Elsevier

Journal of Controlled Release

Volume 306, 28 July 2019, Pages 83-88
Journal of Controlled Release

Subcutaneous nicotine delivery via needle-free jet injection: A porcine model

https://doi.org/10.1016/j.jconrel.2019.05.040Get rights and content

Abstract

Subcutaneous delivery of nicotine was performed using a novel electrically-operated needle-free jet injector, and compared to hypodermic needle delivery in a porcine model. Nicotine was delivered as a single, one-milligram dose into the abdominal skin, formulated as a 50 microliter aqueous solution. Plasma levels of nicotine and cotinine, its main metabolite, were then monitored over 2 h, following which the injection site was excised for histological examination. No irritation or tissue damage were found at the injection sites, and the jet-injected nicotine exhibited comparable absorption into the systemic circulation to that injected using a conventional needle and syringe. The needle-free jet injection of nicotine is a promising and well tolerated method. The data presented from this porcine model will support a first in human trial towards a new promising nicotine replacement therapy.

Introduction

Cigarette smoking is among the leading causes of premature death worldwide, and approximately 50% of smokers will ultimately be killed by their habit [1]. While nicotine is the principal addictive substance in tobacco, it is not itself responsible for the adverse impacts of smoking [2]; as such, nicotine replacement therapy (NRT), in which patients self-administer pure nicotine in lieu of smoking, is seen as a safe and effective method for treatment of tobacco dependence [3]. However, the effectiveness of NRT is not universal, and the ultimate success rate is not high: under 10% of unassisted quit attempts succeed [3,4], and NRT is only able to increase this to about 20%.

One possible reason for the limited success rate associated with NRT is a difference in the rate of nicotine delivery as compared to cigarettes [5,6]. Smoking delivers nicotine directly to the pulmonary circulation, reaching the brain within seconds, while most NRT is delivered transdermally or across oral mucous membranes, with blood nicotine concentrations rising slowly over a period from 30 min to several hours. Smokers suffering from nicotine cravings must therefore suffer a period of discomfort between feeling a craving and receiving an adequate dose of nicotine, discomfort which could be alleviated by resuming smoking rather than waiting for NRT to kick in. As a result, “combination” NRT is often recommended, combining a steady, slow-acting nicotine source, such as a nicotine patch, with a faster-acting nicotine source, such as chewing gum. While commonly available, nicotine gum still offers a relatively slow response, and there has therefore been considerable interest in faster-acting delivery methods [2].

A number of approaches have been proposed to increase the rate of NRT delivery, including higher doses, nasal sprays, and nebulizers [2,5], but these are still unable to approach the delivery rate of smoking, and/or have side-effects that limit their patient acceptance. E-cigarettes are a promising new tool with near-identical pharmacokinetics to conventional cigarettes, but there remain questions about their safety and social acceptability relative to other forms of NRT, and there have yet to be sufficient studies to demonstrate their efficacy [7,8].

One nicotine delivery technique that has seen little exploration to date for NRT is that of subcutaneous injection [9]. This method achieves a comparable delivery rate and maximum plasma nicotine concentration to nicotine cannons or sublingual tablets [2], with fewer side-effects. The limited exploration of this method should perhaps be unsurprising, given the prevalence of needle-phobia and the safety issues associated with hypodermic syringes, but alternative injection mechanisms can bypass these issues. In particular, in this work we propose the use of needle-free jet injection as a technique for subcutaneous nicotine delivery.

Jet injection entails the generation of a small-diameter, high-velocity jet of liquid, capable of penetrating the skin using its own momentum [10,11]. The depth of delivery can be controlled from intradermal [12] to intramuscular by adjusting the velocity of the jet [13], and injections are generally better-tolerated than standard hypodermic injections [14]. Jet injection also often leads to more rapid drug delivery than needle-based subcutanous injections, suggesting a possible additional benefit for NRT [11,15].

