Jet injector

Abstract

The present invention discloses a jet injector with a heating or cooling element that controls the temperature of the fluid or drug, as it flows through the body or out the outlet of the jet injector. In one example a jet injector is disclosed comprising a body, to house a fluid or drug a mechanism in which to develop a pressure in the fluid or drug an outlet that the fluid or drug is ejected out of due to the pressure developed, where in use, the fluid or drug is injected into a patient a heating or cooling element configured to control the temperature of the fluid or drug, as it flows through any one or more of: the body or the outlet.

Description

[0001] JET INJECTOR

[0002] Field of the Invention

[0003] The present invention relates to jet injectors. More particularly the present invention relates to jet injectors with heating to heat the medicament to be injected into the patient.

[0004] Background

[0005] For over a century hypodermic needles have provided a simple, direct method for penetrating the skin and introducing liquid drugs into the body. Despite the popularity of this drug delivery technique, needles present some key drawbacks: low patient compliance due to needle phobia, the spread of disease due to accidental needle stick injury and, in most applications, patients cannot safely and effectively perform the delivery themselves.

[0006] Needle-free jet injection is a promising alternative to hypodermic needles that uses the drug itself to penetrate through the skin. This is achieved by building the drug up to a high pressure and forming it into a high speed, hair-thin jet. Recent versions of this technology, driven by motors or lasers, have demonstrated the ability to control the delivery depth and volume. The controlled, automated nature of this needle-free technology has the potential to allow targeted drug delivery in the absence of a trained professional. Despite the promise of this alternative delivery technique needle-free jet injection is currently limited by; the volume of drug that can be delivered; the ability to controllably spread the injectate under the skin; and patient comfort.

[0007] Needle-free jet injection is typically associated with delivery volumes between 0.01 mL-0.5 mL, although consistent delivery up to around 1 mL has been demonstrated in multiple clinical and ex-vivo studies. A recent clinical study has even reported the delivery of 2 mL with a needle-free jet injection device. Parenteral drug delivery typically needs to be performed intravenously (IV) if the volume exceeds the limit (~2 mL) for subcutaneous (SC) injection. This situation is common with new, highly effective, biologic drugs as their viscosity often prevents them being delivered in high concentration, low volume formulations. The need for IV delivery in these cases causes an enormous cost burden with IV delivery predicted to constitute around 50% of the total treatment cost, and biologic drugs representing 7 of the 10 highest selling drugs available. The development of technologies for high-dose / large-volume SC delivery was the highest priority challenge identified by the SC Drug Delivery and Development Consortium in 2020.

[0008] Highly viscous drugs cannot be delivered through a needle. Typically, this means that these drugs are formulated at lower concentrations, demanding higher delivery volumes, which often must be delivered intravenously.

[0009] Summary of Invention

[0010] In the first embodiment the present disclosure consists in a jet injector comprising: a body, to house a fluid or drug, a piston capable of being moved through the body in order to move the fluid or drug through the body, an orifice or outlet that the piston pushes the fluid or drug toward and out of, where in use, the fluid or drug is injected into a patient, a heating or cooling element that controls the temperature of the fluid or drug, as it flows through any one of the body and the orifice or outlet.

[0011] Preferably the heating or cooling element controls the temperature of the fluid or drug as is flows out of the orifice or outlet.

[0012] Preferably the heating or cooling element increases the temperature of the body.

[0013] Preferably the heating or cooling element increases the temperature of the orifice or outlet.

[0014] Preferably the heating or cooling element increases the temperature of the fluid or drug during the injection of the fluid or drug to the patient.

[0015] Preferably the orifice or outlet is a single outlet.

[0016] Preferably the orifice or outlet is at least 3 but up to 7 outlets.

[0017] Preferably the orifice or outlet has more than 7 outlets.

[0018] Preferably the outlets are formed in an orifice plate as channels to carry liquid through the injector. Preferably the heating or cooling element is a ring that extends about the orifice or outlet, or orifices. In a second embodiment the present disclosure consists in a jet injector comprising: a body, to house a fluid or drug, a mechanism in which to develop a pressure in said fluid or drug, an orifice or outlet that the fluid or drug is ejected out of due to said pressure developed, where in use, the fluid or drug is injected into a patient, a heating or cooling element that controls the temperature of the fluid or drug, as it flows through any one of the body or the orifice or outlet.

[0019] Preferably the heating or cooling element controls the temperature of the fluid or drug as is flows out of the orifice or outlet.

[0020] Preferably the heating element increases the temperature of the body.

[0021] Alternatively, the heating element increases the temperature of the orifice or outlet.

[0022] Preferably the change in temperature increases the flow rate or jet speed of the injected fluid.

[0023] Preferably the change in temperature of the orifice or outlet induces a shape, size, or directional change to the jet of fluid or drug.

[0024] Preferably the heating element increases the temperature of the fluid or drug during the injection of the fluid or drug to the patient.

[0025] Preferably the jet injector has one outlet.

[0026] Preferably the jet injector has more than one outlet.

[0027] Preferably the orifice or outlet is at least 3 but up to 7 outlets.

[0028] Preferably the orifice or outlet has more than 7 outlets.

[0029] Preferably wherein outlets are formed in an orifice plate as channels to carry liquid through the injector. Preferably the heating element is a ring or sleeve that extends about the orifice or outlet, or orifices. Preferably microneed le(s) are used in place of the orifice(s) or outlet(s).

[0030] Preferably the change in temperature of any one of the body or outlet(s) sterilises the injector.

[0031] A jet injector as herein described with reference to the examples and experiments.

[0032] In a third embodiment the present disclosure consists in a jet injector comprising: a body, to house a fluid or drug, a mechanism in which to develop a pressure in said fluid or drug, an outlet that the fluid or drug is ejected out of due to said pressure developed, where in use, the fluid or drug is injected into a patient, a heating or cooling element configured to control the temperature of the fluid or drug, as it flows through any one or more of: the body or the outlet.

[0033] Preferably the heating or cooling element controls the temperature of the fluid or drug as is flows out of the outlet.

[0034] Preferably the more than one outlet, or outlets are formed in an orifice plate as channels to carry said fluid or drug through the injector.

[0035] Preferably the heating element is a ring or sleeve that extends about the or each outlet.

[0036] Preferably the jet injector further comprises an intermediate distribution element between the heating or cooling element and the outlet, the intermediate distribution element configured to distribute heat from the heating or cooling element to the outlet.

[0037] Preferably the jet injector further includes an intermediate distribution element between the heating or cooling element and the outlets, the intermediate distribution element configured to distribute heat from the heating or cooling element to the outlets

[0038] Preferably microneedle(s) are placed within the outlet(s), to pierce the dermis of a patient when the jet injection is in use.

[0039] Preferably the outlet, outlets and / or microneedle(s) are made from a material with high thermal conductivity such that the outlet, outlets and / or microneed le(s) rapidly and evenly change temperature in response to heating or cooling by the heating or cooling element.

[0040] Preferably the material with high thermal conductivity is one or more of brass, copper, stainless steel, mineral or ceramic.

[0041] Preferably in use, a change in temperature of the jet of fluid or drug from the jet injector is induced by the flow of the jet. This jet flow can be measured to imply flow rate and / or jet speed of the fluid or drug. Preferably the heating or cooling element is configured to control the temperature of the outlet.

[0042] Preferably the heating or cooling element is configured to control the temperature of the body.

[0043] Preferably the control of the temperature is configured to increase the flow rate or jet speed of the injected fluid

[0044] Preferably the control of the temperature of the outlet is configured to induce a shape, size, or directional change to the jet of fluid or drug.

[0045] Preferably the heating element is configured to increase the temperature of the fluid or drug during the injection of the fluid or drug to the patient.

[0046] Preferably the heating or cooling element is a ring or sleeve that extends about the or each outlet. Preferably controlling the temperature comprises increasing the temperature of the body and / or outlet. Preferably the control of the temperature is configured to increase the flow rate or jet speed of the fluid or drug, when ejected.

[0047] A method of determining flow rate and / or jet speed of a fluid or drug through a jet injector, where the jet injector comprises: a body, to house a fluid or drug, a mechanism in which to develop a pressure in said fluid or drug, an outlet that the fluid or drug is ejected out of due to said pressure developed, where in use, the fluid or drug is injected into a patient, wherein, the change of temperature of said fluid or drug through said jet injector is measured to determine an estimated or predicted flow rate and / or jet speed of said fluid or drug.

[0048] The disclosed subject matter also provides method or system which may broadly be said to consist in the parts, elements and features referred to or indicated in this specification, individually or collectively, in any or all combinations of two or more of those parts, elements or features. Where specific integers are mentioned in this specification which have known equivalents in the art to which the disclosure relates, such known equivalents are deemed to be incorporated in the specification.

[0049] Unless the context clearly requires otherwise, throughout the description, the words “orifice”, “outlet”, and the like, may be used interchangeably and generally refer to the exit from the jet injector. The term nozzle may also be used to describe the exit to the jet injector, which in use the fluid from the jet injector leaves.

[0050] Further aspects of the invention, which should be considered in all its novel aspects, will become apparent from the following description.

[0051] Brief Description of the Figures

[0052] Figure 1 A is a photograph of a first embodiment of a jet injector of the present invention with seven nozzles. Figure 1 B is a CAD model of the jet injector of Figure 1 A with a seven-orifice nozzle attached to an injection ampoule. The orifice plate is separated from the back plate to show the channels to each orifice and the gasket. Figure 1C is a CAD representation of the fluid domain within the nozzle of Figure 1A. Figure 1 D is a 60° wedge illustration of the fluid domain of one of the nozzles of Figure 1A, used for modelling. Pressure boundary conditions are applied at the inlet (blue) and outlet (red), arrows pointing toward the inlet and out from the outlet are shown. A symmetry boundary condition (yellow) is applied at either side of the wedge, and a wall condition (grey) over all other surfaces.

[0053] Figure 2 are illustrations of arrangements of an orifice head for three tissue injection groups, where green circles represent jet injection orifices while red crosses represent blocked orifices, (a) an injection with orifices in all seven locations, each orifice delivering 150 pm, (b) a ‘large triangle’ arrangement of three 200 pm orifices, and (c) a ‘small triangle’ arrangement of three 200 pm orifices. Figure 3 shows photo frames from a high-speed video of the injector of the present invention where water is injected through the injector into air.

[0054] Figure 4 shows graphs of jet speed of an injector of the present invention (a) jet speed and piston position measurements during an injection where 130 V is supplied to the motor for 0.1 s, (b) shows average jet speed versus supply voltage. Error bars represent the standard deviation over the three injections at each voltage. The average volumetric jet speed predicted by the model for each of these voltage inputs is also shown.

[0055] Figure 5 show graphs of model predictions of jet speed as the orifice size and spacing are varied, (a) showing predicted jet speed over the cross-section of the central (circle) and outer (line) jets during three example injections of Figure 2. The jet speed profile from 100 pm orifices at 3 mm spacing is shown in blue, 150 pm orifices at 12 mm spacing in grey, and 200 pm orifices at 48 mm spacing in yellow, (b) shows the average jet speed through the central (circle) and outer (cross) orifices over spacings between 3 mm and 48 mm.

