Needle-free injector with gas bubble detection function

Abstract

To provide a method of facilitating needle-free injection of an injectate by using a needle-free injector.SOLUTION: A needle-free transdermal injector includes a controller operatively coupled to a motor. The controller is operable to selectively operate a plunger according to any of a first delivery profile, a second delivery profile, and a third delivery profile. The controller may transition from the first delivery profile to the second delivery profile responsive to compression of a gas in the chamber by the plunger, upon detecting a spike in a measured current applied to the motor. The controller may transition from the second delivery profile to the third delivery profile responsive to detecting a steady state condition between the measured current and a velocity of the plunger.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 896,395, entitled "Needle-Free Syringe with Air Bubble Detection," filed September 5, 2019, the entire disclosure of which is incorporated herein by reference for all purposes. [Background technology]

[0002] The present disclosure relates to a needle-free transdermal injection device. In modern medicine, medications are often delivered to a patient's bloodstream through the skin. Traditionally, this is accomplished by inserting a needle through the patient's skin into the target area for injection. However, the use of needles presents significant drawbacks, including patient fear and discomfort, as well as safety issues related to handling used needles.

[0003] Needle-free transdermal injection devices have been developed as alternatives to needle-based syringes. These devices typically use a high-pressure, thin jet of injectate to penetrate the patient's skin, thereby eliminating the need to insert a needle into the patient's skin. However, there is still a need for improvement in needle-free transdermal injection devices. Summary of the Invention

[0004] The needle-free injector monitors the compression of a volume of gas within an injectate cartridge during movement of a plunger through a first delivery profile. Once the volume of gas is sufficiently compressed (as measured by a spike in the measurement current supplied to the needle-free injector motor), operation of the needle-free injector transitions to operation according to a second delivery profile. Operation according to the second delivery profile generates an injectate velocity sufficient to penetrate a permeability barrier. Once the injectate penetrates the permeability barrier and a steady-state condition is reached, operation of the needle-free injector transitions to operation according to a third delivery profile for delivering the injectate to the subject. Detecting gas bubble compression prior to delivery of injectate in this manner allows the flow of injectate to be controlled to more accurately replicate a target injection profile.

[0005] According to one aspect, there is provided a needle-free injector, the needle-free injector comprising: a housing; a cartridge disposed within the housing; a plunger slidably coupled to the chamber and disposed within the chamber; and a motor operatively coupled to the plunger, operable to actuate the plunger within the chamber. The plunger, when slid within the chamber, can be positioned to expel the fixed volume of injectate through the outlet port. The cartridge can include an outlet port and a chamber for holding the fixed volume of injectate. The needle-free injector can further include a controller operatively coupled to the motor, the controller operable to selectively operate the plunger according to one of a first delivery profile, a second delivery profile, and a third delivery profile, the controller operable to transition from the first delivery profile to the second delivery profile in response to detecting a spike in a measured current supplied to the motor concurrent with compression of gas within the chamber by the plunger, and the controller further operable to transition from the second delivery profile to the third delivery profile in response to detecting a steady-state condition between the measured current and a velocity of the plunger.

[0006] In some embodiments, the average velocity of the plunger during operation of the first delivery profile may be greater than the average velocity of the plunger during operation of the second delivery profile.

[0007] In some embodiments, the compression of the gas in the chamber is detected based on a drive current supplied to the motor. In some embodiments, the compression of the gas in the chamber is detected based on a position of the motor measured using a rotary encoder of the motor. In some embodiments, the compression of the gas in the chamber is detected based on an increase in force required to maintain the speed of the motor during the first delivery profile based on a comparison of a drive current supplied to the motor and a position of the motor measured using a rotary encoder of the motor.

[0008] The injectable may comprise an injectable pharmaceutical formulation or a nutraceutical formulation. For example, the injectable pharmaceutical formulation may comprise a high viscosity biological product.

[0009] In some embodiments, the plunger velocity of the second delivery profile can generate an injectate velocity sufficient to penetrate a permeability barrier, which can be the subject's skin. In certain embodiments, the injectate velocity can be from about 150 m / s to about 250 m / s.

[0010] In some embodiments, the first delivery profile can move the plunger at a speed of about 300 m / s to about 500 m / s. In some embodiments, the second delivery profile can move the plunger at a speed of about 60 m / s to about 150 m / s. In some embodiments, the third delivery profile can move the plunger at a speed of about 80 m / s to about 120 m / s.

[0011] According to another aspect, a needle-free injector is provided. The needle-free injector may include a plunger arranged to pressurize fluid and gas within a cartridge having an exit port. The needle-free injector may include a motor operatively coupled to the plunger. The motor may be operable to actuate the plunger in a linear motion along an axis of the cartridge to expel the fluid from the cartridge. The needle-free injector may further include a controller operatively coupled to the motor. The controller may be operable to operate the plunger according to a first delivery profile to compress the gas within the cartridge in response to an injection start signal, and to operate the plunger according to a second delivery profile in response to detecting compression of the gas within the cartridge above a predetermined threshold.

[0012] In some embodiments, detecting the compression of the gas in the cartridge above the predetermined threshold can include detecting a deviation in motor current between a free-running drive current predicted by a model and the measured current supplied to the motor. In some embodiments, detecting the compression of the gas in the cartridge can include detecting an increase in motor current above a predetermined threshold to maintain the plunger velocity within the first delivery profile. In some embodiments, detecting the compression of the gas in the cartridge can include detecting a decrease in the plunger velocity below a predetermined threshold. In some embodiments, detecting the compression of the gas in the cartridge can include simultaneously detecting a decrease in the plunger velocity and an increase in drive current to the motor.

[0013] In some embodiments, the controller may actuate the plunger in response to feedback from an encoder operatively coupled to the motor.

[0014] In some embodiments, the first delivery profile can have a first target speed that is greater than a second target speed of the second delivery profile. In some embodiments, the second profile is a biphasic profile including a puncturing phase and a delivery phase. In certain embodiments, the plunger speed during the puncturing phase can be decreased as a function of time.

[0015] According to another aspect, a method of delivering an injectate using a needle-free injector is provided. The method may include providing a needle-free injector as described herein. The needle-free injector may include a housing having a cartridge for holding a chamber, a plunger constructed and arranged to expel an injectate from the chamber, and a motor operatively coupled to the plunger. The method may be operable to: in response to initiating an injection using the needle-free injector, operate the plunger according to a first delivery profile; monitor a current supplied to the motor during the first delivery profile; transition from the first delivery profile to the second delivery profile in response to detecting compression of gas in the chamber by the plunger based at least in part on a spike in the current supplied to the motor; operate the plunger according to the second delivery profile; transition from the second delivery profile to the third delivery profile in response to detecting a steady-state condition between the measured current and the velocity of the plunger; and operate the plunger according to the third delivery profile until a predetermined amount of the injectate is delivered from the chamber through the outlet port.