While jet injection holds promise for nicotine delivery, there are a number of unexplored issues that must be addressed before it can be attempted in humans. One relates to practical considerations: jet injectors increase in size and complexity as the volume of the delivered dose increases [16], making it desirable to minimize the dose volume through the use of a concentrated formulation. However, jet injection is normally done with standard injectable formulations, not highly-concentrated ones; the pharmacokinetics and tissue reaction to jet injection of a highly-concentrated injectate are not well characterized. Specifically for nicotine, previous studies used subcutaneous delivery of dilute (1 mg/mL) formulations [17], and it is not known whether a concentrated formulation is safe for injection, by needle or jet.

Another unexplored issue is the jet injection behavior of a substance with the transport properties of nicotine. Most jet injection efforts have used large-molecule drugs, such as vaccines, peptide hormones, antibodies, or DNA [12], which disperse slowly through tissues before uptake by the vasculature or contact with immune cells. The main efforts with small-molecule drugs have focused on local anesthetics [10], with some application to sedative drugs and steroids. Of these, sedatives (specifically midazolam) are the only drugs with significant lipophilicity [18] to be jet injected, but they do not approach the ability nicotine has for diffusing through tissue [19]. Thus, while jet injection is well-established as providing faster absorption than needle injection for other drugs, the rapid diffusion of nicotine may overwhelm this behavior.

The objective of this study is to demonstrate, in a porcine model, the properties of nicotine delivery via needle-free jet injection, and to assess the injection site for any evidence of any acute tissue damage or other adverse reaction caused by the injection method and/or concentrated nicotine formulation. Pigs have very similar skin properties to humans [20], and in vivo pig skin has greater similarity to living human skin than does frozen or preserved human skin in vitro [21]; pigs are thus ideally suited as models for comparing transcutaneous delivery methods. However, pigs have been seldom used in nicotine delivery studies, likely due to the general acceptability of nicotine for human experimentation. Live pigs have also seldom been used for jet injection studies, with most work instead using ex-vivo pig skin without its natural tension. There is thus also a need to understand the suitability of this animal model for in vivo jet injection of nicotine. We examined the systemic levels of nicotine and its major metabolite, cotinine, to establish the rate of nicotine delivery and its relative bioavailability, and performed histological analysis of the injection sites. Based on these results, we seek to demonstrate sufficient safety and efficacy to support a future human study.

Section snippets

Materials and methods

All experimental procedures were approved by the University of Auckland Animal Ethics Committee as protocol #001933, and were conducted in accordance with the New Zealand Animal Welfare Act 1999.

Jet injection parameters

Each jet injection device, as defined by the combination of actuator, ampoule, and orifice, can exhibit different drive requirements in order to deliver a particular depth and volume of injection. As such, a series of trial injections were performed on post-mortem pig tissue to empirically determine a set of injection parameters (voltage and time) that provided reliable injections of the target volume to the target depth using our device. Based on observations during these injections, an

Discussion

Subcutaneous jet injection effectively delivers nicotine to the general circulation, with comparable absorption as compared to standard needle injection. It appears that the absorption may be faster, but greater statistical power would be required to support any conclusions about the rate of absorption. It is important to note that porcine skin has reduced vascularization as compared to human skin [20], which may accentuate differences in absorption rate caused by jet-injection-enhanced

Conclusions

Nicotine has been delivered via subcutaneous jet injection. A procedure for reliably delivering nicotine to subcutaneous fat via needle-free jet injection was developed and demonstrated in a porcine model. The jet injection delivery method showed a similar pharmacokinetic profile to subcutaneous needle injection, and caused no acute side-effects. To the best of the authors' knowledge, this is the first time this delivery method has been used with nicotine.

Overall, subcutaneous NRT via jet

Acknowledgements

The authors would like to thank Linley Nisbet, for assistance in performing the animal manipulations, Mahima Bansal, for assistance in preparing the nicotine formulation, Satya Amirapu, for assistance with histology, and Marewa Glover, for the initial inspiration of this project. This work was financially supported by the Tobacco Control Research Tūranga, which was co-funded by the Health Research Council and the Ministry of Health of New Zealand (HRC grant 11/818).

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