NEEDLE FREE DRUG DELIVERY SYSTEM: A REVIEW

Abstract

This review deals with needle less injections ,their applications and

advantages over needle injections .Subcutaneous injections are used for many

reasons ,including immunizations ,administrations of medications such as insulin and

heparin, and to provide local anesthesia ,both for surgery and for intravenous cannulation.

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 , carbondioxide ,or helium gas, to 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.

Approxipriately 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 little to no pain and

are simple to use , convenient ,and effective .This review dealt s with needle free insulin

delivery for diabetes ,the recent trends and other needleless drug delivery systems.

Key words:

Needle free device, power jet, Pulsed microjets, Insulin pills.

1. INTRODUCTION:

As long as drugs have been known to cure diseases, people have searched

for better methods of delivering them. During the early nineteenth century researchers made a

series of discoveries that eventually led to the development of the hypodermic needle by

Alexander Wood in 1853. This device was used to give morphine to patients suffering from

sleeping disorders. In subse-quent years, the hypodermic needle underwent signifi-cant

changes which made them more efficient to use, safer, and more reliable. However, needles

still have significant drawbacks which prompted researchers to find needle-free alternatives.

The first air-powered needle-free injection systems were developed during the

1940s and 1950s. These devices were gun-shaped and used propellant gases to force fluid

medicines through the skin. When a needle is inserted through the skin, the vaccine (or drug)

it carries provides systemic immunity. This is because the vaccine gets into the bloodstream

and provokes the body to create antibodies that are carried throughout the entire body.

Needle injection of drugs is one of the most invasive methods of drug

administering, it damages the tissue which may not heal in case of patients with diabetes, and

in case of careless injection a patient can die from administering tiny bubble of air into a vein,

infection or inflammation, it also is painful if performed improper-ly, also it is very hard to

control the amount of drug administered by an injection and can cause an over-dose and in

some cases death.[1]

In the India and other states like United States, children may get over 13 vaccine

injections by the age of 16. Unfortunately, there are a variety of problems associated with the

hypodermic needles used for these injections. One of the most sig-nificant drawbacks is the

relatively high cost of the needles. Another problem with traditional needles is the lack of

reusability. Additionally, many people have a fear of needles which causes them to avoid

treat-ment

Hypodermic needles are the most common mode of delivering macromolecules in

humans. Currently, 12 billion needle injections are performed every year for the delivery of

vaccines and protein therapeutics such as insulin, growth hormones, and erythropoietin.[2]

Needle although effective has several draw backs:

Needles are expensive. The cost results in a lower vaccination rate, especially for

children in developing countries.

Lack of reusability, if a needle syringe is not sterilized reusing it can lead to the

spread of disease.

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.

Accidental needle sticks lead to injuries and possible infections.

Needles are expensive, so in the developing world they’re often re-used, but “needle re-use

is very dan-gerous because cleaning to appropriate standards is difficult”, yet no viable alternative is

currently avail-able.

“You’re making a large hole that is catching a lot of nerves just because you need rigid walls

for the nee-dle” says bioengineering professor Dan Fletcher.

Diabetes is a major public-health problem and is emerging as a pandemic. As estimated,

135 million people worldwide had diagnosed diabetes in 1995, and this number is expected to rise to

at least 300 million by 2025[3]. People with diabetes generally rotate injection sites to prevent tissue

injury and for the best insulin absorption. Insulin is absorbed most quickly when it is injected into the

abdomen; the thighs and buttocks are other common injection sites. For most patients with type 1

diabetes, the worst part of the disease is to tolerate needle after needle, both for glucose measurement

and to deliver insulin.

These drawbacks have led to the development of al-ternative delivery systems to needle

injections. Needle-free systems solve these problems making them safer, less expensive, and more

convenient.

NEEDLE FREE INJECTIONS

While hypodermic needles were first introduced during the 1800s, needle-free systems are

relatively recent inventions. Motivated by the limitations of injections, needle-free liquid jet injectors

were invented more than 50 years ago and have been used for delivering several vaccines and protein

drugs. The first jet injec-tors were developed in the 1940s for mass administra-tion of vaccines to US

soldiers [4,5] (Patni P et al., 2006 and Narayan krem Gregg et al., 2000). They were effective at

delivering vaccines. These first injectors used com-pressed gas to propel millilitres of liquid into the

skin, even into muscle. The needle-free systems that are most like traditional injections involve the

direct trans-fer of the medicine through the skin. Needle-free injec-tion systems are novel ways to

introduce various medi-cines into patients without piercing the skin with a conventional needle.

Needle-free injection devices propel a small jet of liq-uid or powder at high speed, causing it

to penetrate the skin for subcutaneous, intradermal, or intramuscu-lar administration. These devices

have been used for mass vaccinations for a number of years; however, only recently they are being

promoted as devices for the self-administration of parenteral drugs.