[0056] Figure 6 a shows a graph of the percentage delivered (of the ~2.2 mL maximum) for each injection group from Figure 2, again, error bars represent the standard deviation, Figure 6 b shows images of four samples of skin that has been injected into, A & B represent two samples from the 7 x 150 pm group that have been frozen and cut through a plane that includes three injection sites and C & D show samples from the large and small triangle groups, respectively. Each cut through a plane including two of the injection sites.

[0057] Figure 7 shows a graph of the piston speed required for the jet injector of the present invention that is capable of achieving 150 m / s jets over a range of orifice diameters and total number of orifices.

[0058] Figure 8 is an exploded view of an embodiment of a jet injector, showing the piston, ampoule and nozzles, of the present invention.

[0059] Figure 9 is a further exploded view of the embodiment of the jet injector of Figure 8.

[0060] Figure 10 is side, exploded view of the jet injector of Figure 8.

[0061] Figure 11 is a partially exploded view of the jet injector of Figure 8.

[0062] Figure 12 is side, collapsed view of the jet injector of Figure 8.

[0063] Figure 13 is cross sectional view of the jet injector of Figure 8.

[0064] Figure 14 is exploded view of the lower assembly of the gasket, orifice plate and inserts of the jet injector of Figure 8.

[0065] Figure 15 is an alternative exploded view of the lower assembly of the gasket, orifice plate and inserts of the jet injector of Figure 8.

[0066] Figure 16 is a bottom view of the jet injector of Figure 8, specifically showing the inserts (or orifice outlets).

[0067] Figure 17 is a top perspective view of the orifice plate of the jet injector of Figure 8.

[0068] Figure 18 is a top perspective view showing the ampoule plate adapter transparently to show connection to the orifice plate of the jet injector of Figure 8.

[0069] Figure 19 is a top view of orifice plate of the jet injector of Figure 8.

[0070] Figure 20 is an image illustrating the shape of the liquid cavity 200 inside the jet injector of Figure 8. Figure 21 is a cross-sectional image of a further embodiment of the present invention where the jet injection does not include inserts, but the rest of the jet injector is of the same construction.

[0071] Figure 22 is a cross-sectional view of the jet injector of Figure 20 without inserts.

[0072] Figure 23 shows a jet injector nozzle of an alternative form of the present invention where the nozzle includes microneedles, the microneedle nozzle is shown viewed from above in A and side on in B, while C shows an individual 30G microneedle embedded with a (preferably) stainless-steel insert. Figure 24 a, b, c show frames from a high-speed video of jets into air formed through the nozzle of Figure 23. Figure 24d shows the relationship between the voltage applied to the injection motor and the resulting average jet speed through these microneedles (for the 10 mm ampoule (body)).

[0073] Figure 25 shows the volume delivered into porcine tissue samples when attempting to delivery 2mL to 2.4mL from the injector nozzle of Figure 23. The black represents the total volume ejected from the nozzle during each injection. A, B, and C are needle-free multi-jet injections where A uses seven simultaneous jets while B and C use 3 simultaneous jets. D and E represent multi-jet injection through microneedles. In D injections were performed identically to needle free delivery, but through seven microneedles, whereas in E the injection time was extended to maximise the delivery volume.

[0074] Figure 26 shows two graphs (a and b) and c) images of injected and sectioned tissue samples. Graph a) shows the volume delivered into porcine tissue samples versus jet speed for the injections with the 3.9 mL ampoule. Graph b) illustrates the maximum penetration depth (mean ± standard deviation) versus jet speed. The yellow bars represent the average depth of the boundary between the subcutaneous fat and muscle.

[0075] Figure 27 shows a graph where all experimental tissue injections are represented as the percentage delivered of the total delivery volume that was attempted, comparing needle-free, with microneedles. Figure 28 shows various embodiments of jet injectors in the prior art.

[0076] Figure 29 shows jet injectors including heating in accordance with the jet injector of the present invention.

[0077] Figure 30 shows various embodiments of heating of the nozzle of a jet injector.

[0078] Figure 31 shows another embodiment of a jet injector with a heating coil about the outlet to the jet injector.

[0079] Figure 32 shows yet another embodiment of a jet injector nozzle, with a heating sleeve.

[0080] Figure 33 shows yet another embodiment of a jet injector nozzle with heating coils about the nozzle.

[0081] Figure 34 a graph showing viscosity versus temperature for the experiments including a jet injector with heating element for different water and glycerol concentrations.

[0082] Figure 35 shows the model geometry used in the experiments in relation to heating of a jet injector. Figure 36 shows average jet speed and wall temperatures at the outlet in relation to the experiments of heating a jet injector.

[0083] Figure 37 shows copper tube model geometry showing the solid and fluid regions and boundary conditions used in the experiments in relation to heating of a jet injector.

[0084] Figure 38 shows jet speed profiles of the fluid jets that were recorded in the experiments where a jet injector was heated. Figure 39 shows temperature and viscosity profiles of the fluid jets at were recorded in the experiments where a jet injector was heated.

[0085] Figure 40 shows jet speed and temperature profiles at the outlet to the jet injector during experiments where the jet injector had a heating element.

[0086] Figure 41 shows further jet speed and temperature profiles at the outlet to the jet injector during experiments where the jet injector had a heating element.

[0087] Figure 42 shows a photograph of the tip of the injection ampoule of a jet injector with copper tube glued in place of an orifice during an experiment in relation to a jet injector of the present invention. Figure 43 shows temperature and jet speed profiles during experiments for the jet injector of Figure 42.

[0088] Figure 44 shows a cross section of two tissue samples that have been jet-injected with a glycerol-dye mixture during experiments in relation to the jet injector of the present invention.

[0089] Figure 45 show yet another embodiment of a jet injector of the present invention with a heated element.

[0090] Figure 46 shows a jet speed profile over time as a result of experiments where a constant pressure was developed in a fluid (water or 99% glycerol) while the outlet of the jet injector of Figure 45 was heated to temperatures from 20°C to 90°C.

[0091] Figure 47 shows a jet speed profile compared to temperature for the experiment of Figure 46.

[0092] Detailed Description

[0093] Jet injection may provide an important solution for viscous drug delivery. Jet injection is a needle-free drug delivery technique whereby a liquid drug is formed into a hair-thin (-200 pm) high-speed (>100 m / s) jet that penetrates and delivers itself into tissue. While it may seem that it would be just as difficult to form a viscous drug into a high-speed jet as it is to force it down a needle, this is not the case. Recent work has revealed that ‘viscous-heating’ during jet injection can result in significant temperature increase, and resultant viscosity decrease, in a thin outer-layer of the jet; this phenomenon effectively results in the drug ‘self-lubricating’ as it passes through a jet injection orifice. Despite the potential for this finding to revolutionise the subcutaneous delivery of high-viscosity drugs, little further work in this area has since been reported on. In this work we develop finite element models of needle-free injection to investigate how viscous heating affects jet production, how heat exchange with the orifice material influences this process, and to what extent jet production is affected by the initial temperature of the fluid. We then conduct novel high-speed measurements of jet and orifice temperature changes due to viscous heating. We find that viscous heating is responsible for approximately doubling the speed of jets that can be produced with very viscous fluid (1 Pa s) at room temperature. The thermal conductivity of the orifice can transfer heat away from the perimeter of the jet and thus reduce the lubricating effect of viscous heating. We then show that by preheating 99% glycerol (1 Pa s) from 7 °C to 37 °C the jet speed can be increased 6-fold. We also demonstrate the successful delivery of a very viscous glycerol solution using preheated jet injection into ex vivo porcine tissue. Given that 99 % glycerol is 10- to 100-fold more viscous than current protein therapeutics, our findings demonstrate the potential for jet injection, with or without additional drug preheating, to deliver drug formulations, needle-free, that are much more viscous than those currently delivered through needles.

[0094] As the temperature increase and viscosity decrease occur predominantly at the perimeter of the jet, viscous heating effectively results in the fluid ‘self-lubricating’ its flow through the orifice. The selflubrication effect of viscous heating relies on increases in temperature, which cause decreases in viscosity. While the exact form of this temperature-viscosity relationship will be specific to each drug, protein-based drugs typically exhibit an exponential decrease in viscosity with rising temperature, and there is evidence that >10-fold decreases in viscosity would be expected for some monoclonal antibodies with the temperature changes previously observed during jet injection. In addition to the self-lubricating effect caused by localised heating described above, the bulk drug temperature can have a significant impact on viscosity and ease-of-injection. Many refrigerated drugs and autoinjectors need to be warmed to room temperature prior to injection to ensure successful delivery or reduce the plunger forces required to inject the drug.

[0095] Multi-orifice injector

[0096] Referring to Figures 1 and 8, a jet injector that may be used with the present invention is described and shown in the figures as a prototype multi-orifice jet injection system with a nozzle 1 . The nozzle, in this embodiment, has seven orifices 2 in a hexagonal arrangement to maintain equal spacing between each neighbouring orifice (Figure 1A). Each orifice is 12 mm distant to each of its neighbours, however other appropriate distances could be used. The nozzle 1 is optionally made from two stainless steel plates 3, 4 with a rubber gasket 5 between. The front plate (or orifice plate) 3 accommodates the orifices and the back plate 4 connects to a jet injection ampoule (or injector body) 6. Orifice inserts 2 (from O’keefe Controls Co) were used so orifices of different sizes could be substituted in / out as needed. The default orifice diameter used in this work was 150 pm, although 200 pm orifices were also used. Channels (3 mm wide) extend radially to each outer orifice to allow the fluid to flow from the central ampoule out to each orifice.

[0097] While in this embodiment the nozzle 1 has 7 orifices 2, in other embodiments the nozzle may have less nozzles, but at least 3 orifices. In yet other embodiments the nozzle may have more than 7 orifices, depending on the application and injectable or drug to be injected into the patient or animal.

[0098] Bench-top jet injector

[0099] To perform injections through the multi-orifice injector it was connected to a motor-driven injection device as described in J. W. McKeage, B. P. Ruddy, P. M. F. Nielsen, and A. J. Taberner, “The effect of jet speed on large volume jet injection,” J. Control. Release, vol. 280, pp. 51-57, Jun. 2018. The injector in these experiments uses a voice coil actuator (BEI Kimco LA30-75) with a force constant of 35.5 N / A and stroke of 50 mm to drive a piston in an 8 mm diameter stainless steel ampoule 6. The maximum swept volume of this ampoule was 2.51 mL. To perform an injection power was delivered to the voice coil using a pair of linear power amplifiers (AE Techron 7224). Data recording and motor control was performed using a compactRIO real time controller (Nl cRIO 9224, National Instruments) and control software written in LabVIEW2017. A potentiometer (Omega LP803) was used to measure the position of the motor.

[0100] Modelling

[0101] A computational fluid dynamic model of the jet injector of the present invention was developed using ANSYS Fluent. This built upon an existing model of a single orifice injection ampoule previously developed in R. M. J. Williams, J. W. McKeage, B. P. Ruddy, P. M. F. Nielsen, and A. J. Taberner, “Viscous Heating Assists Jet Formation During Needle-Free Jet Injection of Viscous Drugs,” IEEE Trans. Biomed. Eng., vol. 66, no. 12, pp. 3472-3479, Dec. 2019. The steady-state model used the finite volume method and Menter’s shear stress transport model (SST k-omega) to handle turbulence.

