Needle free injection technology

Needle free technology offers the very obvious benefit of reducing patient concern about the use of needle, feel Vivek Ranjan Sinha, Aman Trehan and Pramil Tiwari

The demand for novel drug delivery technologies is ever increasing. These drug delivery technologies can be broadly classified into four principle routes like oral, transdermal, inhalation and parenteral. The main goal for the delivery of any drug therapy is oral administration with once or twice daily dosing. However, there are large number of therapies, particularly protein-based, gene-based, vaccine-based that cannot be delivered by this route for example insulin, growth hormones and other similar biologics.

Pulmonary delivery is another non-invasive alternative method that is suitable for small molecules and proteins. However, for drugs with very large molecular weights, such as monoclonal antibodies, penetration through the lung for systemic delivery may require some type of transport enhancement mechanism, of which there are several still at the primordial research stage. Therefore, most protein-based drugs are still being developed as injectables for initial market launch.

The pitfalls of needle-based injections are well known. Psychological resistances to self-injection or needle-phobia, have been documented across large demographic groups, such as diabetics. The result of this phobia is that many outpatient injectables are dosed sub-optimally. Furthermore, awareness of serious problems has caused physicians and their patients to either delay therapy initiation or seek out less-invasive alternatives, even at some cost to clinical effectiveness. All parents can relate to the anguish felt when an infant screams and protests at the sight of a vaccination needle.

For some, especially those suffering from chronic diseases requiring injectable products two or three times a day, this process is an ongoing reality of daily life for example diabetics-accepted, but always with the hope that something new will replace the ritual of needle insertion. To overcome the problems related to needle based injections, there is one technology that has received considerable attention during the past few years and that offers all of the sought after benefits is—Needle Free Injection Technology (NFIT).

This technology was first described in the 19th century in France, when the French company-H Galante-manufactured an ‘apparatus for aquapuncture’. Since then, the demand had increased considerably. It was first commercialised in the US in 1960s. Bioject had summed up the reasons for it in their brochure stating ‘‘Patients hate needles, healthcare professionals fear accidental needle stick injuries, drug companies are looking for new and innovative ways of delivering their products.’’

This technology is emerging as a major sector within the drug delivery industry. There are around 1.4 million people in the UK, who have been diagnosed as diabetics, which means that three in every hundred people have the disease. In addition, there are around one million people in the UK who have diabetes but are unaware.

The UK Audit Commission predicts that those suffering from diabetes will increase from 1.4 million to three million by 2010. In the US, in the last decade, the prevalence (the proportion of people diagnosed in a given population at a given time) amongst adults has increased by 33 per cent, which means that six per cent of the population has diabetes but they account for 12 per cent of all healthcare expenditure.

The condition can occur at any age but is rare in infants. It becomes more common with age. If people with diabetes could painlessly inject insulin several times a day, without sticking themselves with needles, we might imagine that the diabetes world would be beating a path to the doors of companies making these devices.

mhi-500 is the novel needle 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.

Figure-1 (Source: Drug Delivery Technology)	Figure-2 (Source: Drug Delivery Technology)	Figure-3 (Source: Drug Delivery Technology)

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.

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.

The design of the device has a major influence on the accuracy of subcutaneous delivery and the stresses imposed on the product to be delivered. The design must ensure that a sufficiently high pressure is generated to puncture the skin, while the subsequent pressure is reduced to ensure that the molecule is deposited comfortably at a level that does not reach the muscle tissue.

High-pressure delivery could potentially damage fragile molecules, such as monoclonal antibodies. Successful delivery of such molecules, therefore, requires a device with carefully controlled power nuances. Several companies are involved in development of this technology, which includes, Antares Pharma Inc, Aradigm Corporation, Bioject Medical Technolo-gies Inc and Biovalve Technologies Inc.

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 ultra-fine stream of high-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.

Biojectorr 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.

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 against accidental needlestick 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.

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 to inspect the dosage prior to injection and visually confirm loading and full discharge of your insulin after each use.

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.

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.

Cool.click is a customised 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.

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 customised version of Bioject’s Vitajet needle-free injection system. The system includes customised dosage features to accurately deliver variable doses of Serostim. The SeroJet received FDA market clearance for delivering subcutaneous injections of Serostim in March 2001.

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 (Figure 1) configured to administer 0.5 to 1.00 ml subcutaneous (Figure 2) or intramuscular injections. The device is distributed “ready to use.” Thus, it requires no additional parts or modifications for function.

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 3) The Iject needle-free injection system is an investigational device, subject to the US Food and Drug Administration clearance for commercial distribution.

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.

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 pre-filled 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.

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.

Various other needle-free technologies are summarised in the table.

Conclusion

Needle-free technology offers the very obvious benefit of reducing patient concern about the use of needle. Additional benefits include very fast injection compared with conventional needles and no needle disposal issues. Not only it can benefit the pharmaceutical industry in increasing product sales, it has the added potential to increase compliance with dosage regimens and improved outcomes. In the developing world, there are major challenges of disease transmission through re-use of needles. Organisations such as WHO and CDC (Centre for Disease Control) and groups like Gates Foundation have supported the development of needle-free alternatives for drug delivery.

The biotech revolution is bringing in a range of protein-based therapeutics into the marketplace at a rapid pace — more than 300 products in active development. These protein-based therapeutics especially monoclonal antibodies (MAbs), which are anticipated to represent 30 per cent of pharmaceutical sales by 2007 and which are otherwise challenging to deliver non-invasively, will continue to be formulated as injectables. There appears to be tremendous opportunity for needle-free technology to have major impact in the industry. It is likely that dramatic change may occur only when a large pharmaceutical or biotechnology company adopts needle-free technology and demonstrates its versatility, acceptance and value in major therapeutic area.

V R Sinha is with University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh-160014, India.
E-mail: vr_sinha@yahoo.com and Aman Trehan and Pramil Tiwari are with National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab, India.