Needle-free injection technology works by forcing liq-uid 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.

Needle-free technologies can be broadly separated into three types:

Powder injections,

Liquid injections and

Depot (or projectile) injections.

Powder Injections

For delivery via skin, the particles must only breach the outermost barrier, the stratum

corneum. So, drugs delivered with powder injection 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 drug[6] (Patel JK 2006).

The Powder injection 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; nor-mal 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 each injection.

The principle of all the devices is the same; i.e. the har-nessing of the energy of a transient

gas jet to accele-rate a pre measured dose of particulate drug formula-tion. The most common orifice

size is 0.127mm, com-pared 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.

The Powder injection systems are powered by a manu-factured 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 micro-cylider 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. The other components of the device are manufactured from medical grade

plastics using standard injection molding techniques[7] (Sarphie DF 1992; Haynes JR 1996).

Ideal characteristics of powder particles:

1. Powder is an essential component of the powder jet technology .For powder injection

particle quality and size distribution is uniquely important, not only traditional shelf life

chemical stability is required.

2. They may consist of pure medicines, or may be formulation containing additional inert

ingredients to dilute or stabilize the product.

3. 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 within the skin.

4. The dis-persed 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 body.

The particles 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 me-ters 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 pe-netration 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 suffi-cient 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 pre-sented by the major histocompatibility complex (MHC) evoke both

cellular and humoral immune responses. The response to a DNA vaccine is similar to that

pro-voked by a natural infection but without the risks of a replacing infectious agent.

In the Powder injection 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 dry-ing pre formed hydrogel beads and emulsion tech-niques to form erodible

micro particles.

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 painless. Bio

erodible carriers, slowly dissolving excipients or specific, less soluble salts or dissolution

aids can pro-vide sustained release or otherwise altered pharmaco-kinetics to improve

drug performance. . Protein drugs are very potent so it fits powderject systems perfectly.

Figure 1: Components of a needle less injection device

Liquid injections

The basic principle of this injection is “if a high enough pressure can be generated

by a fluid in intimate con-tact 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 opera-tion of the powder injection devices.

Depot injections

Depot injections are given in the muscle, where they create a store of a drug that

is released continuously over a specified period of time.

Advantages of NFI technology

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 layers. 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 powder.

Eliminate complexity of reconstitution and any ef-fects of shear.

Provide rapid delivery and reproducibility compara-ble with needle and syringe.

Improve bioavailability over other non- or less inva-sive drug delivery systems.

Improve immune response to DNA and conventional vaccines.

Provide the capability to alter the pharmacokinetics of certain drugs.

Jet injectors are used to deliver mass immunization of influenza, tetanus, typhoid,

diphtheria, pertussis, and hepatitis A vaccines.

Nozzle:

The nozzle has two critical functions; it acts as the passage for the drug and as

the surface which con-tacts the skin. The nozzle contains a flat 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. The orifice controls the drug stream

diameter and speed. A stream diameter of approximately 100 μm and traveling at 100 m/s

can achieve the desired injection depth of 2 mm. A com-parison of relative diameters for

a 24 Gauge (diameter of 460μm) needle, a 100 mm injection stream and a human hair is

shown in Figure 2. From this figure it is seen that the needle-less stream is much smaller

than the average injection needle.

Drug reservoir:

The drug volume holds the injection fluid inside the device.

Pressure source:

The energy source provides the ne-cessary 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 me-chanical method stores energy in a spring which is re-

leased 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.

Needle less injection device mechanism

The mechanism involves high pressure to push the medication through the skin to the desired

penetration site. Using pressure instead of the needle allows for a non-invasive method of drug

delivery. Pressure is produced by using either a gas (carbon dioxide or nitrogen) or a spring

device. The pressure forces the medication through a small opening in the device while it is held

against the skin. This creates a fine stream of the medication that penetrates the skin. There are a

few devices on the market that are spring powered; how-ever, most are gas powered (Shradha R.

Baheti 2011).

Recent trends

Pulsed micro jets:

Despite their long history, needle-free liquid jet injectors are not commonly used as a result of

frequent pain and bruising. It was hypothesized that pain and bruising originate from deep

penetration of jets into skin leading to their interactions with nerves and blood capillaries. This

issue could potentially be addressed by minimizing the penetration depth of jets into the skin;

however, attempts to reduce the penetration depth have led to a concurrent loss of delivery

efficiency (Schram-Baxter J et al., 2004). This issue was solved when a new strategy came into

existences that are pulsed micro jets.

