Injecting golden syrup

20 May 2013 8min read

It’s been 60 years since Watson and Crick published ‘A Structure for Deoxyribose Nucleic Acid’ in the April 1953 issue of ‘Nature’. Nineteen years later, in 1972, Paul Berg’s team at Stanford University created the world’s first recombinant DNA molecule. Wind forward to 1976 when biochemistry professor Robert Swanson shared a beer with venture capitalist Herbert Boyer in San Francisco and roughed out a business plan for the company we now know as Genentech, an event described as ‘the foundation of not just a company but an entire industry’. Just six years later, in 1982, Eli Lilly launched Humulin®, the world’s first human insulin produced using recombinant DNA technology, developed by Genentech working with the City of Hope Medical Research Center in Pasadena.

Since the 1990s, biologically derived drugs have been the centre of attention for the pharmaceutical world, both in terms of therapeutic opportunities and of business activity.

Global sales of biologically derived drugs are expected to exceed $220 billion by 2015, with more than 500 monoclonal antibodies (‘mAbs’) currently in development. So that’s all good isn’t it? After all, previously untreatable conditions are now manageable. But just like insulin, these protein-based drugs are rendered useless if taken orally, so something other than a tablet or capsule is called for. Does that present any new challenges?

Size IS important

People with diabetes have been successfully injecting themselves (daily with insulin) for over 90 years, so you might expect that self-injection of any other drug should be straightforward. However, it’s not that simple; insulin, with a molecular weight of 5.8 kDa, seems a pretty chunky molecule when compared with drugs such as aspirin (at 180 Da) or even penicillin (at around 335 Da).

“People with diabetes have been successfully injecting themselves (daily with insulin) for over 90 years”

Now consider Humira®, a hugely successful product used to treat a range of autoimmune conditions including rheumatoid arthritis, ankylosing spondylitis and Crohn’s disease. It has a molecular weight of approximately 148 kDa. Humira® is 25 times the size of the humble insulin molecule, and is anything but simple – the chemical formula provides a clue here:

As a mAb, it works by binding onto specific target sites on cells; the headcount of individual mAb molecules has to be large to address the cell targets, hence a therapeutic mAb dose comprises a large payload of bulky, complex molecules, which have to be delivered by injection.

So what are the practical options?

The cost and convenience drivers for self-administered therapies, especially for chronic conditions, result in regular but infrequent injections of relatively large payloads of molecules, injected weekly, possibly fortnightly or even quarterly. Injection of 1ml in a single, self-administered dose has historically been regarded as the threshold of acceptability, but single injected doses of up to 2.5 ml are now being actively explored. Discomfort or pain are major considerations, but time also forms a part of the equation; in general, patients don’t want to hold an autoinjector (an increasingly common delivery device format for biological drugs) in place for more than 15 seconds, a time window which includes needle insertion as well as the actual injection.


This term refers to the force required to inject a given solution at a given rate via a chosen needle length and gauge. Flow through a hollow needle is characterised by the Hagen-Poiseuille equation.

Injecting golden syrup

Although syringe plunger friction and tissue resistance at the needle tip will add to syringe plunger force, viscous resistance within the needle is particularly relevant as larger molecules and higher mg/ml concentrations result in higher viscosity formulations. Needle gauge is key; although a finer needle means easier and less painful insertion, it also has a smaller bore. Equation 1 (overleaf) shows that plunger force varies with D4; change from a 27g needle with a bore of 0.191mm to a 30g needle with a bore of 0.140mm and the plunger force increases by 350%, if the flow rate, Q, (hence the injection duration) is to stay the same.

For a spring-powered autoinjector, the spring must provide adequate force at the end of stroke (as the last drop of drug is delivered). However the stiffness or ‘rate’ of a traditional coil spring dictates that at the start of delivery, the spring force will be significantly higher. Add on the syringe plunger friction and tissue resistance, plus a safety margin to allow for tolerances, and it becomes apparent that some surprisingly high forces have to be handled by the injector mechanism and, specifically, reacted through the injector’s small glass syringe. Not surprisingly, breakages, failures and malfunctions are among the problems faced by autoinjectors delivering higher viscosity biologic drugs.

Responses to these challenges are being developed, including thin-walled or tapered needles to reduce viscous resistance and minimise pain; constant force springs and dampers to minimise peak forces; precisely moulded cyclic polyolefin syringes which are more robust than glass; and reduced friction stoppers and syringes. But why not just change our approach to injected delivery and side-step some of these challenges?

The time machine

If we treat injection time as an opportunity, not a challenge, it presents a very interesting device scenario. When applying the Hagen-Poiseuille equation for an autoinjector, the flow rate, (Q, in equation (1), of 1ml or 2ml in perhaps 10 seconds), is driven largely by the acceptable operating time for the patient. But if the injection device could be worn, say for an hour, then the flow rate for the same injection size reduces by 36,000% – and equation 1 tells us that the plunger force would reduce in the same ratio. In fact, the drug formulation could be less concentrated (and less viscous), though of larger volume, say 5ml or even 10 ml, while the flow rate and force to deliver would remain very manageable. Welcome to the LVI (large volume injector) or ‘bolus delivery device’.

A number of devices of this type are in development, and use a variety of primary containers (glass, plastic, flexible, rigid, ‘traditional’ and novel variants), and a range of mechanisms, power sources and control systems (mechanical, electrical, electronic, hybrid). The LVI addresses some key autoinjector challenges and much effort is being devoted to the technical, pharmaceutical and user related aspects of LVI devices.

When’s he going to talk about Golden Syrup?

OK, I hadn’t forgotten. Golden Syrup (or Karo Syrup, if you’re from the USA) is around 3000 cP and although few pharmaceutical products have viscosities this high, injection of higher viscosity products remains of interest. Needle-free delivery has been a reality since the late 1940s, and several technologies are now available.

Needle-free delivery uses a fine, high velocity jet generated by driving liquid through an orifice at high pressure in order to pierce the skin and underlying tissue. The governing equation (by Bernoulli) can be rearranged as shown (see equation 2).

Comparing this with the Hagen-Poiseuille equation (1), the only fluid property in the Bernoulli equation is (density) and there is no viscosity term. Since drug formulations generally have densities close to that of water, the implication is that a needle-free device will deliver the same volume, at the same rate, using the same energy, largely irrespective of viscosity.

Injecting golden syrup

Strictly speaking, this holds true for orifice plates of zero length and hence is not the only governing relationship for a practical, real life device. Nevertheless, although practical orifii do have a finite length and do exhibit some viscous loss, needle-free devices are largely unaffected by product viscosity in the practical range of interest, as the above figure kindly provided by Zogenix illustrates.

Which to choose?

All three injection technologies discussed above have their place, but often selection is left until late in the development of the drug product. This can mean that opportunities can be missed. Early exploration of formulation options together with the increasingly wide range of real, practical, options for parenteral delivery can provide significant benefits to everyone from the Pharmaco to the patient.

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