Elsevier

Journal of Controlled Release

Volume 280, 28 June 2018, Pages 51-57
Journal of Controlled Release

The effect of jet speed on large volume jet injection

https://doi.org/10.1016/j.jconrel.2018.04.054Get rights and content

Highlights

  • The jet injection of 1 mL required a greater jet speed later in the injection than that reported for volumes ≤0.3 mL.

  • A two-phase jet speed profile successfully delivered 1 mL at a reduced energy cost relative to single-speed injections.

  • Subcutaneous injections demonstrated a correlation between the volume delivered and the penetration depth.

Abstract

Jet injection presents a promising alternative to needle and syringe injection for transdermal drug delivery. The controllability of recently-developed jet injection devices now allows jet speed to be modulated during delivery, and has enabled efficient and accurate delivery of volumes up to 0.3 mL. However, recent attempts to inject larger volumes of up to 1 mL using the same methods have highlighted the different requirements for successful delivery at these larger volumes. This study aims to establish the jet speed requirements for delivery of 1 mL of liquid using a controllable, voice coil driven injection device. Additionally, the effectiveness of a two-phase jet speed profile is explored (where jet speed is deliberately decreased toward the end of the injection) and compared to the constant jet speed case.

A controllable jet injection device was developed to deliver volumes of 1 mL of liquid at jet speeds >140 m/s. This device was used to deliver a series of injections into post-mortem porcine tissue in single and two-phase jet speed profiles. Single-phase injections were performed over the range 80 m/s to 140 m/s. Consistent delivery success (>80% of the liquid delivered) was observed at a jet speed of 130 m/s or greater. Consistent penetration into the muscle layer coincided with delivery success. Two-phase injections of 1 mL were performed with a first phase volume of 0.15 mL, delivered at 140 m/s, while the injection of the remainder of fluid was delivered at a second phase speed that was varied over the range 60 m/s to 120 m/s. Ten two-phase injections were performed with a second phase speed of 100 m/s producing a mean delivery volume of 0.8 mL ± 0.2 mL, while the single-phase injections at 100 m/s achieved a mean delivery volume of 0.4 mL ± 0.3 mL. These results demonstrate that a reduced jet speed can be used in the later stages of a 1 mL injection to achieve delivery success at a reduced energy cost. We found that a jet speed approaching 100 m/s was required following initial penetration to successfully deliver 1 mL, whereas speeds as low as 50 m/s have been used for volumes of <0.3 mL. These findings provide valuable insight into the effect of injection volume and speed on delivery success; this information is particularly useful for devices that have the ability to vary jet speed during drug delivery.

Introduction

Needle and syringe injection has been the standard procedure for transdermal drug delivery since its development in the mid-19th century [1]. While this technique provides an effective way to penetrate the skin and deliver a drug to a chosen tissue layer, the need for a needle presents several drawbacks. These include the spread of infection from accidental needle-stick injury, handling of sharps waste, and reduced patient compliance due to needle-phobia [2].

Jet injection is a promising alternative to needle and syringe injection that avoids the need for a needle by using the liquid drug itself to penetrate the skin. In jet injection systems the liquid drug is pressurised within an ampoule which has a single outlet – an orifice which is typically between 100 μm and 300 μm in diameter [2]. As the pressurised drug is forced out of this orifice it is formed into a high speed jet, which is capable of penetrating the skin and delivering the drug to the underlying tissue. The penetration and delivery of a jet injected liquid depends on both the speed and diameter of the jet [3].

Commercial jet injection efforts have typically used the release of compressed springs or gases to pressurise the liquid and perform the injection [1]. These devices, while energetically efficient, provide little control of the jet speed as the injection takes place [4]. Recent research has focussed on the development of controllable methods such as voice coil actuators [5,6], piezoelectric actuators [7] or pulsed lasers [8]. These methods provide the ability to control the jet speed during delivery and therefore precisely control the injection volume and depth.

One way in which the controllability of these devices has been used is to deliver the jet injection in two phases [5,7]. This technique is based on the principle that a high jet speed (120 m/s to 200 m/s) is typically only required at the beginning of the injection while the jet penetrates through the tougher epidermal and dermal layers [4,7,9]. The jet speed can thus be reduced later in the injection at no cost to the delivery success, while also reducing the energy input. The energy dissipated during a voice coil driven injection has been to shown to be proportional to the cube of jet speed [10]. Reducing the energy required to perform a jet injection can increase the volume deliverable and/or reduce the size of injection devices.