[0016] In some embodiments, transitioning from the first delivery profile to the second delivery profile can include transitioning from the first delivery profile to the second delivery profile upon detecting a spike in measured current supplied to the motor concurrently with compression of the gas. In some embodiments, transitioning from the first delivery profile to the second delivery profile can include reducing the current supplied to the motor to within a range of 0 A to about 10 A.

[0017] In some embodiments, operating the plunger according to the second delivery profile can include operating the plunger at a velocity sufficient to overcome a restoring force on the plunger and deliver the injectate through the permeability barrier. For example, operating the plunger according to the second delivery profile can include operating the plunger while maintaining the compression of the gas within the chamber. In some embodiments, operating the plunger according to the second delivery profile can result in the velocity of the injectate being sufficient to penetrate a permeability barrier, such as the skin of a subject.

[0018] In some embodiments, operating the plunger at the third delivery profile can include adjusting the velocity of the plunger as the injectate is delivered. For example, operating the plunger at the third delivery profile can include adjusting the velocity of the plunger as the injectate is delivered.

[0019] According to another aspect, a method for facilitating needle-free injection of an injectate is provided. The method can include providing a needle-free injector as described herein. The needle-free injector can include a motor operatively coupled to the plunger and a controller. The provided controller can be operable to: operate the plunger through a first delivery profile; monitor a current supplied to the motor during the first delivery profile; transition from the first delivery profile to the second delivery profile in response to detecting compression of gas in the chamber by the plunger based at least in part on a spike in the current supplied to the motor; operate the plunger through the second delivery profile; transition from the second delivery profile to the third delivery profile in response to detecting a steady-state condition between the measured current and the velocity of the plunger; and operate the plunger according to the third delivery profile until a predetermined amount of the injectate is delivered from the chamber through the outlet port.

[0020] In a further embodiment, the method may further include providing instructions to a user for loading the injectate cartridge into the needle-free injector.

[0021] In a further embodiment, the method may further include providing instructions to a user for operating the needle-free injector. [Brief explanation of the drawings]

[0022] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component depicted in the drawings is designated by a like number. For clarity, not every component is numbered in every drawing. The drawings are as follows: [Figure 1] FIG. 1 is a schematic diagram of a controllable needle-free transdermal injection device. [Figure 2] FIG. 2 is a cutaway view of the ball screw actuator. [Figure 3]FIG. 3 is a block diagram of the controllable needle-free transdermal injection device of FIG. [Figure 4] FIG. 4 is a detailed block diagram of the controllable needle-free transdermal injection device of FIG. [Figure 5] FIG. 5 is a detailed block diagram of the power supply of the controllable needle-free transdermal injection device of FIG. [Figure 6] Figure 6 shows the target displacement profile. [Figure 7] Figure 7 is the rotational motor speed profile associated with the target displacement profile in Figure 6. [Figure 8] FIG. 8 is the injectate jet velocity profile associated with the target displacement profile of FIG. [Figure 9] FIG. 9 is a flow chart of a method for operating a syringe. [Figure 10] Figure 10 compares the two control techniques. [Figure 11] Figure 11 is a model of the unloaded operation of a syringe powered by a rotary motor. [Figure 12] FIG. 12 is a time-continuous equation that estimates the behavior of the system of FIG. [Figure 13] FIG. 13 illustrates an embodiment of a cartridge and plunger before the start of an injection, according to one embodiment. [Figure 14] FIG. 14 shows the current supplied to the motor, plunger speed, and injectate speed as a function of time for injections with three delivery profiles, according to one embodiment. [Figure 15] 15A-15C show the plunger speed (FIG. 15A), current supplied to the motor (FIG. 15B), and applied power (FIG. 15C) for an injection with three delivery profiles, according to one embodiment. [Figure 16] 16A-16B show the relationship between injectate velocity and current supplied to the motor (FIG. 16A) and the relationship between injectate velocity and plunger velocity (FIG. 16B) for a third delivery profile, according to one embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0023] In the following document, references to singular items are to be understood as including the plural items and vice versa, unless otherwise stated or evident from the context. Grammatical conjunctions are intended to express all disjunctive and conjunctive combinations of joined clauses, sentences, words, and the like, unless otherwise stated or evident from the context. Thus, the term "or" should generally be understood to mean "and / or," etc.

[0024] The recitation of ranges of values herein is not intended to be limiting; rather, unless otherwise specified, each value within the range refers individually to every value within the range, and each individual value within the range is incorporated herein as if it were individually set forth herein. When words such as "about," "approximately," and the like are associated with numerical values or physical properties, they are to be construed as indicating a deviation that would be understood by one of ordinary skill in the art to operate to fulfill the intended purpose. Similarly, approximation words such as "approximately" and "substantially," when used in connection with physical properties, should be understood to contemplate a range of deviation that would be understood by one of ordinary skill in the art to operate to fulfill the corresponding use, function, purpose, and the like. Ranges of values and / or numerical values are provided herein as examples only and do not constitute limitations on the scope of the described embodiments unless expressly stated otherwise. The use of any and all examples or exemplary language ("for example," "such as," or the like) provided herein is intended merely to further clarify the embodiments and does not constitute a limitation on the scope of the embodiments. No language herein should be construed as indicating any non-claimed element as essential to the practice of the embodiment.

[0025] In the following description, it should be understood that terms such as "first," "second," "upper," "lower," "above," and "below" are used for convenience only and are not to be construed as limiting terms.

[0026] Needle-free transdermal injection device 1 , a controllable needle-free transdermal injection device 100 for delivering an injectate (e.g., a medication or vaccine in any one of several states, such as a liquid or powder state) through a patient's skin includes a needle-free transdermal injector head 104 extending from a housing 102. The injector head 104 includes a chamber 106 for holding the injectate and a nozzle 108 disposed at a distal end 110 of the injector head 104. The nozzle 108 includes a head 112 and an opening 114 through which a jet of injectate is emitted from the chamber 106. In operation, the opening 114 is positioned near or against the skin 115 when the injectate is to be expelled.

