particles or the gels.
Adjuvants are required to increase the immunogenicity of nonliving vaccine that
are administrated to the nasal mucosa. The adjuvants could be developed using
substituting amino acids to create non-toxic mutant forms of cholera toxin and
4.2 Aerosol vaccines
Aerosol vaccine delivery system involves small
particles which are generated by the nebulizer are targeted towards the lungs.
Aerosol delivery is a promising system for pediatric vaccine delivery. Aerosol vaccines
could be used in air-borne infectious diseases such as measles, plaque
tularemia. The use of nebulizer, creates a smaller particle of 5µm which are
later deposited into the lower respiratory tract.
4.3 Advantages of mucosal immunization
The mucosal vaccines provide better targeting and
localization of the drug at a specific site. As the mucosal vaccines have
greater bonding between drug form and the absorptive mucosa, it results into
high drug flux at the absorbing tissue. Oral vaccines which are commonly used
for polio, cholera, typhoid have shown better immunological responses and the
ease of administration.
Needle free vaccine delivery systems have proven t be
desirable due to many reasons such as improved safety, reduced risk of
transmission of infectious diseases, better compliance, reduced pain and needle
phobia and faster vaccine delivery. The needle free delivery systems could be efficiently
used in case of natural pandemic and mass vaccination campaign. The systems
mentioned in this paper have its own advantages and limitations. The needle
free jet injectors have improved immunogenicity, speed of delivery. The
transcutaneous patches are easy to use and there is no pain at the administrated
site. The mucosal vaccination provides best immunological responses. As the mucosal
site are first pass site where all the pathogens enter the body. The mucosal
vaccination tends to be promising vaccine delivery system as with the jet
injectors, even though we do not have any needle to assist the drug, the
injector device can still cause stress and phobia among patients. The high
pressure at the administration site can still cause pain. The transdermal patch
is an external additional patch which a patient has to wear for certain
duration of time. This patch can cause irritation due to the adhesive present
on the patch and few adults might not prefer it to wear the patch for longer
duration of time.