[0102] Geometry and Boundary Conditions

[0103] Unlike single orifice injection, multi-orifice jet injection is not axisymmetric, thus this model needed to be 3D. The shape of the fluid domain to be modelled 10 (see Figure 1 C) was based on a prototype multi-orifice injector that used seven orifice inserts (150pm diameter) arranged in a hexagonal pattern with 12 mm spacing between each neighbouring orifice. With six identical orifices surrounding the central orifice a 60° wedge (11 , see Figure 1 D) could be modelled instead of the full geometry to reduce computational effort. As shown in Figure 1 D, symmetry boundary conditions were used on the side faces of the wedge, pressure boundary conditions at the inlet and outlets, and a no-slip wall condition over all remaining surfaces. The inlet pressure was typically set at 10 MPa (although adjusted to match experimental conditions when needed) and the outlet pressure was atmospheric pressure (101 kPa). The fluid was modelled as water. The model was considered converged and computation stopped when the average outlet velocity had changed by less than 1 x 105m / s for 10 consecutive iterations.

[0104] Mesh

[0105] The geometry was meshed using the meshing tool within ANSYS workbench. The meshing strategy involved a default element size of 7.5 x105m with targeted areas of increased refinement around each orifice and an inflation layer over all walls (excluding planes defined as inlet, outlet or symmetry). All elements within a distance of 5.5 x 104m of the centre of an orifice were set to a target element size of 7.5 x 106m. An inflation layer of 20 elements was set up over a thickness of 2 x 105m. The total number of nodes and elements were 1 .57 x 106and 3.95 x 106respectively.

[0106] A mesh convergence study was performed to confirm the simulations demonstrated mesh independence. In this study four different default element sizes were used: 2.5 x 104m, 1 x 104m, 7.5 x 105m, and 5 x 105m. In each case the refined region around the orifices used a target element size one order of magnitude smaller than the default: 2.5 x 105m, 1 x 105m, 7.5 x 106m, and 5 x 10’ 6 m. The inflation layer was unchanged during the independence study. The parameter of interest in this study was the volumetric average of jet speed at the outlets. As shown in table 1 the coarsest mesh (default size 2.5 x 104m) produced an average jet speed within 5% of the finest mesh (default size 5 x10'5m). The difference in average outlet velocity between the finest two meshes in the study is just 0.68%, demonstrating that the result is independent of mesh density at this level of refinement. Experimental methods

[0107] High speed video

[0108] To provide a qualitative observation of jet development through the seven-orifice prototype a highspeed (1000 frames per second) video was taken of an injection into air. A FLIR Blackfly BFS-U3- 16S2M camera with frame size of 1440 pixels by 208 pixels was used to record the video. A voltage of 130 V was supplied to the motor for 50ms to produce the jets in the recording.

[0109] Jet speed measurements

[0110] The speed of the jets formed through the seven orifices were measured over a series of injections at five voltage inputs to the motor: 10 V, 30 V, 70 V, 100 V, and 130 V. Injections were performed by applying the voltage for 100 ms and three injections at each voltage level were performed. During each injection, the jet speed was measured in two ways: a volumetric measurement based on the measured motor position and by recording the force as the jets were impinged onto a force sensor (PCB Piezotronics 208C01). The volumetric measurement of jet speed (v7) is made based on the measured motor speed and assuming conservation of mass: where Apis the cross-sectional area of the piston, Aois the cross-sectional area of a single orifice, and n is the number of orifices. This equation assumes we have ‘n’ identical orifices, which is the case for all injections in this work. A second measurement of jet speed was made by measuring the force exerted by the jets as they impinged on a flat plate. The jet speed was estimated from the measure force F using: where p is the density of the fluid.

[0111] Ejected volume measurement

[0112] To measure the consistency of the jets produced across the seven orifices three injections were performed in which all fluid leaving each orifice was collected into separate vials. The change in weight of these vials was used to imply the volume of fluid ejected from each orifice during the injection. Five injections were performed with an input of 100 V supplied to the injector for 50ms.

[0113] Model validation

[0114] To validate the modelling the predicted jet speeds were compared to the jet speed measurements described above where the motor was supplied with five different voltages 10 V, 30 V, 70 V, 100 V, and 130 V. The average jet speed measured in the steady state portion of the injection (defined here as 30ms - 90ms after the start of the injection) was used for comparison to the modelling.

[0115] To compare the jet speed measurements to the modelling an estimate of the pressure in the ampoule was needed for each injection. Pressure was computed from the force applied by the motor (after accounting for the friction between the ampoule walls and O-rings) divided by the cross-sectional area of the ampoule. Motor force was estimated based on the measured current supplied to the motor and the motor’s force constant (35.5 N / A), while the cross-sectional area of the ampoule was calculated from its measured diameter. Friction was estimated using a coefficient of friction of 0.11 . From this process, we estimate that the static pressure within the ampoule during the injections at 10 V, 30 V, 70 V, 100 V, and 130 V was 0.97 MPa, 4.51 MPa, 8.18 MPa, 11 .95 MPa, and 15.73 MPa respectively. Each of these pressures was set as the inlet pressure in the model and the resulting predicted average jet speed (by volume) at the outlets was recorded.

[0116] Orifice spacing, size, and radial distance

[0117] Following validation of the model it was used to predict the effects of spacing on jet development, and whether this is affected by orifice size. The model was run using geometries representing orifices spaced 3 mm, 6 mm, 12 mm, 24 mm, and 48 mm apart, and orifice diameters of 100 pm, 150 pm, and 200 pm. The inlet pressure was set at 10 MPa for each injection, and the output parameters of interest were the average jet speeds (by volume) at the central and outer orifices.

[0118] Tissue Injection

[0119] To investigate multi-orifice delivery into tissue the prototype seven-orifice nozzle and bench-top injection system described above were used to perform injections into samples of porcine tissue. Tissue was obtained in accordance with the University of Auckland Code of Ethical Conduct for the Use of Animals for Teaching and Research. Samples of skin including subcutaneous fat and at least one layer of muscle (typically around 25 mm thick) were collected from the upper torso of animals around 3 months of age then vacuum-sealed and stored at -80 °C. Prior to injection samples were thawed to room temperature and cut into 45 mm by 45 mm blocks. The injected fluid was water with approximately 0.1 % blue food colouring (Brilliant Blue FCF, Queen Fine Foods Pty. Ltd.) to visualise the location of the delivered fluid in the tissue.

[0120] Injections into tissue samples were performed with three different orifice configurations (Figure 2). Firstly, the hexagonal arrangement of seven 150 pm orifices, Figure 2a, as has been described previously. Then two triangular arrangements, Figure 2b and c, of three 200 pm orifices with different orifice spacing. These triangular arrangements were formed by blocking four of the seven orifice locations in the multi-orifice plate. The ‘large triangle’ group, Figure 2b, had the three 200 pm orifices arranged in an equilateral triangle with a side length of 20.8 mm, while this spacing was 12 mm for the ‘small triangle’ group, Figure 2c. Five injections were performed in each configuration. Each injection was performed using a 130 V input to the motor. In the case of the 7x 150 pm group this voltage is held for 120ms while for the 3x200 pm groups the voltage was held for 150ms. The difference in injection time was so that all groups could target a maximum deliverable volume of around 2.2 mL ejected from the ampoule in each injection. The volume of fluid delivered into the tissue was measured by recording the change in mass of the tissue sample. Any excess fluid on the surface after injection was mopped up prior to measuring the post-injection weight. Injected tissue samples were refrozen then cut through the injection sites to observe the depth and lateral spread of the injected fluid. Results

[0121] High-speed video

[0122] Example frames from a high-speed video recording of a multi-orifice injection into air are shown in Figure. 3. The video showed that all seven jets look very similar and progress through the air at very similar rates.

[0123] Jet speed measurements

[0124] The average jet speeds measured at the five voltage inputs to the motor are shown in Figure 4, each point represents the mean of the measurements across the three injections performed at each voltage. The standard deviation in the average jet speed at each voltage is greatest at the 130 V input where it is just 2.17 m / s for the volumetric measurement and 2.07 m / s for the force measurement.

[0125] Ejected volume measurements

[0126] The volume ejected from each orifice was individually measured during five injections. In all injections, the volume that flowed through each orifice was very similar. Across these five injections the largest volume ejected by a single orifice was 142.3 pL (14.9 % of the 957 pL total) while the smallest was 119.2 pL (12.5% of the 957 pL total). The mean (± standard deviation) percentage of volume that flowed through the central orifice in these injections was 13.4 % ± 0.5 %, while each outer orifice ejected, on average, 14.4 % ± 0.4 % of the total volume.

[0127] Model validation

[0128] The average jet speed predicted by the modelling is compared to the experimental measurements in Figure 5. Given the average jet speed is calculated by volume, comparison of the model predictions to the volumetric measurement is most relevant. The model matches the measured values closely across this entire range of jet speeds, the greatest difference (7.1 %) is observed at the 130 V input.

[0129] Orifice spacing, size, and radial distance

[0130] Figure 5 shows the predicted average jet speed as orifice spacing and orifice diameter are varied. This shows that for each orifice diameter changing the spacing from 3 mm to 48 mm between each orifice has negligible effect on the jet speed. The average jet speed at the central orifice is very similar to that at the outer orifice across all spacing distances and diameters investigated. Increasing orifice diameter leads to a slight, but consistent, increase in the average jet speed.

[0131] Tissue Injections

[0132] The results of the injections into porcine tissue samples are shown in Figure 6a. The volume of fluid delivered is represented as a percentage of the total volume (~2.2 mL) ejected from the ampoule. The greatest mean percent delivered was observed in the small triangle (3x200 pm) group, although all injection groups were fairly similar with a mean percent delivered over 80%. All of the 15 injections delivered >1 .5 mL into the tissue and two delivered >2.0mL. For the 7 x 150 pm group the fluid was distributed mainly in the SC layer for all samples even when some small amount of penetration into the muscle was observed, as shown in Figure 6b. Eight of the ten samples in the 3 x 200 pm groups instead showed roughly similar distribution between the SC and muscle layers or were mainly intramuscular (IM) delivery. The fluid delivered in the 7 x 150|jm, and small triangle groups showed overlap in the dispersion between neighbouring injection sites, this was not evident in the large triangle group, see Figure 6c.

[0133] Discussion

[0134] Large volume subcutaneous drug delivery

[0135] In this work we present a prototype multi-orifice jet injection nozzle capable of delivery of >2 mL into tissue samples in a 0.12 s injection. This represents one of the largest delivery volumes reported by a clinically motivated jet injection system. The vast majority of previous jet injection studies have delivery volumes of <0.5 mL, with a few others focussing on the 1 mL mark. A delivery volume of 2mL was also reported in a recent clinical study comparing jet injections of 1 mL and 2mL. In that study the 2mL injection was through a single orifice and injection site rather than the three or seven orifices used here. Perhaps much greater delivery volumes (>5 mL) could be achieved if >1 mL was delivered at each injection site of a multi-orifice system. Spreading the volume across many injection sites may also prove to be a more comfortable delivery mode for patients. As emphasised by the SC drug delivery and development consortium, there is an urgent need to better understand how these larger volumes can be delivered in a way that improves, or at least does not diminish, patient experience.