[0027] The dimensions of the nozzle 108 can be adapted to control the shape and pressure profile of the injectate flow exiting the nozzle 108. For example, the inner diameter of the opening 114 can range from 50 μm to 300 μm, and a taper along the longitudinal axis 122 toward the opening can be used to shape the exiting flow of the injectate. It will also be appreciated that the geometry of the chamber 106 relative to the opening 114 can affect how linear motion of a plunger or the like within the chamber 106 translates to an exit velocity or pressure of the injectate through the opening 114. The outer diameter of the head 112 of the nozzle 108 can narrow to the opening 114, remain uniform, or expand to provide a suitable resting surface for the head 112 of the nozzle 108. The nozzle 108 can have a length along the longitudinal axis 122 of about 500 μm to about 5 mm. Similarly, the chamber 106 can have any suitable length along the longitudinal axis for containing the injectate and displacing it through the opening 114 with one or more needleless injections.

[0028] The chamber 106 can have a proximal end 116 and a distal end 110. An actuator (i.e., piston or plunger 120) can be slidably disposed within the chamber 106. Movement of the plunger 120 in either direction along a longitudinal axis 122 can affect the pressure within the chamber 106. In some embodiments, the chamber 106 is integral with the device 100. In other embodiments, the chamber 106 can be separately attached to the device 100.

[0029] In some examples, the injection device 100 includes a sensor 107 (e.g., a mechanical or capacitance sensor) for detecting contact of the device with the patient's skin. In some examples, the sensor 107 is configured to detect the angle of the cartridge relative to the patient's skin. In some examples, the sensor 107 is configured to detect the position of the injection opening relative to the patient's skin 115 or body. In some examples, the sensor 107 communicates with the injection controller 100 to prevent an injection from occurring when the device is not in contact with the patient's skin 115 or when the angle or position of the device relative to the patient is incorrect.

[0030] Rotary motor The injection device 100 can include an electromagnetic rotary motor 126 that applies a force to the plunger 120 via a linkage 130 to inject the injectate in the chamber 106 through the skin 115. The linkage can include a ball screw actuator 130, or the linkage can additionally or alternatively include any other suitable mechanical coupling for converting the rotational force of the rotary motor 126 into a linear force suitable for displacing the injectate from the chamber 106. For example, the linkage can include one or more of a lead screw, a linear motion bearing, and a worm gear drive, or other suitable mechanical component or combination of mechanical components. As noted above, linear motion can be usefully inferred from the rotation of a lead screw, or the like, and the injection device 100 can be instrumented to monitor rotation to provide feedback to a controller regarding the position of the plunger 120 during injection.

[0031] Referring to FIG. 2, an example of a ball screw actuator 130 includes a screw 332 and a nut 334 (which are coupled to the housing 102 of FIG. 1), each having a matching helical groove 336. The ball screw actuator 130 may include a recirculating ball screw having a plurality of miniature balls 338 or similar bearings that recirculate through the groove 336 and provide rolling contact between the nut 334 and the screw 332. The nut 334 may include a return system 333 and a deflector (not shown) that deflects the miniature balls 338 into the return system as the screw 332 or nut 334 rotates. The balls 338 travel through the return system in a continuous path to the opposite end of the nut 334. The balls 338 then exit the ball return system and enter the groove 336. In this manner, the balls 338 continuously recirculate in a closed circuit as the screw 332 moves relative to the nut 334.

[0032] In some examples, the rotary motor 126 is of a type selected from a variety of rotary electric motors (e.g., brushless DC motors). The rotary motor 126 applies a torque (i.e., τ M ) to move the screw 332 of the ball screw actuator back and forth along the longitudinal axis 122. This torque rotates either the screw 332 or the nut 334, thereby generating an input force F proportional to the torque applied by the motor. M (t) will be added to the screw 332.

[0033] Torque τ applied to screw 332 M causes the application of a force to plunger 120, resulting in movement of plunger 120 along longitudinal axis 122. P is determined by the following equation, which represents the ideal relationship between torque and force in a ball screw actuator: TIFF2025114774000002.tif46107

[0034] where F P is the force applied to the plunger 120 by the screw 332, τ M is the torque applied to the screw 332 , η is the efficiency of the ball screw actuator 130 , and P is the lead of the screw 332 .

[0035] Control Loop Referring again to FIG. 1 , the transdermal injection device 100 can include a displacement sensor 140, an injection controller 135, and a three-phase motor controller 141. Generally, the displacement sensor 140 measures the displacement x(t) of the screw 332 and / or plunger 120 of the ball screw actuator 130. The displacement sensor 140 can measure the incremental displacement of the screw 332, for example, by storing an initial displacement value (i.e., x(0)) and monitoring the deviation from the starting value over time. In other examples, the displacement sensor 140 measures the absolute displacement of the screw 332 relative to the position of the displacement sensor 140 or other fixed reference point. In another embodiment, the displacement sensor 140 can be coupled to the nut of a ball screw or other component that controls linear motion. In this configuration, the displacement sensor 140 can measure the rotation of the screw slot, which can be computationally converted to linear displacement for purposes of controlling the operation of the device 100.

[0036] The displacement x(t) measured by (or calculated using data from) displacement sensor 140 may be provided as an input to injection controller 135. As will be described in more detail below, injection controller 135 processes the displacement x(t) to determine a motor control signal y(t). The motor control signal y(t) is provided to a three-phase motor controller 141, which, in conjunction with a power supply 143, drives a rotary motor 126 in accordance with the motor control signal y(t). Motor 126 generates a torque τ M (t) is applied to the screw 332. M(t) causes movement of screw 332 (or any other suitable linear actuator) in a direction along longitudinal axis 122 .

[0037] System diagram Referring to FIG. 3, the schematic diagram of the system of FIG. 1 includes, in step 344, a rotational motor torque τ M is applied to the ball screw 130. The application of a rotation motor torque by the rotation motor at any time t1 applies a force F to the thread 332 of the ball screw 130, as shown in step 345. M (t1) is applied, which displaces the screw 332 in step 348.

[0038] The displacement of the thread 332 of the ball screw 130 is measured by the displacement sensor 140 and fed back to the injection controller 135. As will be described in more detail below, the injection controller 135 processes the measured displacement to provide sensor feedback 348 to determine a motor control signal y(t1) that is supplied to the three-phase motor controller 141. The three-phase motor controller 141 drives the rotation motor 126 in accordance with the motor control signal y(t1), causing the motor 126 to generate a torque τ M (t2) is applied to the screw 332 of the ball screw 130. As described above, the torque τ M The plunger 120 is subjected to a force F P is added, and F P is calculated as follows: TIFF2025114774000003.tif46107

[0039] where F P is the force applied to the plunger 120 by the screw 332, τ M is the torque applied to the screw 332 , η is the efficiency of the ball screw actuator 130 , and P is the lead of the screw 332 .