Microjets were produced by displacing the drug solution through a micro nozzle (50–100 m in

final diameter) by using a piezoelectric transducer. Other modes of fluid displacement, including

dielectric breakdown and electromagnetic displacement, can also be potentially used (Fletcher D

et al., 2001; Fletcher D et al., 2002); however, the piezoelectric-based mechanism was preferred

as a result of its robustness and energy efficiency. The piezoelectric transducer, on application of

a voltage pulse, expands rapidly to push a plunger that ejects the fluid from the micro nozzle as a

high speed microjet. The volume of the microjet is proportional to the amplitude of the voltage

pulse measured with a colorimetric assay) and the velocity of the microjet is proportional to the

rise time. Ideally, a rise time of 10 _s would lead to a mean velocity of 127 m/s for a 10-nanoliter

microjet delivered from a 100-_m diameter micro nozzle (v _ Q/At, where Q is the micro-jet

volume, A is the cross-sectional area of the micro nozzle, and t is the rise time). The high-

velocity of mi-crojets (v _100 m/s) ensures skin penetration but small jet diameters (50–100µm)

and extremely small volumes (a few nanoliters) limit the penetration depth. Pulsed microjet

injectors could be used to deliver drugs for local as well as systemic applications without using

needles.

Needle less injection for migrane:

FDA has just approved the first needle less pain free sumatriptan injection made by

zogenix, named as sumaveldespro, that make migraine fast and pain free.Despro is a first needle

free system for subcutaneous sumatriptan injection that provides migraine relief within 10

minutes for some patients.zogenix plans to launch sumavel dspro with its own sales force and a

copromotion partner, and will make the product commercially available as soon as possible.

.

Other needle less drug delivery systems

Patches have been introduced as needle free delivery systems. These devices, which look

like bandages, slowly transfer medicine through the skin. In one type of patch, thousands of tiny

blades are imbedded on itssurface. The patch is covered with medicine and then placed on the

skin. The blades make microscopic cuts in the skin that opens a path for drugs to enter through

when an electric current is applied; the medicine is forced into the body. This process, called

iontophoresis, does not hurt.

Nasal sprays, suppositories, and eye and nose drops

These are forms of needle free systems that deliver medications through the mucous

membrane, where 90% of all infections occur. The mucous membrane is found throughout the

body and includes the lining of the res-piratory tract, digestive tract, and urinary and genital

passages. These needle free systems prompt the body to produce both antibodies at the mucosa

surfaces and system-wide. The nasal shot may be the first needle-free flu shot. It is a syringe-like

device that has an aerosol sprayer substituted for the needle. It delivers a weak flu virus directly

to the nasal passages and creates immunity to the flu with minimal side effects. Inhalers are

another type of needle-free delivery system. In these systems, liquids or powders are inhaled and

delivered into the lungs. These devices are good for delivering protein drugs because the lungs

provide a rapid absorption into the bloodstream. In one system there is a pump unit that atomizes

a powdered medication. This allows the patient to inhale the proper amount of medicine without

it getting trapped in the back of the throat.

Oral vaccines

They are needle-free systems that may replace vaccine injections. This technology has

been difficult to perfect for many reasons. The primary problem with this type of delivery system

is that the environment of the digestive system is harsh and typically destroys vaccines and other

drugs. Also, vaccines do not work as well in provoking antibody production in the digestive

lining. One of the latest oral vaccines involves freeze drying the medicine and mixing it with a

salt buffer to protect it when it is in the stomach. Other edible forms include a sugar solution of a

vaccine against the bacterium that causes ulcers. For travelers, a typhoid-vaccine capsule has

been developed as an alternative to the two painful shots typically required.

Genetic engineering has enabled the production of oral vaccines in food. In 1998,

potatoes were produced that contained genes from the virus that causes cholera. These potatoes

showed efficacy in protecting people from this disease. This is particularly useful for developing

countries where potatoes are a dietary staple and the refrigeration that is typically required for

transporting vaccines is not readily available.

Needle free insulin delivery Insulin inhalers:

The rationale behind developing a pulmonary drug delivery system is to ensure that

insulin powder is delivered deep into the lungs, where it is easily absorbed into the bloodstream,

in a hand-held inhalation device. The device converts the insulin powder particles into an aerosol

cloud for the patient to inhale. Nektar Therapeutics (formerly Inhale Therapeutic Systems, Inc.)

completed their initial phase III clinical trials of insulin inhaler (Exubera) in 2002 in partnership

with Pfizer Inc. and Aventis Pharma. Pfizer and Aventis are currently carrying out further

longterm trials looking at the safety and efficacy of Exubera. Exubera represents a novel prandial

insulin delivery method. Good glycemic control, comparable to modern subcutaneously

administered insulin preparations, has already been demonstrated, and no unexpected safety

concerns have been reported with inhaled insu-lin (Preeti Patni et al., 2006).

Insulin spray

The buccal route is another promising alternative for insulin delivery. With the buccal

area having an abundant blood supply, it offers some advantages such as a means to deliver the

acid labile insulin, and elimination of insulin destruction by first pass metabolism (Narayani R

2001). The buccal spray formulation being developed by Generex Biotechnology, based in

Toronto, delivers insulin to the buccal cavity as a fine spray using company's 'rapidmist' device.