[0136] The delivery of ~2 mL into the subcutaneous fat demonstrates the ability of needle-free jet injection to rapidly deliver volumes up to what has been traditionally viewed as the upper limit for SC injection. Highly parallelised injection strategies offer a promising method to overcome the volume constraints of subcutaneous tissue that have led to the perceived injection limit of ~2 mL. A promising alternate method to overcome these limits is to depolymerise the interstitial matrix using hyaluronidase. Multiorifice jet injection offers a couple potential advantages over the depolymerisation approach, namely, faster delivery, and no change to drug formulation. These advantages may mean multi-orifice jet injection is preferable in many delivery applications. The combination of these two approaches may also provide an opportunity for even larger delivery volumes and / or improved patient experience.

[0137] Current technologies available for large volume SC delivery can generally be categorised as autoinjectors, slow SC infusion, or ‘on-body delivery systems’ (OBDS). Both SC infusion and OBDS are capable of delivery of 10’s or even 100’s of millilitres over extended injection times, typically at least several minutes. Autoinjectors are typically associated with volumes up to ~2mL over a timescale of seconds or 10’s of seconds, although more recent models are being advertised for up to 5 mL delivery volume. Multi-orifice jet injection offers the rapid (< 1 second) delivery of these larger volumes without a needle. While the timescale is similar to the autoinjector approach multi-orifice jet injection could still be much quicker than autoinjectors for the same delivery volumes (<0.5 s vs ~1 Os). It is also possible that multi-site delivery could offer an inherently more comfortable patient experience. Considerations for multi-orifice jet injection

[0138] The results presented here indicate that jet development is largely unaffected by orifice spacing and the radial distance of the orifice from the centre of the ampoule. The modelling predicted no significant effect on jet speed for orifice spacing from 3 mm to 48 mm, and the experimental results (ejected volume, jet speed, high speed video) suggest very similar jets were formed through each of the seven orifices in the prototype nozzle. These results indicate that the development of multiple parallel jets for drug delivery is relatively similar to the single jet case. Thus, jet formation seems unlikely to present a significant barrier to the development of future multi-jet delivery systems which could be designed with tightly packed orifices or widely spread orifices depending on the target application. Despite the relative ease of jet formation, it is not clear whether ease of penetration and delivery into tissue will be significantly affected by orifice spacing. Overlap in the boluses formed underneath each injection site were observed for the 7 x 150 pm and small triangle groups, indicating that the fluid delivery may be influenced to some extent by neighbouring orifices. However, this does not appear to have negatively affected the delivery volume at this spacing (12 mm - 21 mm).

[0139] While orifice spacing appears to have a largely insignificant impact on jet formation, a more significant issue could be accommodating greater flow rates (thus greater piston / plunger speeds) without comprising the pressure developed within the drug. Needle-free jet injectors typically work by an actuator, such as a spring or a motor, moving a piston within an ampoule to pressurise and displace the fluid drug, forcing it out of the orifice as a high-speed jet. The speed at which the actuator needs to move the piston is proportional to the orifice area and, in the multi-orifice case, the number of orifices (Figure 7). Thus, multi-orifice jet injection demands greater piston speeds than single-orifice injection. This is a key consideration for driving multi-orifice systems as the force production capabilities of many actuators (e.g. motors) diminish at greater movement speeds.

[0140] Another important consideration for multi-orifice injection will be how to contact the tissue to ensure similarly successful injection at each site. The way in which the injection nozzle, and the jet itself, contact the tissue has a significant effect on the success of the subsequent injection. While exactly how to best contact the tissue to ensure successful jet injection is not well understood, jets should typically be formed perpendicular to the skin surface, and with a contact force applied between the nozzle and skin. Consistent and effective multi-orifice jet injection will require techniques to ensure contact with the tissue is very similar across the multiple injection sites.

[0141] In this work we presented a prototype multi-orifice jet injection nozzle for needle-free drug delivery. This prototype was used to perform rapid (0.12 s), large volume (>2 mL) subcutaneous delivery into samples of ex-vivo porcine tissue. Injections were similarly successful when performing delivery through three versus seven injection orifices. A computational fluid dynamic model of multi-orifice jet injection was also presented. This model predicted that jet production would be largely unaffected by spacing orifices between 3 mm and 48 mm apart. This was backed up by measurements made during injections with the prototype nozzle that showed very similar jets were produced through all seven orifices. These findings demonstrate the feasibility of multi-orifice jet injection for needle-free delivery of large volumes. This promising technique has the potential to improve patient experience and reduce healthcare costs in large volume parenteral delivery applications.

[0142] Figures 8 to 20 show various views, including exploded views, of the jet injector of the present invention. The jet injector includes a piston 7, ampoule body 6, plate adapter (back plate) 4, gasket 5, orifice plate (front plate) 1 and orifice inserts 2. In the preferred form the jet injector of the present invention has 7 orifice holes in the orifice plate and 7 inserts. However, in alternative forms the jet injector of the present invention may have less or more orifices and inserts, however, to be effective, ideally the jet injector requires at least 3 orifices and inserts. This is necessary to achieve higher volume and spread of the delivered drug and potentially to reduce discomfort to the patient during injection.

[0143] Preferably the jet injector of the present invention includes small channels 100 in the orifice plate that direct the fluid to each orifice, rather than the orifices protruding from a 'shared' reservoir. This is an important feature in such a jet injector because in such a high-pressure system, the channels reduce the force that acts on the back of the orifice plate. In Figure 13 the channels - that in effect form the nozzles are labelled as 100. In this cross sectional view only 3 of the 7 channels 100 are shown.

[0144] Figure 20 shows an illustration of the channels alone, illustrating the shape of the liquid cavity 200 inside the preferred form of the jet injector.

[0145] In other forms of the present invention the orifices need not be separate inserts but could instead be holes manufactured into an orifice plate, similar to the orifice plate as shown in Figures 8 to 20. An illustration of a jet injector with an orifice plate 300 with holes 301 and no inserts is shown in Figures 21 and 22.

[0146] This embodiment of a jet injector may lend itself to injectables (drugs) that are more viscous. Viscous drugs can require large forces to push through a needle, making the delivery process much more difficult. Automated technologies such as this, can avoid the risk of incorrect or incomplete delivery due to viscosity.

[0147] In other forms of the jet injector of the present invention the nozzles on the jet may include microneedles. Adding microneedles allows an increase in volume being delivered through the injector. The microneedles pierce the tough outer layer of skin (the epidermis) allowing for reduced jet speeds, thus reduced pressures, to be used. The jets formed through the microneedles are still formed at a sufficient speed to penetrate beyond the needle tip into the deeper layers of tissue (the subcutaneous fat or muscle) that can accommodate greater delivery volumes. Many current auto injectors have difficulty injecting more than 2ml. In particular, this may be due to spills and the patient’s skin not being able to take up more volume, and high-volume injections can cause pain for the patient.

[0148] Adding microneedles may also mean that less pressure is required through the injector to deliver the same volume as the non-micro needle embodiment. As such, in yet other embodiments of the present invention, the ampule body could be altered (made larger) to accommodate more volume, as the higher pressures are not needed to push the injectable through the patient’s skin.

[0149] In yet another embodiment of the injector of the present invention, the jet of the injectable could be created using a gas driven pneumatic mechanism, instead of an electric motor.

[0150] One particular use of an injector with a set of microneedles is that the needles can help to pierce tougher skin, from animals, for example an animal’s hide. The needles help to break the top layer of skin (dermis) or penetrate hide or push through hair. Then the multiple jets of the injectable into the patient or animals’ subcutaneous layers can result in better spreading of the injectable in a wider area in the subcutaneous layers.

[0151] A benchtop jet injection system was tested by the inventors and used to perform jet injections through a prototype nozzle. Measurements of jet speed, shape, and volume were performed to assess the consistency of jet production through the microneedles. The system is then used to perform injections of very large volumes (up to 3.9 mL) into ex vivo tissue samples.

[0152] Methods

[0153] Microneedles

[0154] In some forms of the jet injector of the present invention, a jet injector nozzle 400 includes microneedles 401 , see Figure 23. In Figure 3, has seven microneedles 401 are shown and arranged in a hexagonal pattern with each microneedle 12 mm spaced from its neighbours. A motor-controlled injection system was used to develop fluid pressure and thus form high-speed jets through each of the microneedles simultaneously.

[0155] While in this embodiment the nozzle 400 has 7 orifices and microneedles 401 , in other embodiments the nozzle may have less nozzles, but at least 3 orifices. In yet other embodiments the nozzle may have more than 7 orifices, depending on the application and injectable or drug to be injected into the patient or animal.

[0156] The microneedles are preferably made from 30G stainless steel needles (BD Microlance 3, Becton Dickinson) and have an exposed length of ~1 mm (Figure 23c). Each needle is shortened to a total length of ~4 mm before being mounted within a stainless-steel insert. These inserts were in the multijet orifice as described above, thus arranging them in a seven-needle hexagonal pattern. Channels (3 mm wide) extended radially to each outer microneedle to allow the fluid to flow from the central ampoule out to each microneedle.

[0157] Bench-top jet injector

[0158] Jets were formed through the microneedles using a motor-driven injection device. This system is described in J. W. McKeage, B. P. Ruddy, P. M. F. Nielsen, and A. J. Taberner, “The effect of jet speed on large volume jet injection,” Journal of Controlled Release, vol. 280, pp. 51-57, Jun. 2018, doi: 10.1016 / j.jconrel.2018.04.054. The injector uses a voice coil actuator (LA30-75, BEI Kimco) with a force constant of 35.5 N / A and stroke of 50 mm to drive a piston in a stainless-steel ampoule. Two ampoules were used in this work, one with a diameter of 8 mm and maximum deliverable volume of 2.5 mL; the second had a 10 mm diameter and 3.9 mL volume. The 8 mm / 2.5 mL ampoule was used for the 2 mL-2.5 mL injection experiments to allow direct comparison to needle-free jet injection; all other experiments used the 10 mm / 3.9 mL ampoule.

[0159] To perform an injection, power was delivered to the motor using a pair of linear power amplifiers (AE Techron 7224). Data recording and motor control was performed using a real time controller (Nl cRIO 9224, National Instruments) and control software written in LabVIEW2017. A potentiometer (Omega LP803) was used to monitor the position of the motor.

[0160] Experimentation

[0161] High speed video

[0162] To provide a qualitative observation of jet development through the seven-orifice prototype, a highspeed (1000 frames per second) video recording was taken of an injection into air, as shown in Figure 24. A camera (FLIR Blackfly BFS-U3-16S2M) with frame size of 1440 pixels by 208 pixels was used to record the video. A voltage of 130 V was supplied to the motor for 50 ms to produce the jets in the recording. Three images are shown in Figure 24, at 0ms (Figure 24a), at 3ms (Figure 24b) and at 30ms (Figure 24c).

[0163] Jet speed vs voltage

[0164] The speed of the jets formed through the seven microneedles was measured over a series of injections at four voltage inputs to the motor: 40 V, 70 V, 100 V, and 130 V (see Figure 24d). Injections were performed by applying the voltage for 100ms; three injections were performed at each voltage. During each injection a volumetric measurement of jet speed (yj) was made based on the measured motor speed (vp) and assuming conservation of mass: where AAis the cross-sectional area of the ampoule, Amis the cross-sectional area of a microneedle bore, and n is the number of microneedles. This equation assumes we have ‘ri microneedles with the same internal diameter, which is the case for all injections in this work. Ejected volume measurement

[0165] To measure the consistency of the jets produced across the seven microneedles, injections were performed in which all fluid leaving each microneedle was collected into separate vials. The change in weight of these vials was used to imply the volume of fluid ejected from each microneedle during the injection. Five injections were performed with an input of 100 V supplied to the injector for 50ms.