[0040] 4, in some examples, the injection controller 135 includes a target displacement profile 450, a summing block 452, and a motor control signal generator 454. Very generally, the injection controller 135 receives a displacement value x(t) at time t from the displacement sensor 140. The time t is provided to the target displacement profile 450, which calculates the target displacement value x(t) at time t. T Find (t).

[0041] In some examples, the target displacement profile 450 includes a mapping between a target displacement value and multiple times associated with an injection cycle (i.e., a range of times over which the plunger 120 of the device travels). For example, in the target displacement profile 450 shown in FIG. 4, the displacement starts at zero at the beginning of the injection cycle (i.e., at time t0) and changes (e.g., increases) over time as the injection cycle progresses, with each moment in time of the injection cycle being associated with a corresponding displacement value. As described in more detail below, in some examples, the rate of change of the displacement value varies over time, with different time intervals of the injection cycle being associated with different rates of change of the displacement value. For example, controlling the plunger displacement with the target displacement profile 450 can be used to perform complex injections. For example, in one embodiment, the plunger 120 displaces relatively quickly during an initial puncture phase to penetrate the skin barrier, and during other time intervals, the plunger 120 displaces relatively slowly to deliver the injectate through the opening formed during the initial puncture phase. In another embodiment, the target displacement profile 450 can control multiple consecutive injections, each having a biphasic profile with a puncture phase and a drug delivery phase. In practice, the actual displacement profile of plunger 120 may differ from the ideal target displacement profile due to physical limitations and other constraints of the system.

[0042] The measured quantile x(t) and the target quantile x T (t) are both fed to summing block 452. Summing block 452 calculates the target displacement value x T (t) to obtain the error signal xE (t) to obtain the error signal x E The error signal y(t) is provided to a motor control signal generator 454, which converts the error signal into a motor control signal y(t). The motor control signal y(t) is provided to a three-phase motor controller 141 or other suitable drive system, which then drives the motor 126 in accordance with the motor control signal y(t).

[0043] In some examples, the rotary motor 126 may be a three-phase motor having three windings 447 and three Hall sensors 449, with each Hall sensor 449 corresponding to a different one of the three windings 447. Each of the windings 447 is wound around a laminated soft iron core (not shown) so as to form a magnetic pole when a current is applied thereto. Each of the three Hall sensors 449 generates a corresponding output signal 456 in response to the presence (or absence) of a magnetic field in its corresponding winding 447.

[0044] The three-phase motor controller 141 includes a switch control module 445 and a switching module 448. The switching module 448 includes three pairs of switches 451 (having a total of six switches 451), each pair of switches corresponding to a different one of the windings 447 of the rotary motor 126 and configurable to electrically connect the corresponding winding 447 to the power source 143 (thereby energizing the winding) or to ground. The switch control module 445 receives as inputs a motor control signal y(t) from the injection controller 135 and three Hall sensor output signals 456, and processes these inputs to generate six switch control signals 455, each configured to open or close a corresponding switch 451 in the switching module 448.

[0045] The above configuration implements a feedback control approach whereby the combination of the control torque applied by the motor 126 to the screw 332 of the ball screw 130 ensures that the displacement of the plunger tracks the target displacement profile 450 as the screw 332 is displaced.

[0046] power supply 5, in some examples, the power source includes a battery 560 (e.g., a nickel-cadmium battery, a nickel-metal hydride battery, a lithium-ion battery, an alkaline battery, or any other suitable type of battery) configured to provide a voltage V1 to a DC / DC converter 562 (e.g., a boost converter). The DC / DC converter 562 receives a supply voltage V1 from the battery 560 as an input and generates an output voltage V2 that is greater than V1. In some examples, the DC / DC converter 562 is configured to boost the supply voltage by a factor ranging from 5 to 20. While the battery 560 may be rechargeable, the battery 560 may also usefully store enough energy to provide multiple injections, such as two or more 1-milliliter injections, from, for example, multiple replaceable single-dose cartridges or a single multi-dose cartridge.

[0047] The output voltage V2 may be provided in parallel to the supercapacitor 564 and to the switching module 448 of the three-phase motor controller 141 via a diode 566. In operation, the output voltage V2 charges the supercapacitor 564 when the transdermal injection device 100 is in an inactive state. When an injection operation is initiated, the switch 451 of the switching module 448 closes (in accordance with the switch control signal 455) and connects the winding 447 of the rotary motor 126 to the supercapacitor 564. This results in the discharge of the supercapacitor 564, causing current to flow through the winding 447 of the rotary motor 126 and causing the rotary motor 126 to rotate.

[0048] In some examples, the supercapacitor 564 includes multiple supercapacitors coupled together with a switching network. When the transdermal injection device 100 is in an inactive state, the switching network may be configured to connect the multiple supercapacitors in parallel for charging. When an injection is initiated, the switching network may be reconfigured to connect the multiple supercapacitors in series for discharging. In some examples, the supercapacitor 564 is configured to provide 200 watts or more of peak power to the ball screw 130 via the rotary motor 126.

[0049] In general, the supercapacitor may be any high-capacity capacitor suitable for accepting and delivering an electrical charge more quickly than a battery or other electrical energy source. A wide variety of supercapacitor designs are known in the art and may be adapted for use as the supercapacitor 564 contemplated herein, such as double-layer capacitors, pseudocapacitors, and hybrid capacitors. Similarly, the supercapacitor 564 may usefully include any number and arrangement of supercapacitors suitable for providing power in an amount and rate suitable to drive the rotary motor 126 of the injection device 100, as contemplated herein.

[0050] Target Displacement Profile 6 , an example of a target displacement profile includes multiple injection phases, each associated with a corresponding time interval. A first injection phase 670 is associated with a first time interval from time t0 to time t1. During the first injection phase 670, the target displacement of the plunger 120 is a fixed initial position P0 at which the plunger 120 engages the injectate in the chamber 106. During this phase, the injection device 100 is generally ready to perform an injection operation. Generally, prior to the first injection phase 670, any number of preparatory steps or phases may be performed, such as loading the injection device with the injectate (or a cartridge containing the injectate), removing air bubbles from the injectate if necessary or appropriate, measuring environmental conditions, measuring parameters at the injection site, and any other step or combination of steps useful for performing or preparing to perform a needleless injection as contemplated herein.