The company's leading product is Oralin. It is currently in phase II B clinical trial. The patient

does not inhale with the buccal spray device; instead, the drug is sprayed onto the buccal mucosa.

The high-speed spray allows the drug to be rapidly absorbed into the blood stream. The

deposition of the drug onto the buccal mucosa also allows the developers to bypass earlier

concerns about any risks to lung tissue that have been raised regarding investigative inhaled

insulin formulation.

Insulin pill

Recently several biotech companies have been conducting pilot trials in the effort to

develop an insulin pill as a potential alternative to injected or pumped insulin. The attempt

requires the development of novel delivery technology. For example, Nobex Corporation has

developed hexyl-insulin monoconjugate 2 (HIM- 2) in which single amphiphilic oligomer is

covalently linked to the free amino group on the Lys-β 29 residues of recombinant human insulin

via an amide bond. This alters the physical- chemical characteristics, leading to enhanced stability

and resistance to intestinal degradation of ingested insulin (Ms Komal R et al., 2009). Oral

HIM-2 (Kipnes N et al., 2003) is safe and reproduces the physiological pathway of insulin

secreted by pancreas (Clement S et al., 2002).

Insulin analogues

Traditional insulin preparations such as NPH (Neutral Protamine Hagedom)

insulin have duration of action 14 h and plasma insulin peak level 4-6 h after administration

(Pandey Shivanand 2010). As a consequence, NPH insulin may need to be administered up to

three times daily in type 1 diabetic patients to provide sufficient insulin supply throughout the day

(Andreas Hamann et al., 2003). Multiple dosing regimens are less optimal in terms of adherence,

flexibility and choice for the patients to adapt treatment to their individual lifestyle. To satisfy the

need for optimized basal insulin, recombinant human insulin analogues have been developed, like

Glargine (Raskin P 2000) and Aspart. Glargine-treated patients experienced significantly less

weight gain than those treated with NPH insulin (Raskin P 2000), which had a lower risk of

nocturnal hypoglycemia (Pieber T et al., 2000; Ratner RE et al., 2000) and was well tolerated,

whether it is injected once daily before breakfast, dinner or at bedtime in Type 1 diabetic patients

(Andreas Hamann et al., 2003). Similarly, Aspart is also now well established as an effective and

convenient means of providing glycemic control.

Insulin complement:

Apart from the new insulin, one new drug, Symylin, is ready to be launched

by Amylin Pharma, San Diego. Symylin is a synthetic version of the human hormone amylin,

which moderates the glucose lowering effect of insulin. Symylin has been designed to

complement insulin action and has been shown to reduce blood glucose without causing an

increase in hypoglycemic episodes. It could provide a potential adjunct to insulin therapy in both

type 1 and type 2 diabetics.

Implantable insulin pumps:

Continuous improvements in microelectronics, as well as in the

development of biomaterials and stable insulin solutions, have led to the availability of

implantable pumps able to infuse insulin by the peritoneal route, in a continuous and

programmable way, for several years (Renard E et al., 2002). The Medtronic/Minimed 2007

system may offer treatment advantages for diabetic patients who have difficulty in maintaining

consistent glycaemic control. This system delivers insulin into the peritoneal cavity in short,

frequent burst or ''pulses'' similar to how pancreatic β cells secrete insulin. This system is placed

external to the rectus muscle. Current model has eight years battery life expectancy. The system's

reservoir is refilled with fresh insulin every two or three months.

Transdermal patch:

Ozin and Landskron announced recently that they had created an unusual

material using manmade molecules called dendrimers. It can store drugs and, when spread on the

skin as a film, allow them to dissipate into a patient's bloodstream like a new type of patch. The

problem with current drug delivery systems is that it is either injected in such a manner that

acquires too high concentration to ensure that it stays in the system but can be toxic, or it is

injected too little into a person such that it is not effective. The new material, Periodic

Mesophorus Dendrisillicus (PMD) would let drugs seep through a person's skin in just the right

amount and stay at that level.

Conclusion:

The future of needle-free injection systems looks bright, with a steady

growth due to increasing demand for prevention of needle stick injuries and painless delivery of

medication and this fact is further strengthened by the strong clinical trial data available. The

prices of needle-free devices are expected to erode in the coming years, which in turn are

expected to increase sales volume, spurring revenues for the manufacturers. Increased awareness

and patient acceptance is expected to play a crucial role in the market penetration of the needle-

free technology. Some of the applications expected to be key to the success of needle-free

technologies include vaccines, biotechnology drugs - protein and peptide delivery, gene delivery,

and insulin. Needle-free devices have come a long way to the present state and are expected to

play an increasingly important role in the novel drug delivery technologies markets in the coming

years .