[0166] Tissue tests

[0167] Referring to Figures 25 to 27, to investigate multi-jet delivery through microneedles into tissue the seven-microneedle system was used to perform injections into samples of porcine tissue. Tissue was obtained, postmortem, following the completion of other ethically approved experiments, in accordance with the University of Auckland Code of Ethical Conduct for the Use of Animals for Teaching and Research. Samples of skin including subcutaneous fat and at least one layer of muscle (typically around 25mm thick) were collected from the upper torso of animals around 3 months of age then vacuum-sealed and stored at -80 °C. Prior to injection, samples were thawed to room temperature and cut into 45 mm by 45 mm blocks. The injected fluid was water with approximately 0.1 % blue food colouring (Brilliant Blue FCF, Queen Fine Foods Pty. Ltd.) to visualise the location of the delivered fluid in the tissue. A force transducer positioned underneath the tissue sample recorded the contact force applied by the device on the tissue sample, the injection was triggered when this force was ~20 N.

[0168] The volume of fluid delivered into the tissue was measured by recording the change in mass of the tissue sample. Any excess fluid on the surface after injection was mopped up prior to measuring the post-injection weight. Injected tissue samples were frozen then cut through the injection sites to observe the depth and lateral spread of the injected fluid.

[0169] Comparison to needle-free multi-jet injection (2 mL - 2.4 mL)

[0170] To compare delivery with this microneedle system to needle-free jet injection, ten injections were performed using the same 8 mm, 2.5 mL ampoule as described above. Five of these injections were performed using the same injection parameters as described above: 130 V supplied to the motor for 120ms, producing jets with a jet speed of approximately 120 m / s. For the other five samples the injection parameters were adjusted to attempt to deliver the full contents of the ampoule (2.5 mL): 120 V supplied to the motor, producing jets of approximately 110 m / s, for 160ms.

[0171] 3.9 mL ampoule

[0172] To test delivery volumes in excess of 2.5 mL a new ampoule with 10 mm diameter and 3.9 mL maximum volume was produced. While this ampoule can accommodate greater volume this comes at the cost of pressure development (as the same motor force is now spread over the larger piston area). Thus, the injection system was only capable of producing jets up to ~95 m / s with this ampoule. This ampoule was used to perform 15 injections over three different jet speeds (n=5 at each): 50 m / s, 70 m / s, and 90 m / s. The injection time was varied such that all injections attempted to deliver the full 3.9mL. The injection parameters for the 50 m / s, 70 m / s, and 90 m / s injections were: 35 V for 630ms, 70 V for 400ms, and 120 V for 300ms, respectively.

[0173] Results

[0174] Figure 24d shows the jet speeds achieved through the microneedles as a function of the voltage supplied to the injection motor when using the 3.9 mL ampoule. At 130 V the average jet speed through the microneedles was approximately 93 m / s. Figures 24 a to c show frames from a highspeed video at 0ms, 3ms and 30ms respectively of the jets formed through the seven microneedles travelling through air. This video demonstrates that all jets are qualitatively very similar with all seven forming simultaneously and with a similar jet shape. The jets appear to exit the needles at a slight angle, deflecting away from the sharp tip, presumably due to the bevel of the needle. The observation of similar jet formation through each microneedle is supported by the ejected volume measurements. A very similar volume of fluid flowed through each microneedle over the course of each injection implying each jet is travelling at a similar jet speed. With seven jets we would expect each to eject 14.3% of the total volume; through the ejected volume measurements we found that each orifice ejected 14.3% ± 2.7% (mean ± standard deviation).

[0175] The results of the injections into porcine tissue samples when attempting to deliver ~2 mL and ~2.5 mL are shown in Figure 25. In both cases the microneedle-assisted jet injection was very successful in consistently delivering the entire volume. The results are compared to those where injections were otherwise identical to the 2 mL injections and performed needle-free, see A, B and C. These results demonstrate that the addition of microneedles, see D and E, has improved delivery success and consistency relative to needle-free injection.

[0176] The results of the tissue injections at jet speed between 50 m / s - 90 m / s and a target delivery volume of 3.9 mL are shown in Figure 26a and b. At 90 m / s, consistent successful delivery of the 3.9 mL is observed. The injections at 70 m / s were also largely successful with just one injection failing to deliver >3.6mL. More variable delivery volumes were observed at 50 m / s, although all but one delivered more than half of the target volume. Figure 26 c also shows the maximum penetration depths observed through these injections. Much greater penetration depths are observed at 90 m / s where most injections penetrated the muscle despite dispersion predominantly occurring in the subcutaneous fat. At 50 m / s and 70 m / s the maximum depth was very similar to the depth of the fat-muscle boundary, with very limited evidence of penetration into the muscle at these speeds.

[0177] Discussion

[0178] These results demonstrate rapid delivery of 3.9 mL to the subcutaneous and / or intramuscular tissue, a volume that is almost double the perceived limit for subcutaneous delivery and the maximum volume deliverable by current autoinjectors (2.25 mL). The injections of 3.9 mL at 90 m / s presented here took just 0.3 s to complete. Other techniques in development for the delivery of >2.25 mL rely on extending the injection time to allow the tissue to support this volume. This requires wearing or holding an infusion device for hours, or the use of devices similar to traditional autoinjectors that are held against the skin for extended periods, typically >30s. While much further study of these developing devices is needed, extending injection time can increase the opportunity for user error and reduce patient comfort. Multi-jet injection through microneedles provides a promising alternative that can accommodate volumes much greater than 2.25 mL without extending injection time.

[0179] Relative to needle-free jet injection, microneedle-assisted multi-jet injection seems to improve the consistency of delivery success. The microneedles also allow a reduced jet speed to be used. For example, 90 m / s was the greatest jet speed formed through microneedles when performing the 3.9 mL injections here, whereas the results needle free plotted on Figure 27 required needle-free injection at ~130 m / s. The reduced jet speed reduces the pressure that must be developed in the drug by the injection device which will allow a smaller device to perform the delivery. However, injection through microneedles does come at the cost of the need for dealing with sharps waste and the risk of needlestick injury.

[0180] The injections presented in this work were all performed by a benchtop device driven by an electric motor that is highly controllable but not very energetically efficient, thus is much too large to produce a clinically suitable device. Smaller, clinically suitable injection devices could be produced by instead driving the injection by a spring or compressed gas, or even other kinds of electric motors such as that used and described in E. L. Kelley et al., “Advances in Large Volume Subcutaneous Injections: A Pilot Tolerability Study of an Innovative Needle-Free Injection Platform,” PDA J Pharm Sci Technol, vol. 76, no. 6, pp. 474-484, 2022, doi: 10.5731 Zpdajpst.2021 .012670. The upper limit of 3.9 mL investigated in this study was set by the capability of our injector, not some fundamental limit of multi-jet injection through microneedles, so we anticipate even greater delivery volumes will be possible with this technique.

[0181] Clinically implementing a microneedle assisted jet injection device will require the production of microneedle arrays that can withstand the pressures associated with jet injection (10 MPa). Here we have used 30G stainless steel needles shortened to an exposed length of ~1 mm. Microneedles constructed from stainless steel appear to be the most promising option as they provide sufficient strength and toughness, and methods for manufacture should be somewhat similar to existing techniques for hypodermic needles. Stainless steel offers the potential for re-sterilisation, and thus a reusable device. However, most existing autoinjectors are disposable; a disposable microneedle multijet injector would require the manufacturing cost of the microneedle plate to be very low for this to be clinically and commercially feasible.

[0182] Large -volume delivery using multi-jet injection promises to facilitate self-administration of delivery volumes >2.25 mL without compromising patient experience or injection time. It is believed that multijet injection will improve patient comfort as it is so quick and avoids pressure-induced pain at any single injection site. However, it remains to be determined whether the creation of a group of simultaneous injection sites, by needles or jets alone, has an impact on patient comfort, pain and acceptability.

[0183] Conclusion

[0184] In this work we demonstrate the subcutaneous delivery of 3.9 mL in just 0.3 seconds using jet injection performed through microneedles. This volume is almost double the maximum volume of current autoinjectors and the perceived limit for subcutaneous injection (2.25 mL). Our novel multi-jet prototype forms seven simultaneous jets through 30G needles that have been shortened to have an exposed length of just ~1 mm. By distributing the drug over multiple injection sites, this technique avoids the volume constraints of traditional subcutaneous delivery techniques. Relative to the equivalent needle-free multi-jet approach the use of microneedles improves delivery success and consistency. We also find that jet speeds of 70 m / s and below do not achieve complete delivery of 3.9 mL with our prototype system. These results demonstrate the promise of multi-jet injection through microneedles to accommodate volumes much greater than current autoinjectors, and thus allow selfadministration in many more delivery applications.

[0185] In yet other embodiments of the present invention, the needles in the orifice head may not be submillimetre sized but could be larger, it is anticipated that longer or larger needles could provide additional volume under the patient’s (or animals) skin (hide). It is anticipated that longer or larger needles could allow additional volume to be injected under the patient’s (or animals) skin (hide). A longer needle may allow the jets to penetrate more deeply into the tissue; a larger diameter needle may allow greater volumes of fluid to delivered for the same driving pressure. However, a downside to longer needles is that they add more resistant to fluid flow, making it more difficult to form the liquid into high-speed jets, that are capable of penetrating more deeply into the tissue.

[0186] Heating or cooling of the Jet Injector

[0187] To further overcome problems with the injection of viscous drugs, a jet injector, with or without microneedles, may include preheating orjust-in-time heating of the jet injectorto allow for fluids or drugs of 10x-100x greater viscosity to be injected subcutaneously.

[0188] Figure 28 shows three versions of jet injectors, and injections into the skin of a patient - the three layers of a patient’s skin are shown, the epidermis 500, dermis 501 , subcutaneous fat 502. This illustration shows a comparison between a hypodermic needle 503, a single jet injector 504, a multijet injector 505 and a jet injector with three needle injectors 506.

[0189] In other embodiments of jet injectors, similarly, as described below in relation to heating, cooling could alternatively be provided to the jet injector body. Figure 29 shows the same illustrations of injectors as shown in Figure 28 but includes heating near the outlet / nozzle of the injector. Again, this illustration shows a hypodermic needle 503, a single jet injector 507 with heating 510, a multijet injector 505 with heating 510 and a jet injector with three needle injectors 506, each with heating 510.

[0190] The heating element may be a ring or sleeve embedded near the nozzle (or outlet of the jet injector) that is connected to a power source that can be heated at the time of injection or before injection. In other forms, as shown in Figure 30, the heating element 550 may heat locally around the outlet, as a ring (in B) an elongated ring in A or the material completely surrounding the outlet (either a metal, ceramic, mineral, plastics or composite) may be heated, as in C. Or in D, in the instance of where a micro needle is used, both the outlet and the needle may be heated.

[0191] In some embodiments of the jet injector of the present invention, heating will only be at the tip or end of the outlet / orifice / nozzle. As such, the bulk of the fluid may still be at room or refrigerated temperatures, but fluid is heated to reduce viscosity only for the brief moment that it flows through the orifice, outlet or nozzle, or multiple nozzles or outlets. Where there are multiple nozzles or outlets in a jet injector, each nozzle may be separately heated or the whole orifice plate, as described in the configurations of Figures 1 and 8, or Figure 23, may be heated by a heating element.