[0051] In one embodiment, rotary motor 126 can be mechanically engaged with ball screw actuator 130 (or any other suitable linear actuator) while rotary motor 126 is stationary in first injection phase 670. That is, rotary motor 126 is pre-engaged with ball screw actuator 130 and can be preloaded to remove any mechanical slack in the mechanical parts of the system. In this configuration, a mechanical switch or the like can be used to prevent relative movement of the components, and / or a gate or seal can be used at the nozzle outlet to prevent leakage of drug from chamber 106. In another embodiment, rotary motor 126 can be slightly spaced from engagement with ball screw actuator 130. In this latter configuration, rotary motor 126 can be usefully accelerated (unloaded) to engage ball screw actuator 130 at the end of first injection phase 670 or the beginning of second injection phase 672 to facilitate a greater initial velocity of the injectate from the nozzle. This may include, for example, one full revolution of the rotary motor 126 from engagement with the ball screw actuator 130, or a fraction of a full revolution suitable to facilitate very high initial rotational acceleration.

[0052] The second injection phase 672 is associated with a second time interval spanning from time t1 to t2. During the second injection phase 672, movement of the plunger 120 can begin. During this phase, the target displacement of the plunger 120 increases at a relatively high first rate to move the plunger 120 from an initial position P0 to a first position P1. Generally, movement of the plunger 120 during this phase can eject a jet of injectate from the chamber 106 of the injector head 104 (through the opening 114) at a first velocity V1 sufficient to penetrate human tissue to at least a certain depth subcutaneously. In some examples, the second injection phase 672 spans a time interval of less than 100 ms (i.e., the difference between t1 and t2 is less than 100 ms). In some examples, the second injection phase 672 spans a time interval of less than 60 ms (i.e., the difference between t1 and t2 is less than 60 ms). In some examples, the second injection phase 672 spans a time interval of less than 10 ms (ie, the difference between t1 and t2 is less than 10 ms).

[0053] More generally, during this second injection phase 672, the injection device 100 may be configured so that the initial flow of injectate is substantially instantaneous, e.g., the plunger 670 transitions from a rest position to a target velocity at a velocity sufficient to achieve the puncture velocity without substantial leakage or loss of injectate at the surface. By configuring the linear drive system described above to accelerate from a fixed position to the puncture velocity in this manner, the injection device 100 may advantageously mitigate loss of injectate. As a further advantage, an injection device having this capability can usefully perform multiple successive injections without requiring any physical repowering or resetting of the mechanical stored energy system.

[0054] A third injection phase 674 is associated with a third time interval spanning from time t2 to time t3. During the third injection phase 674, the target plunger displacement increases at substantially the same rate as the first rate to move the plunger 120 from the first position P1 to the second position P2. During this third injection phase 674, the plunger 120 can be moved at a velocity that causes a jet of injectate to exit the chamber 106 of the syringe head 104 at a second velocity V2 that is equal to or greater than the first velocity V1. While the velocity of the plunger 120 movement and the velocity of the injectate stream can vary during this third injection phase 674, subject to limitations related to, for example, control precision, physical system components, etc., the plunger 120 should generally be driven at a minimum velocity suitable for penetrating tissue at the target site to deliver the injectate to the desired depth. The injectate jet can also have a maximum velocity selected to avoid over-penetration or other undesirable tissue damage.

[0055] A fourth injection phase 676 is associated with a fourth time interval spanning from time t3 to time t4. During the fourth injection phase 676, the target displacement of the plunger 120 increases at a third rate that is relatively slower than the first rate to move the plunger 120 from the third position P3 to the fourth position P4. During this fourth injection phase 676, the injection device 100 may generally decelerate the plunger 120 to eject a jet of injectate from the chamber 106 of the injector head 104 at a third velocity V3 that is slower than the first velocity V1, which may generally be any velocity suitable for non-piercing delivery of additional injectate at the current depth of the injectate flow within the target tissue.

[0056] The fifth injection phase 678 is associated with a fifth time interval, from time t4 to t5. During the fifth injection phase 678, the target displacement of the plunger 120 continues to increase at a third rate to move the plunger 120 from the fourth position P4 to the fifth position p5. During the fifth injection phase 678, the injection device 100 may generally deliver the injectate (typically the majority of the injectate in the chamber 106) to the subcutaneous depth achieved during the previous puncture phase. The rate of movement may generally be constant or may vary to maintain subcutaneous drug delivery without further puncturing the tissue.

[0057] It will be appreciated that the puncture may continue to some extent during the fifth injection phase 678. This additional puncture should not affect the efficacy of the transdermal drug delivery, provided that it does not create a pathway below the subcutaneous depth within the target tissue that could result in loss or misdelivery of the therapeutic dose. It will also be appreciated that the total displacement of the plunger 120 controls the amount of drug delivered over the course of the injection, and the duration of the fifth injection phase 678 may correspondingly be selected according to the intended dose.

[0058] Finally, the sixth injection phase occurs after time t5. During the sixth injection phase, the target displacement of the plunger 120 stops increasing, causing the plunger 120 to essentially stop at a sixth position p6. The sixth injection phase is associated with the completion of the injection operation. As noted above, from this position, additional injection cycles can be initiated, provided, of course, that sufficient additional medication remains within the injection device 100 to complete the additional injection.

[0059] To quickly reach the penetration velocity and avoid loss of medication at the surface of the injection site, the second injection phase 672 (in which the injectate is accelerated) may be shorter than the penetration phase maintained after the penetration velocity is achieved. Thus, in some examples, the time interval associated with the third injection phase 674 ranges from 2 to 20 times the time interval associated with the second injection phase 672. In some examples, the time interval associated with the second injection phase 672 has a duration between 30 and 100 milliseconds, and the time interval associated with the third injection phase 674 has a duration between 100 and 1000 milliseconds.

[0060] More generally, the duration of each phase may depend on the diameter of the injectate stream, the nature of the injectate, the tissue characteristics at the injection site, etc. Thus, an injection profile may usefully be employed for any duration suitable for accelerating to a penetration rate sufficiently rapidly to avoid substantial loss of injectate, maintaining the penetration rate until a target depth (e.g., subcutaneous depth) is achieved, and then maintaining a non-penetration rate to deliver the full dose at the target depth.