Uncontrolled injectors (spring or gas driven) have demonstrated delivery of up to 1 mL in humans [11], and up to 5 mL in veterinary applications [12]. Controlled injection systems have typically been associated with much smaller injection volumes. Piezoelectric and laser-based jet injection systems have been used to deliver volumes of 0.1 μL to 6 μL [7,8,13] while systems actuated by electric motors have focussed on delivery up to 0.3 mL [4,5,14]. Recently, increased focus has been placed on the controlled delivery of volumes of 1 mL or greater. Toward this goal a wide range of controllable electric motors have been trialled [15,16], and other techniques such as mechanical amplifiers [17] have been investigated. The study reported in [15] represents the first electronically controllable injector to perform delivery of up to 1 mL into humans. The interest in the controlled delivery of larger volumes is motivated by the fact that many common injections in clinical practice are delivered as 1 mL doses, or greater, including some vaccines, monoclonal antibodies and hormones [4,11,18].

While the volume deliverable by controllable jet injectors is approaching that of spring and gas driven devices, the previous lack of control at volumes up to 1 mL has meant that the requirements for successful delivery are poorly understood relative to those for volumes <0.3 mL. A previous study attempting to deliver 1 mL was unable to inject the full volume despite using jet speeds which had been shown to successfully deliver 0.3 mL [17]. This revealed that the ability of a liquid jet to penetrate and remain within skin is dependent upon the delivered volume, an effect that has yet to be explored in the literature. Thus, there is a need to gain a better understanding of the way in which injection volume affects what is required for successful jet injection.

In this work we construct a jet injection device capable of commanding jet speeds of up to 200 m/s for injections of volumes >1 mL. With this device, an investigation into the relationship between jet speed and fluid delivery for volumes of 1 mL is conducted using post-mortem porcine tissue. In addition, we investigate the degree to which jet speed can be reduced following the initial penetration of the jet while ensuring successful (≥80%) delivery of the target volume.

Section snippets

Injection system

The injection device developed for use in this study is shown in Fig. 1. The injector was based on a voice coil actuator (BEI Kimco LA30-75) rigidly connected to a stainless steel piston, which moved within a liquid-filled stainless steel ampoule with an inner diameter of 6 mm. Nitrile-rubber O-rings provided a seal between the piston and the ampoule. At the opposite end of the ampoule, an orifice of 200 μm diameter (O'Keefe Controls Co.) provided the outlet through which the jet was formed. A

Single-phase injections

The volume delivered to each sample, as measured by the change in mass, is plotted against the jet speed in Fig. 3A. At 130 m/s and 140 m/s all injections demonstrated delivery of >0.85 mL while all injections at 80 m/s and 90 m/s demonstrated very low volume delivered. Large variability is observed in the volumes delivered at 100 m/s, 110 m/s, and 120 m/s. This variability appears only in those injections which penetrated as far as the subcutaneous fat. Every injection which penetrated into

Single-phase vs two-phase

The effectiveness of the two-phase approach can be evaluated by comparing the energy input required for successful delivery relative to single-phase injection. Electrical energy consumption (E) was calculated from the voltage (V) and current (I) measurements over the time (t) course of the injections based on:E=VIdt

Energy consumption is plotted against volume delivered for all single and two-phase injections in Fig. 5A. The two-phase data appear shifted to the left relative to that of the

Conclusions

A controllable voice-coil driven jet injection device was developed and used to deliver 1 mL into post-mortem porcine tissue using single- and two-phase jet speed profiles. These injections demonstrated that a two-phase jet speed profile can be used during 1 mL injections to achieve delivery success at a reduced energy cost. The use of a two-phase jet speed profile achieved a mean volume delivered of over 0.8 mL while expending just 140 J, whereas similar success with a single-phase profile

Conflicts of interest

None.

Acknowledgements

The authors would like to thank Mr. Stephen Olding for his assistance with the construction of the large-volume injection device, and, Mr. Samuel Richardson for his help with the collection of post-mortem porcine tissue. This work was supported by the MedTech Centre of Research Excellence (grant number #3505716), funded by the Tertiary Education Commission of New Zealand; and the Science for Technological Innovation National Science Challenge (grant number CRS-S3-2016), funded by the New

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