[0192] In some embodiments of the jet injector of the present invention heating will only occur to the outer layer of the fluid close to the wall of the body or orifice(s). This will lead to reduced viscosity only in this outer layer which lubricates the rest of the flow. In these embodiments, the heating increases the temperature of the fluid at the wall of the orifice / outlet but, as much as possible, does not heat the high-speed flow toward the middle of the fluid.

[0193] The heating has the purpose of increasing the temperature and thereby lowering the viscosity of the fluid leaving the injector. In some forms, the injector may include an element that generates (or absorbs) heat and may also have an intermediate element that assists in the flow of heat between the heating element and the fluid.

[0194] In some forms the heating or change in temperature of any one of the body of the jet injector, or outlet(s), causes the injector to be sterilised.

[0195] The element(s) generating heat could directly transfer this heat into the fluid. Or a heating element will generate heat which will be transferred to an intermediate distribution element. For example, in some embodiments, as in Figure 31 , a jet injector 600 may have an orifice heating coil 601 , that sits about the orifice insert 602. Figure 31 A is a cross-sectional view of a jet injector 606, including the ampoule body 604 and piston 605 of the injector 606, the orifice insert 602 and orifice 603 itself. Figure 31 B shows a close-up perspective view of the orifice insert 602 with the wound heating coil 601 , while Figure 31 C shows a perspective view of the orifice insert 602. The heating coil heating coil will heat up when a current is applied to the coil. In preferred forms the heating coil is a coil of nichrome wire. Figure 32A shows a perspective illustration of an alternative embodiment of the outlet of a jet injector 610 with an orifice ‘sleeve’ 611 covering the approach to the orifice, this distribution element will transfer heat to and from the fluid that is expelled from the injector 610. The sleeve 612 shown here sits about the outlet, near the outlet of the injector. The sleeve represents an element that generates heat, when a current is applied through it. This heat flows into the sleeve which distributes the heat over a wide surface area of the fluid flowing through the body and out the outlet. In preferred forms the sleeve is made of copper, but other materials that can transfer heat when currents are applied to them may be used. The outlet (orifice) 612 should also be constructed from a heat conducting material as, so that induction heating from the sleeve can heat up the outlet. Such materials may include, metals, such as, copper, brass, stainless steel, minerals such as, diamond, sapphire, ruby or plastics and ceramics or other materials such as silicon.

[0196] While in the preferred form of the jet injector of the present invention there are multiple orifices or outlets, the heating element / coil may be included in other forms of jet injectors, including those with a single outlet / orifice, or to those have two or three outlets / orifices. Heating elements could be included for each outlet or at the orifice plate that each outlet or nozzle is connected to.

[0197] Figure 33 shows a cross-section through a jet injector body 620 similar to that shown in Figure 32. However, in this embodiment heat is generated in the orifice 622 via inductive heat transfer from a coil

[0198] 621 . The coil around the body 623 is the primary coil that induces the inductive heat generation in the orifice. Here the coil, heats the body 620 about the orifice (outlet) 622, which in turn heats the orifice

[0199] 622, so direct heating of the orifice itself is not needed in this configuration.

[0200] The element generating heat may do so by one of or any of the methods listed below:

[0201] • Joule heating, including inductive heating

[0202] • Bidirectional thermoelectric heat pump (such as a Peltier device) Light / NIR

[0203] • Microwave

[0204] • Chemical reaction, including combustion, other exothermic reactions and biological / organic reaction

[0205] • Friction

[0206] • Pressure changes (causing phase changes (eg compressor))

[0207] • Nuclear fission / fusion.

[0208] Where there is an intermediate distribution element (such as in Figure 33, the body 623 of the jet injector) that sits at or near the nozzle / orifice of the injector may be made from; metals (eg. copper, brass, stainless steel), minerals (such as, diamond, sapphire, ruby), plastics, ceramics or other materials (such as silicon). The distribution element must be capable of and designed so as to distribute heat from the heating element to a greater surface area of the fluid.

[0209] A jet injector with heating capability will result in the following:

[0210] • Reducing the viscosity of the fluid to be injected, allowing much more viscous drugs to be delivered. Heating could be done such that just the outer layer of fluid is heated to reduce viscosity (utilising a lubricating effect) or it could heat the bulk of the fluid. Controlling the viscosity via heating could effectively allow control over the jet speed, and therefore the injection depth, through the course of the injection.

[0211] • Sterilise the orifice and / or ampoule.

[0212] • Induce chemical / structural changes to the drug as it is injected (for example, trigger the setting of a hydrogel that is liquid in the device and forms a gel in the tissue after passing through the orifice).

[0213] • Spatial modulation of jet temperature could be used to modulate the flow direction / shape.

[0214] • Induce shape changes to the orifice which could change the flow path, allowing the jet shape, size, or direction to be changed. This could involve shape memory alloys which can change shape dramatically and with very large forces when exposed to temperature changes. This could also involve shape changes due to relative volumetric thermal expansion of different materials when heated.

[0215] Experimental work

[0216] The inventors have conducted some experiments that demonstrate the impact of temperature dependent viscosity on jet injection. The effects of heating caused by friction or shear forces in the fluid was shown to cause an increase in temperature to >60 °C, and thus a 10-fold decrease in viscosity at the perimeter of the jet in some cases. This investigation was performed using 1) water as the injected fluid, 2) 85% glycerol fluid and 3) 99% glycerol as the fluid. The change in jet speed due to this ‘viscous-heating’ effect was most pronounced for the 85 % and 99 % glycerol fluids, particularly toward the outer edge of the jet stream of the fluid. The deliberate addition of heat to the injector was also investigated in this work. The predicted jet speed of the fluid at the outlet, was compared when 99% glycerol was heated to ~37 °C, at room temperature (~27 °C), and refrigerated (~7 °C). For the same 10 MPa input pressure fluid at body temperature, 22 °C, and 7 °C formed jets with average jet speeds of 69 m / s, 50 m / s, and 11 m / s, respectively. These results indicate the promise of heating to drastically increase jet speed for the delivery of very viscous drugs.

[0217] A detailed account of the experimentation is given below from computational fluid dynamics models of jet injection that incorporate viscous heat production and heat exchange with the surrounding ampoule. To complement and validate the modelling framework temperature measurements were preformed using infrared imaging and a tiny thermocouple attached to an injection orifice. We used these tools to investigate the extent to which viscous heating increases the jet speed and the effect of the material of the ampoule and orifice. Additionally, we considered the effect of actively pre-heating the fluid before injection, thus decreasing its initial viscosity. We present experimental validation of the benefits of preheating on jet development and use this approach to demonstrate the delivery of a very viscous fluid (~0.5 Pa s) into porcine tissue.

[0218] Methods

[0219] CFD model

[0220] In this work the flow of fluids through a jet injector was modelled using ANSYS FLUENT (ANSYS 2022, ANSYS Inc). Similarly to previous work modelling jet injection (the finite volume method was utilised, using Menter’s shear stress transport model for turbulence. The model included both a fluid domain and the surrounding solid domain of the ampoule / orifice to model the heat exchange between the liquid and solid using Conjugate Heat Transfer. The material of the ampoule was modelled using a thermal rigid solid formulation; the mechanical deformation of the ampoule geometry was not considered in this model.

[0221] In this work we investigated the effect of viscous heating on the delivery of three solutions of differing viscosities. These were: 99 % glycerol, 85 % glycerol and water. At room temperature these fluids had viscosities of approximately: 1 Pa s, 0.1 Pa s and 0.001 Pa s respectively and a graph showing viscosity versus temperature of each in Figure 34. Glycerol- Water solutions were used as glycerol is convenient to work with experimentally and it replicates the viscosity and temperature dependence of some protein solutions. Glycerol has been used in previous jet injection studies to investigate the effects of fluid viscosity.

[0222] Geometry

[0223] The geometry used in the model was based on that of a polycarbonate jet injection ampoule (Injex 30) with an internal bore diameter of 3.57 mm that tapers down to an outlet diameter of 170 pm over a length of approximately 3 mm (see Figure 35). In Figure 35, on the left-hand side the solid and fluid regions and boundary conditions are shown, whereas on the right-hand side the meshed geometry is shown with an inset that shows the inflation layer at the edge of the fluid domain.

[0224] The geometry was modelled using a 2D axisymmetric approach, to simplify the meshing process and minimise solving time. The geometry included the distal 5.6 mm of the ampoule near the orifice, as only the flow of the fluid at or near to the orifice was of interest. The boundary conditions applied to the model are shown in Figure 30. The boundary wall was specified to be thermally coupled, so heat could conduct between the fluid domain and the solid domain. An inlet pressure boundary condition was used with a value of 10 MPa. This pressure lies in the middle of the range typically developed in a jet injector of this type. The outlet pressure of the orifice was set to atmospheric pressure. The bottomline line indicated in Figure 35 represents the rotational axis of symmetry. The external solid wall had a convection boundary condition with a convective heat transfer coefficient of 10 W / m2-K to model heat transfer with surrounding still air. The air itself was not explicitly modelled. Mesh & mesh independence

[0225] A quad-dominant mesh was used to ensure accuracy without the need for a lengthy meshing process. From previous work it was known that the velocity and temperature gradients at the wall were of particular importance to capture the effects of viscous heating on the flow. A very fine inflation layer thus provided a very high resolution near the wall. In total there were 53 nodes across the outlet boundary. The profiles at the outlet were integrated to find the average speed (by volume) of the jet and the average temperature of the jet, which were later compared to experimental results. A mesh convergence study was performed to confirm that the simulations demonstrated mesh independence. In this study element sizes between 1 x 10- 4 m and 5 x 10- 6 m were investigated to produce meshes with between 9000 and 250,000 elements. The parameters of interest were the average jet speed and the wall temperature at the outlet. As shown in Figure 36, both the average jet speed and wall temperature do not vary significantly when the mesh is refined beyond ~100,000 elements. The mesh used for the subsequent studies had 97,997 elements with an average element size of 10 pm. Note, the average jet speed is shown in Figure 36 as black crosses (left axis), and wall temperature is shown as grey circles (right axis) at the outlet as the mesh is refined. The red markers indicate the mesh used for the subsequent studies.

[0226] Model variations

[0227] Viscous heating

[0228] To investigate the manner in which viscous heating contributes to jet development we compared the predicted jet speed at the outlet when viscous heating was included in, to when it was excluded from, the model. The profile of jet speed across the radius of the outlet and the volumetric average jet speed at the outlet were recorded. This process was performed for water, 85 % glycerol, and 99 % glycerol. The model was otherwise in the default setup with a 10 MPa inlet pressure and the solid modelled as polycarbonate.

[0229] Orifice materials

[0230] To investigate how the thermal properties of the orifice influence jet development the solid material was represented as polycarbonate, stainless steel, and copper (properties shown in Table 2). The jet speed and temperature at the outlet were computed in these models.

[0231] Table 2

[0232] Preheating

[0233] In addition to the passive effects of viscous heating, we were also interested in understanding the impact of deliberately preheating the fluid. This would effectively decrease the initial viscosity (which would be decreased further at the perimeter by viscous heating). We thus varied the initial temperature in the model between 7 °C and 47 °C to investigate how this changed the jet speed and temperature at the outlet. In each case we also computed the proportion of the fluid at the outlet that developed temperatures that were 5 °C, 10 °C, 15 °C, 20 °C, 30 °C, and 40 °C above the initial temperature.