[0061] Also, although a single injection cycle is illustrated, it will be understood that the injection device 100 contemplated herein may be usefully configured to perform multiple successive injections. As such, any number of injection cycles may be usefully performed, and any such multiple injection applications are expressly contemplated by this description.

[0062] Rotational Motor Speed Referring to FIG. 7 , during the first injection phase 670, the injection controller 135 controls the rotary motor 126 to maintain its speed at substantially 0 revolutions per minute (RPM) to ensure that the plunger 120 remains stationary at the initial position P0. This can include actively maintaining the rotary motor 126 in a fixed position, for example, by monitoring its position and activating the rotary motor 126 in response to detected movement or drift, or by controlling a magnetic, mechanical, or electromechanical lock that securely engages the plunger 120 at the initial position P0. In another embodiment, this can include passively maintaining the rotary motor 126 in a fixed position by not providing a control or drive signal from the rotary motor 126. It will also be appreciated that combinations of the above can be advantageously employed. For example, the plunger 120 can be secured with a mechanical lock during storage or other periods of non-use, and the rotary motor 126 can then be used to electromechanically and actively secure the position of the plunger 120 when the mechanical lock is released in preparation for injection. In this way, power can be conserved during long-term storage, while the position can be reliably and controllably fixed using the rotary motor 126 in the period immediately prior to injection, for example, to prevent leakage of the injectate.

[0063] In the second injection phase 672, the injection controller 135 controls the rotation motor to move the plunger 120 from the initial position P0 to the first position P1 at a first rotation motor speed S1 (e.g., 33,000 RPM) from 0 RPM. In the third injection phase 674, the injection controller 135 controls the rotation motor 126 to maintain a speed equal to or greater than the first rotation motor speed S1 to move the plunger 120 from the first position P1 to the second position P2. In the fourth injection phase 676, the injection controller 135 controls the rotation motor 126 to decelerate to a second rotation motor speed S2 (e.g., 11,000 RPM) that is less than the first rotation motor speed S1 to move the plunger 120 from the second position P2 to the third position P3. In the fifth injection phase 678, the injection controller 135 can control the rotational motor 126 to maintain the second rotational motor speed S2, moving the plunger 120 from the third position P3 to the fourth position P4 at a substantially consistent speed to deliver the injectate at the target depth for the injection.

[0064] During the sixth injection phase, the injection controller 135 may control the rotary motor 126 to decelerate its speed from the second rotary motor speed S2 to 0 RPM, substantially stopping the movement of the plunger 120 at the fourth position P4. While the supercapacitor 564 within the power supply 143 described above may be used during any portion of the injectate delivery, the supercapacitor 564 may be particularly advantageous during phases where high mechanical loads are expected, such as during the initial acceleration and puncture phases, and where it is necessary or useful to quickly decelerate or stop the plunger 120, such as at the fourth position P4. Thus, the supercapacitor 564 may be particularly used during the second injection phase 672 and the third injection phase 674, and, optionally, during the fourth injection phase 676 when high power is needed to maintain the target speed while decelerating the injectate to the drug delivery rate and / or when high power is needed to quickly decelerate or stop the plunger 120.

[0065] Injectate speed Referring to FIG. 8 , in a first injection phase 670, no injectate is ejected from the chamber 106 (i.e., the initial injectate velocity V is 0 m / s). In a second injection phase 672, the injectate velocity increases from 0 m / s to a first velocity V that is at least sufficient to pierce human tissue. In some examples, the first velocity V is at least 200 m / s. If piercing is not initiated quickly, significant loss or leakage of the agent may occur. Thus, in some embodiments, the rotary motor 126 can be usefully configured to reach the first velocity V for injection from a stationary starting point in three or fewer rotations, e.g., less than two or less than one rotation.

[0066] During the third injection phase 674, the injectate velocity can be maintained at a second velocity V2 equal to or greater than the first velocity V1 to continue penetrating tissue at the target site. If the first velocity V1 is a minimum velocity for penetrating tissue, the second velocity V2 is preferably maintained at a velocity greater than the first velocity V1 to continue penetrating tissue throughout the third injection phase 674. However, the first velocity V1 may instead be a minimum or optimal velocity for initiating penetration, in which case the second velocity V2 may advantageously be any velocity greater than, equal to, or less than the first velocity V1 suitable for continuing to penetrate tissue to the desired target depth. Similarly, the second velocity V2 may vary over the duration of the third injection phase 674, provided that the second velocity V2 remains within a range of useful penetration velocities.

[0067] During the fourth injection phase 676, the injectant rate is increased to a third rate V3 (maximum third rate V) sufficient to deliver the majority of the injectant in the chamber 106 to a consistent subcutaneous depth. 3Max and the minimum third velocity V 3MinDuring the fifth injection phase 678, the injectate velocity may be substantially maintained at the third velocity V3 while the majority of the injectate in chamber 106 is delivered to the subcutaneous depth through the channel formed during the third injection phase 674. It should be understood that during the course of the fifth injection phase 678, the third velocity V3 may be varied between any values (typically greater than zero and less than the puncture velocity) that can result in delivery of the injectate at the target depth. Finally, during the sixth injection phase 680, the injectate velocity may be reduced to 0 m / s as the injection operation is completed.

[0068] injectable In some examples, the volume of the injectate in the chamber is at least 1 milliliter. Thus, in one embodiment, the injection device 100 can be configured to deliver 1 milliliter of medication subcutaneously in a single dose or as multiple sequential doses over a period of time, e.g., to different locations or over an extended administration schedule. The chamber can advantageously have a larger volume if multiple sequential administrations or larger single doses (e.g., greater than 1 milliliter) are intended. For multi-dose applications, the contents of the chamber 106 can be conveniently dispensed and used separately using a rotary motor and linear drive system as contemplated herein. In some examples, the volume of the injectate in the chamber is about 0.5 milliliters or less. In some examples, the volume of the injectate in the chamber is about 0.3 milliliters or less. In some examples, the injectate in the chamber is a therapeutic amount of injectate.

[0069] In some instances, the injectate includes a biological agent. In some instances, the injectate has a viscosity of at least 3 centipoise at a temperature between 2 and 20 degrees Celsius. In some instances, the injectate has a viscosity of about 3 to about 200 centipoise at a temperature between 2 and 20 degrees Celsius. Thus, the systems described herein can be usefully used with large molecule therapeutic agents or other agents that have relatively high viscosities.

