Feature Article

By: G. Mayer and V. Knappertz, Bayer HealthCare Pharmaceuticals Inc., Montville, New Jersey, USA P. Kinast, melab Medizintechnik und Labor GmbH, Leonberg, Germany

More than 50 million injections of disease-modifying therapies (DMTs) for multiple sclerosis (MS), a chronic, disabling neurological condition, are performed annually. In other therapy areas such as diabetes where the injection burden is far greater, immense strides have been made to improve patient comfort by decreasing needle size and thickness.

Currently, all DMTs approved for the treatment of MS are administered by injection. Although injection-site pain (ISP) and injection-site reactions (ISRs) occur in a substantial proportion of patients, these adverse events rarely lead to therapy cessation. However, a patient’s perception of ISP and ISRs may decrease adherence to treatment, which may contribute to disease progression.

The Betaferon versus Rebif InvestigatinG Higher Tolerability (BRIGHT) study demonstrated that 30 gauge (G) needles cause less ISP than 27 G needles.1,2 To investigate this phenomenon, an in vitro study was performed that compared the physical characteristics, including penetration forces of needles used to deliver MS DMTs.

Hypodermic needle design

A hypodermic needle comprises a connecting hub, needle shield and cannula with a pointed tip. The gauge corresponds to the diameter of the cannula, higher gauges denote thinner needles. The tip can be ground into a three- or five-angled (bevel) needle point. Five-bevel needles have a thinner profile than three-bevel needles. This may facilitate injection, because the former requires 25% less force to penetrate skin than the latter; however, this finding came from a study limited to prefilled syringes with preattached/staked needles.3

There is another type of prefilled syringe that is also commonly used. This has a luer cone sealed by a tip cap (Figure 1) and with this design, prefilled syringes are separate from the needle. A staked needle is an integral part of the syringe and is embedded in a rubber shield to prevent medicine loss. In general, staked needles are coated with a friction reducing agent, commonly silicone oil. When the rubber shield is pierced, some of the oil may be removed and/or the needle may become damaged, which increases friction and patient discomfort.

The needles under test

This article focuses on three needles used from April 2008 to administer MS DMTs: 30 G, three-bevel (Betaferon; interferon beta [IFNB]-1b); 27 G, five-bevel (Copaxone; glatiramer acetate); and 29 G, five-bevel (Rebif; IFNB-1a, subcutaneously) (Table I, Figure 2). Avonex (IFNB-1a) is not reported because it is administered intramuscularly with a 23 G needle. Copaxone and Rebif come in prefilled syringes with preattached/staked needles, and the needle used to deliver Betaferon is separate from its syringe. Thirty-two samples of each needle size were tested by an independent laboratory (melab GmbH, Germany).

Penetration force

Table I: MS product details and the needles used for their administration. In December 2008, Copaxone switched from the 27 G, five-bevel needle to the 29 G, five-bevel needle. (click to enlarge)

Table II: Results of the penetration force tests. (click to enlarge)

Penetration force, the force applied on the needle point to pierce skin or a skin substitute such as polyurethane foil, is measured with a detector that calculates the load produced as the needle is moved at a speed of 100 mm/ min over 8 mm (Figure 3A). Penetration resistance is presented as a load/testing length diagram (Figure 3B).

Other measurements

Figure 3: (A) Schematic of instrumentation used to measure penetration force; (a) cannula, (b) testing foil, (c) foil support, (d) transferring unit, (e) load cell, (f) amplifier, (g) recording unit, (F0) piercing force, (F1) maximum cutting force, (F2) maximum dilatation force, (FR) friction. (B) Representative load displacement diagram. (Adapted from Vedrine 20033). (click to enlarge)

Figure 4: Bevel geometry. (click to enlarge)

Geometric data such as gamma and delta angles were collected using a Mitutoyo micrometer (www.mitutoyo.com), FACET laser angle measuring unit (www.melab.de), Olympus SZH microscope (www.olympusamerica.com/index.asp) and Werth profile projector (www.werthinc.com) (Figure 4). Gamma angles represent the combined secondary bevel angle and delta angles denote tip angles. Greater gamma angles correspond to greater delta angles and therefore higher piercing resistance.

Penetration test results

Of the needles tested, the 30 G, three-bevel needle had the lowest piercing force, suggesting that it required the least amount of pressure to penetrate the skin substitute (Table II). The piercing force of the 30 G, three-bevel Betaferon needle was 147% and 113% less than the 27 G, five-bevel Betaferon and the 29 G, five-bevel Rebif needles, respectively.

The five-bevel needle had a greater delta angle between the cutting edges than the three-bevel needle. The additional tipping of the five-bevel points resulted in higher piercing resistance and shorter cuts (Figure 4). Thus, five-bevel needles have an enlarged coring tendency, especially when wall thickness is reduced as it is with the 29 G needle.

Evidence for action

In the BRIGHT study, patients who self-administered therapy with a 30 G needle experienced significantly less ISP or ISRs than those who used a 27 G needle. In vitro data suggest that these phenomena may be the consequence of finer needles, which produce smaller cuts. Smaller cuts may result in less patient trauma. The 30 G, three-bevel needle, with a penetration length of 12 mm, was the smallest tested and required less force to enter the skin substitute. It is hoped that these data will lead to the development of needles that require less penetration force. Less ISP and fewer ISRs should improve overall injection experiences and reduce preinjection anxiety. These features are important to patients who self-administer therapy; those with MS require frequent dosing and high medication adherence.

Gerhard Mayer,* PhD is Director International Product Management, Betaseron LifeCycle Management, GBU Specialised Therapeutics, Bayer HealthCare Pharmaceuticals Inc., PO Box 1000 Montville, NJ 07045, USA, tel. +1 973 487 2068, e-mail: gerhard.mayer@bayer.com, www.bayer.com, and Volker Knappertz, MD is Global Medical Affairs at Bayer HealthCare Pharmaceuticals Inc.. Peter Kinast, PhD is Managing Director at melab Medizintechnik und Labor GmbH, Mollenbachstrasse 19, D-71229 Leonberg, Germany, www.melab.de

* To whom all correspondence should be sent