[0234] Experimental methods

[0235] Copper tube geometry

[0236] To enable a comparison between model predictions and experimental measurements a second geometry was used that involved forming the jet through an orifice in a copper tube (155 pm inner diameter, 270 pm outer diameter, 2.4 mm length). The copper tube provided an object in which temperature would be spatially consistent on which to perform temperature measurements. The computational representation of this geometry is shown in Figure 37. This geometry was manufactured by drilling a hole in the tip of an Injex ampoule and then gluing the copper tube in this hole using epoxy adhesive. This was performed such that ~ 1 .2 mm of the 2.4 mm total length of copper tube was exposed. The rest of the geometry was modelled identically to that shown in Figure 35. The temperature was measured by two different methods: 1 . using an infrared camera (Gobi-384, Xenix) and 2. by a custom thermocouple soldered to the outer surface of the copper tube. The thermal camera recorded images at a frame rate of 27 frames per second, so could only provide an estimate of the copper temperature at steady-state. The thermocouple was used to provide precise measures of orifice temperature, with measurements captured at a rate of 10 kHz. An E-type thermocouple was manufactured from 25 pm wires, providing a sensitivity of 60 pV / K. The ‘hot junction’ of the thermocouple was adhered to the distal end of the copper tube by a dot of solder. The voltage developed at the ‘cold junction’ was amplified by a low-noise amplifier (A10, EM Electronics) and digitised by a 24-bit A / D converter (NI-9239, Nl). The temperature of the ‘cold junction’ was monitored by a platinum resistance temperature detector (1 PT100K, Omega) and a benchtop Data Acquisition Unit (34970A, Agilent). An existing bench-top jet injector was used to form jets through the copper tube, where a voice coil actuator was used to drive a 3.57 mm diameter piston to produce pressure in the ampoule. A potentiometer (ALPS RDC10) was used to measure piston position, and by assuming conservation of mass, estimate the average jet speed (by volume) through the tube. To compare these measurements to model predictions we estimated the pressure that was generated in the ampoule during these experiments. Pressure was computed from the force applied by the motor (after accounting for the friction between the ampoule walls and O-rings) divided by the cross-sectional area of the ampoule. Motor force was estimated based on the measured current supplied to the motor and the motor’s force constant (3.0 NZ / W), while the cross-sectional area of the ampoule was calculated from its measured diameter. Friction was estimated using a coefficient of friction of 0.11 . From this analysis, we estimate that the static pressure within the ampoule during the injections was approximately 9.25 MPa. This value was used for the inlet pressure when modelling the copper tube geometry.

[0237] Preheating validation

[0238] A further experimental validation of the model was achieved by performing injections through the original Injex geometry (Figure 35) at different temperatures. The same injector described above was used to form jets through an Injex ampoule by developing approximately 9.25 MPa of pressure on 99 % glycerol. The ampoule and 99 % glycerol were preheated by immersing the tip of the injector in warm water. The temperature of the warm water was monitored as it slowly cooled and when it reached body temperature (~37 °C) five injections were performed. Five further injections were performed with the ampoule and fluid at room temperature (~22 °C). The average jet speeds were measured and then compared to those predicted by the modelling.

[0239] Tissue injection

[0240] Given the significant jet speeds predicted and achieved by preheated (37 °C) 99 % glycerol we sought to demonstrate the injection of this fluid into ex vivo porcine skin, commonly used as model of human skin. Porcine tissue samples were collected postmortem in accordance with the University of Auckland Code of Ethical Conduct for the Use of Animals for Teaching and Research. Abdominal skin, with subcutaneous fat and at least one muscle layer, was excised (typically to a thickness of ~25 mm), vacuum sealed, and stored at - 80 °C. Tissue was thawed to room temperature (~22 °C) before being cut into 30 mm x 30 mm samples for injection. In these injections, an injex ampoule containing the glycerol was mounted on an existing bench-top jet injector (previously described in (McKeage et al., 2018. Power-efficient controlled jet injection using a compound ampoule. J. Control. Rel. 291 , 127- 134)). This injector developed a pressure in the fluid in of around 25 MPa resulting in a jet travelling at approximately 140 m / s. The fluid used was a 20:1 ratio of 99 % glycerol with blue food colouring added to observe the location of the delivered fluid in the tissue. This mixture was thus equivalent to ~96 % glycerol and had a viscosity of 0.5 Pa-s at room temperature. The ampoule and fluid were warmed to approximately 37 °C prior to injection. Three injections of around 270 pL were performed into separate tissue samples. The volume of fluid delivered into the tissue samples was implied by the change in weight of the sample, and the location of the delivered fluid was observed by cutting the sample through the injection site.

[0241] Results

[0242] Viscous heating

[0243] The effect of viscous heating on the jet formed at the outlet is illustrated in Figures 38 and 39. Figure 38A shows the jet speed profile across the 170 pm outlet for water (green), 85% glycerol (blue) and 99% glycerol (red). The profile is shown both with viscous heating (solid) and without viscous heating (dashed) included in the model. Figure 38B shows the change in the predicted jet-speed profiles due to viscous heating. Figure 38C shows the change in the average jet speed at the outlet for each fluid with and without viscous heating.

[0244] The outlet jet speed profile (Figure 38A) for water demonstrates that most of the fluid emerges from the orifice at the same speed across the diameter of the jet, and that viscous heating makes little difference to the resulting speed. However, viscous heating causes much greater increases in jet speed for 85 % and 99 % glycerol, particularly toward the outer edge of the jet (Figure 38B). For 99% glycerol, viscous heating almost doubles the average jet speed at the outlet from around 22 m / s to around 42 m / s (Figure 38C). The temperature of each fluid increases predominantly at the outer ~ 10 pm annulus of the jet (Figure 39). The temperature (Figure 39A) and viscosity (Figure 39B) are shown at the outlet for water (green), 85 % glycerol (blue), and 99 % glycerol (red). The majority of the flow remains at ambient temperature (22 °C) despite the very significant temperature increases, and thus viscosity decreases, at the perimeter of the jet. For 99 % glycerol the model predicts a temperature increase in excess of 60 °C at the wall, which causes the viscosity to decrease by greater than 10-fold in this region.

[0245] Orifice material

[0246] The resulting jet speed and temperature at the outlet when the material properties of the solid material were adjusted between those of polycarbonate, stainless-steel, and copper, are shown the graphs of Figure 40. Jet speed (40A) and temperature (40B & 40C) at the outlet with the solid ampoule modelled as polycarbonate (red), stainless steel (blue), and copper (green). The average jet speed of 99 % glycerol at the outlet was 39.9 m / s when developed in polycarbonate, 36.9 m / s for stainless steel, and 30.9 m / s for copper. The peak temperature in the fluid is predicted to be much greater with a polycarbonate orifice (~87 °C) compared to both stainless steel (66 °C) and copper (49 °C). The peak temperature in the fluid is predicted to occur 1 pm and 3 pm from the wall when the solid is modelled as stainless steel and copper, respectively.

[0247] Preheating

[0248] Figure 41 shows the predicted impact of preheating the fluid and orifice prior to injection, for 99 % glycerol driven by 10 MPa of pressure. In Figure 41 A, the average jet speed at the outlet versus the initial temperature. Black represents model predictions while red are experimental measurements. Figure 41 B shows the difference between the initial wall temperature and the wall temperature at the outlet, while Figure 41 C represents the percentage of fluid exiting the orifice at temperatures greater than the x-axis value. The legend refers to the initial temperature.

[0249] The model predicts that preheating glycerol to around body temperature (37 °C) would allow it to be formed into a jet travelling around 75 m / s, whereas this speed would be around 50 m / s at 27 °C and merely 12 m / s at 7 °C. The extent to which viscous heating further heats the fluid seems to peak when the fluid is preheated to ~27 °C (viscosity ~ 0.7 Pa-s). Figure 41 C shows the percentage of fluid exiting the orifice at, or above, a given temperature. This metric was evaluated at temperatures 5 °C, 10 °C, 15 °C, 20 °C, 30 °C, and 40 °C above the initial temperature. Despite the high peak temperatures observed right at the wall, this indicates how little of the fluid is heated significantly above the initial temperature. For all initial temperatures tested here, less than 10 % of the fluid was heated by 10 °C or more. The injections through the Injex ampoule at ~22 °C and ~37 °C produced jet speeds of 50 m / s and 70 m / s, respectively (Figure 41 C). These measurements are very similar to the speeds predicted by the model, confirming the significant improvement in jet speed that can result from preheating the fluid. Experimental results and model validation

[0250] Figure 42A shows a photograph of the tip of the injection ampoule 630 with copper tube glued in place of the orifice 631 (note; the thermocouple wires are not visible at this scale). Figure 42B shows a thermal (infrared) image of an 85 % glycerol jet 632 at steady-state formed through the copper tube 631.

[0251] Measurements of jet speed and orifice temperature for the copper tube geometry are shown in Figure 43. In Figure 43A the temperature change in the copper tube measured by the thermocouple during injection of water (green), 85 % glycerol (blue), and 99 % glycerol (red). In Figure 43C the average jet speed predicted (black) and measured (red) through the copper tube versus fluid viscosity. The thermocouple measurements demonstrate that the temperature of the copper tube increased by approximately 7 °C with water, 36 °C with 85 % glycerol, and 24 °C with 99 % glycerol. Infrared imaging estimated similar temperature increases in the copper: 4 °C, 27 °C, and 19 °C for water, 85 % glycerol, and 99 % glycerol, respectively. These measurements compare well with the model which predicted temperature increases in the copper of 5 °C, 29 °C, 14 °C, respectively. In each fluid the thermocouple measurements show that the copper tube took a very short period of time (<20 ms) to be heated to its maximum temperature. Note also that the temperature reached by the copper is highly sensitive and responsive to the jet speed, as evidenced by the high frequency (~270 Hz) undulations in temperature that are particularly evident in the jet injection of water (green traces in Figure 43B).

[0252] Measurements of jet speed through the copper tube were similar to those predicted by the model. The measured speeds were 92 m / s, 51 m / s, and 12 m / s for water, 85 % glycerol and 99 % glycerol, respectively, while these values were predicted to be 114 m / s, 41 m / s, and 5 m / s by the model.

[0253] This experimentation shows that a change in temperature of the jet of fluid or drug from the jet injector can be induced by the flow of the jet. And as such, the jet flow can be measured and from that flow rate and / or jet speed of the fluid or drug can be estimated or predicted.

[0254] Tissue injection The five injections of ~ 96 % glycerol into porcine tissue were successful, with 83.5 %±15.6 % (mean ± standard deviation) of the 270 pL injection volume delivered into the tissue. A cross section of two of the injected samples can be seen in Figure 44, one where the jet penetrated into the muscle layer while only penetrating as far as the subcutaneous fat layer in the other one.