[0070] others In one aspect, the injection controller can be configured to cause the needle-free transdermal injection device 100 to perform multiple successive injection operations close in time to one another. The injection device 100 can be usefully instrumented to support this operation by sensing the movement of the injection device 100 and providing tactile, visual, audible, or other feedback to assist the user in carefully performing the multiple injection sequence.

[0071] In another embodiment, multiple successive injection actions can be performed without reversing the rotary motor's motion (i.e., without retracting the plunger). Thus, at the end of an injection cycle, if enough additional injectate remains in the injection device 100 for an additional dose, the rotary motor 126 may remain stationary and a second complete injection cycle may begin from this new starting position. In this context, the rotary motor 126 may be manually locked or electromagnetically maintained in a fixed position to prevent leakage or other loss of therapeutic product.

[0072] In some examples, a linkage (e.g., a ball screw linkage) is bidirectionally coupled to the rotary motor and plunger to allow bidirectional displacement of the contents within the chamber, for example, by moving the plunger toward the outlet nozzle to eject the contents, or by moving the plunger away from the outlet nozzle to load additional medication into the injection device 100.

[0073] In some examples, the transdermal injection device includes a sensor system for detecting when the device is properly positioned to perform an injection. In some examples, once the device is properly positioned, the injection controller is configured to initiate the injection without any observable latency. That is, the sensor system can monitor the injection device 100 and determine when the injection device 100 is properly positioned and stationary, and then begin the injection. Depending on the duration and feel of the injection, the injection may usefully be preceded by a beep, vibration, or other human-perceptible signal that alerts the user that an injection is about to occur.

[0074] In some examples, one or more conventional capacitors (eg, electrolytic capacitors) can be used instead of or in addition to the supercapacitors.

[0075] In some examples, the injection controller is configured to not perform more than one injection action within a predetermined minimum injection cycle time. Thus, for example, if a dosage regimen specifies a minimum time between injections, or if injections are performed as a series of injections into adjacent but non-identical locations, the injection controller can monitor activation of the injection device 100 to ensure that all rules of the corresponding injection protocol are adhered to.

[0076] In some examples, the needle-free transdermal injector head is formed as a removable cartridge for containing the injectate. The removable cartridge has an opening with a predetermined shape for ejecting the injectate in a stream with a predetermined shape. In some examples, the needle-free transdermal injector includes a movable cartridge door mechanism. A user can interact with the movable cartridge door mechanism to load and remove the cartridge from the needle-free transdermal injector.

[0077] While the above description primarily relates to methods and devices for injecting a therapeutic agent through human tissue to a subcutaneous depth, it should be noted that in some instances, the above methods and devices may be used to inject a therapeutic agent through human tissue to other shallower or deeper depths. For example, the methods and devices may be used to inject a therapeutic agent shallowly into the dermis, or more deeply through the fat and connective tissue of the subcutaneous layer and into the patient's muscle tissue.

[0078] In one embodiment, a syringe as contemplated herein can be improved by monitoring the compression of air bubbles within the injectate cartridge during plunger movement in the pre-injection phase. When a cartridge of a liquid injectate, such as a therapeutic drug, contains air bubbles, either as a regulatory requirement or a manufacturing artifact, the introduction of a compressible region in the otherwise generally incompressible injectate volume can make accurate injection control more difficult. Separating the phase of injection during which the air bubbles are highly compressible (e.g., during compression) from the phase of injection during which the air bubbles are relatively incompressible can improve the control system. Generally, once the air bubbles are sufficiently compressed (e.g., at or near the equilibrium pressure during the penetration phase), the needleless syringe plunger speed is altered to a penetration speed for delivery of the injectate to the target. Detecting air bubble compression prior to injectate delivery in this manner can control the injectate flow to more accurately reproduce the target injection profile. For example, integrator errors in the syringe control model can be reduced, flow optimization / maximization can be achieved, and overshoot of the syringe response (e.g., flow rate or plunger movement) can be minimized.

[0079] In one embodiment, an open or free-running model is created that models the behavior of the syringe hardware when there is no injectate load. This model provides estimates of free-running characteristics, such as plunger speed and plunger position, of the system operating to move the plunger linearly without ejecting any injectable fluid. This free-running state is generally linear in nature, facilitating an analytical solution that can be deployed on a computational platform such as a microcontroller for a medical device.

[0080] A free-running system model can be expressed as a second-order linear ordinary differential equation (referred to as "ODE").

[0081]

number

[0082] where: C1 is the inertia of the entire system as seen from the actuator. It is represented as TIFF2025114774000005.tif5140, C2 is the damping of the entire system as seen by the actuator. It is represented as TIFF2025114774000006.tif3942, θ'(t) is TIFF2025114774000007.tif3942 is the rotation speed, θ''(t) is TIFF2025114774000008.tif3942 is the rotational acceleration, τ is TIFF2025114774000009.tif3942 is the torque applied by the motor.

[0083] The general solution to a second-order inhomogeneous linear equation is:

[0084]

number

[0085] where θ c is a cosolution, θ p is a particular solution. To solve the ODE for cosolutions, set Eq. 1 equal to 0 and assume a general solution of the form TIFF2025114774000011.tif2478TIFF2025114774000012.tif2489TIFF2025114774000013.tif22124

[0086] The characteristic polynomial is:

[0087]

number

[0088] Solving for the characteristic root gives: TIFF2025114774000016.tif3499

[0089] This solution has two distinct real roots, giving the following two solutions: TIFF2025114774000017.tif20144

[0090] The co-solution is of the form:

[0091]

number

[0092] A particular solution requires any function that satisfies an inhomogeneous equation. For equation 1, the form is determined using the method of undetermined coefficients, where: TIFF2025114774000019.tif2382TIFF2025114774000020.tif2582TIFF2025114774000021.tif2582.

[0093] Substituting this into equation 1 gives: TIFF2025114774000022.tif21146

[0094] Solve for the coefficient A. TIFF2025114774000023.tif3982

[0095] Then we get the following particular solution:

[0096]

number

[0097] The general solution is θ c (expressed in Equation 4) and θ p (expressed in Equation 5) into Equation 2.

[0098]

number

[0099] The solution for the constants k1 and k2 can be found by assuming the following initial conditions: TIFF2025114774000026.tif14166

[0100] This results in the following set of equations from Equation 6: TIFF2025114774000027.tif58147

[0101] Solve for k1 and k2. TIFF2025114774000028.tif61133

[0102] Finally, the solution can be obtained by substituting k1 and k2 into Equation 6.