[0255] Discussion

[0256] In this work, we have demonstrated that the temperature dependence of a fluid’s viscosity can have a very significant effect on its susceptibility to be formed into a jet. The results shown in Figure 38 demonstrate that viscous heating causes the resultant jet speed for 99 % glycerol to almost double relative to the case where the temperature dependence of viscosity is ignored. In addition to the viscous heating occurring during every jet injection we have shown that preheating the entire fluid to ~37 °C increases the jet speed achievable from 99 % glycerol 6-fold relative to when it is injected at ~7 °C. The jet speeds predicted and measured for 99 % glycerol at 37 °C are close to those required to penetrate the skin and deliver the fluid using jet injection. The jet speed could be increased beyond that required for delivery by increasing the pressure from the modest 10 MPa value used in these tests. This was our approach in conducting the tissue injections presented here which demonstrated successful delivery of ~96 % glycerol (~0.5 Pa-s) into porcine tissue. This demonstrates that simply preheating a drug to body temperature would facilitate jet injection of fluids that otherwise cannot be injected. Note that the viscosity of 99 % glycerol at room temperature is approximately 1 Pa-s, which is 10- to 100-fold more viscous than current protein therapeutics (which are typically <0.05 Pa.s). In the motor driven injections presented here, and in previous work by the inventors between 100 J and 500 J of energy was required to develop the pressure in the ampoule and form the jet. While this is dependent on the volume, jet speed, and injector used, we expect preheating the fluid may facilitate a much more energy efficient means of increasing jet speed for very viscous drugs such as 99 % glycerol. Preheating a volume of 0.3 mL of 99 % glycerol from 7 °C to 37 °C requires only around 21 J (assuming a specific heat capacity for glycerol of 2.35 J.g- 1 -K- 1) yet facilitates a 6-fold increase in jet speed (Figure 36). Such an increase in jet speed would require much greater than 100 J of energy to achieve by increasing the pressure in the ampoule and would likely require an ampoule of much larger ultimate strength. The amount of viscous energy loss determines the jet speed profile observed at the outlet. In a situation where there is very little viscous loss, such as the flow of water in Figure 38A, almost all the fluid flows out the orifice travelling at the same speed. When the viscosity increases (such as with 85 % or 99 % glycerol) the greater viscous energy loss results in a reduced jet speed that begins to resemble a parabolic profile. Viscous heating effectively acts to reduce the extent of viscous energy loss. Thus, we observe that this phenomenon shifts the parabolic profiles in Figure 38 by adding a steep increase in speed at the walls. Viscous heating could be viewed as having negative feedback on viscous energy loss where the heat and viscosity changes caused by the viscous energy loss result in less viscous energy loss in the subsequent fluid flow. This could explain why we see a peak in the extent of viscous heating in Figure 41 , where the highest temperature, lowest viscosity, highest speed flows have less total viscous loss for viscous heating to reduce, whereas the lowest temperature, highest viscosity flows prevent flow speed from increasing to the point that sufficient heat is generated to lower the viscosity. When heat is generated in the fluid due to viscous heating, some is conducted into the solid walls of the ampoule. The higher the thermal conductivity of the ampoule material, the more quickly this heat is transferred away from the wall into the bulk of the solid material. As evidenced by the results in Figure 40 where the greater thermal conductivity of copper appears to be detrimental to jet development, as heat is conducted away from the wall through the copper, leading to a lower temperature, and thus higher viscosity, at the perimeter of the jet. The other important thermal properties of the solid are the heat capacity (i.e. the amount of heat required to change its temperature) and the total mass of material. These effectively determine how difficult it is to change the temperature of the material. In the case of the copper tube geometry, as there was only a very small mass of copper, it took very little heat to increase the temperature of the entire tube to the higher temperatures (>50 °C in the 85 % glycerol case) at the edge of the jet. The thermocouple measurements demonstrate that the heat rate of the jet was such that it increased the temperature of the entire tube to the steady-state value within the first ~20 ms of the injection. Additionally, when injecting water, we were able to observe oscillations in temperature apparently due to oscillations in jet speed, suggesting that changes in viscous heating are causing measurable temperature changes in the copper tube over very short timescales (<1 ms).

[0257] This work used glycerol to mimic a viscous injectable drug. Glycerol allowed us to easily mix different concentrations to vary viscosities. An important aspect of future work will be testing how these findings compare when drugs are used, particularly viscous, protein-based therapeutics. As viscosity typically decreases exponentially with increasing temperature in protein solutions (Woldeyes, M.A., Qi, W., Razinkov, V.I., Furst, E.M., Roberts, C.J., 2020. Temperature dependence of protein solution viscosity and protein-protein interactions: insights into the origins of high-viscosity protein solutions. Mol. Pharm. 17 (12), 4473-4482), we expect our findings in glycerol to be very relevant to these protein therapeutics. When working with proteins it will also be important to confirm that increases in temperature do not otherwise negatively affect the function of the drug. Temperatures above body temperature risk damaging the protein molecules, however as shown in Figure 39 and Figure 41 , it is only a very small proportion of the drug at the perimeter of the jet that is subjected to these temperatures, and for such a short time period that we expect no significant impact on drug function caused by viscous heating. This is supported by previous studies testing the activity and conformation of proteins following jet injection, which found no significant impact on conformation, stability, or binding (Hogan, N.C., Taberner, A.J., Jones, L.A., Hunter, I.W., 2015. Needle-free delivery of macromolecules through the skin using controllable jet injectors. Expert Opin. Drug Deliv. 12 (10), 1637-1648 and Hogan, N.C., Cloutier, A.M., Hunter, I.W., 2015. Jet injection of a monoclonal antibody: A preliminary study. In: 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). IEEE, pp. 7336-7340).

[0258] These findings suggest that the temperature dependence of a fluid’s viscosity can have a very significant effect on its susceptibility to being formed into a jet and thus be delivered into the body. Both modelling and measurement show temperature increases in excess of 30 °C at the perimeter of jets formed with 85 % glycerol, which, in turn, cause a >10- fold decrease in viscosity in this region. By preheating the injectate we demonstrated very significant increases in the jet speeds achieved with glycerol (99 %), achieving in excess of 70 m / s at 37 °C. We then demonstrated the successful delivery of this very viscous fluid into samples of ex vivo porcine tissue using preheated jet injection. As 99 % glycerol (1 Pa-s) is 10- to 100-fold more viscous that current protein therapeutics, these findings demonstrate the potential for this technique to be leveraged in jet injection, with or without preheating, to enable the subcutaneous delivery of very viscous drugs. Heated orifice / outlet

[0259] A further embodiment of an injector nozzle 644 is shown in Figure 45, the injected nozzle here has a heating element 640, optionally made of a ceramic material) attached to a block of aluminium 641 , that is an intermediate distribution element. This heating element 640 heats the block of aluminium 641 , which heats by conduction the orifice 642, that is attached or connected to the intermediate distribution element 641 . In this embodiment, the orifice insert must be made from a thermally conductive material, such as brass or copper or the like (as described above). This embodiment is aimed at heating just the outer layer of the jet as it travels through the orifice 642. As is described above, the jet injector is motor controlled to develop the fluid or drug within the injector to a controlled pressure.

[0260] Figures 46 and 47 show the results of experiments where a constant pressure was developed in the fluid (water or 99% glycerol) while the outlet / orifice 642 was heated to temperatures from 20 °C to 90 °C. Figure 46 shows example measurements of jet speed over time when injecting 99% glycerol at 22 °C (red line), 99% glycerol at 90 °C (red dashed) and water (blue line). Figure 47 shows the average jet speed over an entire injection at a range of different temperatures between 20°C to 90°C. The error bars in the glycerol data indicate the standard deviation over n=3 injections. The results shown in both Figures 46 and 47 demonstrate that as the orifice temperature increases the jet speed of glycerol increases. This occurs to the extent that heating the orifice to 90 °C resulted in the very viscous glycerol (~1 Pa.s) being ejected at a similar jet speed to water.

[0261] Throughout the description like reference numerals will be used to refer to like features in different embodiments.

[0262] Unless the context clearly requires otherwise, throughout the description, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to”.

[0263] Although this invention has been described by way of example and with reference to possible embodiments thereof, it is to be understood that modifications or improvements may be made thereto without departing from the scope of the invention. The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features. Furthermore, where reference has been made to specific components or integers of the invention having known equivalents, then such equivalents are herein incorporated as if individually set forth.

[0264] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Claims

Claims:1 . A jet injector comprising: a body, to house a fluid or drug, a mechanism in which to develop a pressure in the fluid or drug, an outlet that the fluid or drug is ejected out of due to the pressure developed, where in use, the fluid or drug is injected into a patient, a heating or cooling element configured to control the temperature of the fluid or drug, as it flows through any one or more of: the body or the outlet.

2. A jet injector of claim 1 where the heating or cooling element is configured to control the temperature of the body.

3. A jet injector of claim 1 or claim 2 wherein the heating or cooling element is configured to control the temperature of the outlet.

4. A jet injector of any one of claims 1 to 3 wherein the control of the temperature is configured to increase the flow rate or jet speed of the fluid or drug, when ejected.

5. A jet injector of claim 3 wherein the control of the temperature of the outlet is configured to induce a shape, size, or directional change to the jet of fluid or drug.

6. A jet injector of any one of claims 1 to 5 wherein the heating element is configured to increase the temperature of the fluid or drug during the injection of the fluid or drug to the patient.

7. A jet injector of any one of claims 1 to 6 wherein the outlet is one outlet.

8. A jet injector of any one of claims 1 to 6 wherein the outlet is more than one outlet.

9. A jet injector of any one of claims 1 to 6 wherein the outlet is at least 3 but up to 7 outlets.

10. A jet injector of any one of claims 1 to 6, 8 and 9 wherein the outlet is more than 7 outlets.

11. A jet injector of any one of claims 8 to 10 wherein the more than one outlet, or outlets are formed in an orifice plate as channels to carry the fluid or drug through the injector.

12. A jet injector of any one of claims 1 to 11 wherein the heating or cooling element is a ring or sleeve that extends about the or each outlet.

13. A jet injector of any one of claims 1 to 7 further comprising an intermediate distribution element between the heating or cooling element and the outlet, the intermediate distribution element configured to distribute heat from the heating or cooling element to the outlet.

14. A jet injector of any one of claims 8, 9, 10 or 11 further comprising an intermediate distribution element between the heating or cooling element and the outlets, the intermediate distribution element configured to distribute heat from the heating or cooling element to the outlets.

15. A jet injector of any one of claims 1 to 14 wherein microneed le(s) are placed within the outlet(s), to pierce the dermis of a patient when the jet injection is in use.

16. A jet injector of any one of claims 1 to 15 wherein the outlet, outlets and / or microneedle(s) are made from a material with high thermal conductivity such that the outlet, outlets and / or microneedle(s) rapidly and evenly change temperature in response to heating or cooling by the heating or cooling element.

17. A jet injector of claim 16 wherein the material with high thermal conductivity is one or more of brass, copper, stainless steel, mineral or ceramic.

18. A method of determining flow rate and / or jet speed of a fluid ordrug through a jet injector, where the jet injector comprises: a body, to house a fluid or drug, a mechanism in which to develop a pressure in the fluid or drug, an outlet that the fluid or drug is ejected out of due to the pressure developed, where in use, the fluid or drug is injected into a patient, wherein, the change of temperature of the fluid or drug through the jet injector is measured to determine an estimated or predicted flow rate and / or jet speed of the fluid or drug.

19. A jet injector as herein described with reference to the examples and experiments.

20. A jet injector as herein described with reference to the figures.

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