[0103]

number

[0104] This solution can be used to estimate the free-running plunger position of the injection device given the initial position θ0, initial rotational speed θ'0, motor torque τ, and time step t. Taking the time derivative of the position in Equation 7 gives the velocity equation:

[0105]

number

[0106] The system inertia C1 is derived from the physical system. For the model to accurately simulate the physical system, inertial loads must be taken into account. Inertia is imparted by all moving parts of the actuator assembly, including:

[0107] Motor (I m ): Inertia of the internal moving parts of the Maxon ECX 16. This value is listed in the motor datasheet. For the ECX16, the datasheet states that the rotor inertia is 1.2 g cm 2 or 1.2e - 7 kg cm 2 It is clearly stated that:

[0108] Gear 1 (I G1 ): This is the first gear attached to the motor output shaft. Inertia can be calculated in Solidworks or another suitable modeling environment given the gear dimensions and material. I calculated this in Solidworks and found it to be 8.9e - 10 kg cm 2 was obtained.

[0109] Gear 2 (I G2 ): This is the second gear attached to the motor output shaft. The gear's dimensions and material were used to calculate its inertia in Solidworks. Since its rotational speed is different from the rotational speed of the motor shaft, we need to calculate the inertia reflected through the drive chain. The inertia is 5.862e - 7 kg cm before being transferred through the drive train. 2 It was calculated to be. TIFF2025114774000031.tif17170

[0110] Lead screw (I LS ): For the lead screw, we need to determine how the inertia of the linearly moving mass affects the rotational inertia of the motor. TIFF2025114774000032.tif15170

[0111] This inertia also acts on the gear train, so it is transformed in the same way as gear 2. TIFF2025114774000033.tif16170

[0112] The total rotational inertia load on the motor is obtained by adding up each of the above parts. TIFF2025114774000034.tif9170

[0113] The damping constant C2 of the system was inferred by obtaining data from the physical device during injection and selecting the value of C2 that minimized the model error. For one physical example of a needleless injector driven by a rotary motor, typically described above, the calculated value was 15.0 e-7 (N m s) / rad.

[0114] The above-described approach produced a model whose plunger velocity estimate converged to within 50 mm / s of the actual velocity and within 25 mm / s of the actual (measured) velocity during steady-state free-running when the syringe was in the bubble compression phase. It is understood that the actual error may vary from device to device and may depend on other conditions, such as injection rate, fluid viscosity, and temperature. It is understood that other techniques for estimating free-running or unloaded plunger velocity may additionally or alternatively be employed, and any technique that provides an estimate suitable for use in a control system such as that contemplated herein may additionally or alternatively be used to provide a velocity estimate without departing from the scope of this disclosure. It is also noted that certain other physical characteristics, such as deformation of the plastic cartridge containing the injectate, may be considered. While satisfactory models were developed without considering this and other physical characteristics of the system, these aspects can also be modeled using, for example, lookup tables, calibration, additive modeling, or some combination thereof. It has been observed that without considering these other physical aspects, the physical response lags behind the model response, especially during periods of large change (e.g., high acceleration). This may result in larger than expected measurement errors under certain conditions, especially during times when bubble compression is expected. To account for this, a larger threshold may be used to evaluate the error between estimated and actual velocity to mitigate false positives of bubble compression, either at all times or when the estimated velocity varies significantly.

[0115] Typically, during an injection, this model (an estimate of the free-running plunger velocity in response to control inputs such as the motor controller output) can be run simultaneously with the collection of real-time measurements from the syringe. During the bubble compression phase, this model should generally match the measured behavior. However, as the bubble approaches full compression, the plunger loading behavior that pushes the injectate out of the cartridge will deviate significantly from the free-running model. This error can be used to detect when the bubble is substantially fully compressed, at which point the controller can change from the bubble compression speed to a fluid injection speed intended to push the injectate out of the syringe according to the injection profile.

[0116] It should be understood that "full compression" or "substantially full compression" in this context can refer to a variety of physical states. Generally, the compressibility of a gas, such as air (or other inert, sterile, or other gas contained in the cartridge with the injectate) changes with compression or pressurization. Thus, the state of "full compression" as used herein need not refer to a specific degree of physical compression, but instead can generally refer to a state in which the remaining injectate can be controlled, for example, as an incompressible or substantially incompressible fluid with no compressible gas present, to achieve a desired injection rate profile. As a practical matter, this state of full compression can refer to compression of the gas substantially equal to the amount of compression during steady-state injection operation, or it can refer to compression where the compressibility has fallen below a predetermined threshold, or compression of the gas where a meaningful error signal can be detected between the physical operation and a free-running model, or any other quantitative, physical, or other compression state useful for controlling the operation of a syringe as contemplated herein.

[0117] FIG. 9 is a flowchart of a method for operating a syringe. More specifically, method 900 can be used to operate a needleless syringe to eject a stream of injectate from a chamber containing the injectate and an air bubble. In general, the model described above can be used to estimate the plunger's response to a control signal, e.g., the speed at which the plunger should move for a particular control or input signal. During operation, the actual speed can also be measured and compared to the speed estimated from the model. When the actual speed deviates from the estimated speed by a predetermined threshold, e.g., when the error exceeds a certain minimum amount, the syringe controller can change from a bubble compression speed selected to compress the air bubble in the cartridge to an injection speed selected to eject the fluid from the cartridge at the needleless syringe's puncture speed.

[0118] Method 900 can begin with preparing a syringe, such as any of the syringes described herein. This can include a needleless syringe having a controller, a cartridge containing an injectate and an air bubble, a plunger, a nozzle or other injection orifice, and a drive system that drives the plunger in response to control signals from the controller. The syringe can also include any number of sensors, etc., for controlling the initiation of injection and monitoring the operation of the syringe during operation.

[0119] As shown in step 902, method 900 may include providing a model, such as any of the models described above, that characterizes the free-running response of the injector to a control input. For example, this may model the response of a needleless injector to the operation of a plunger drive system into a chamber with no injectate in the cartridge. As described above, this model may include any suitable control model, such as an analytically developed ODE model that relates inputs, such as control signals or motor drive signals, to estimated rotational or linear velocities. The model may also be refined, as described above, to account for cartridge deformation, motor start-up, or other physical aspects of the system that may affect the response to the control input. In general, the model may be stored in the memory of the injector's controller in any manner suitable for execution and use in real time during an injection.

[0120] In another aspect, the model may include generalizations based on the modeled free-running response of the device or empirically observed behavior. For example, the model may be simplified to provide a drive current threshold above which sufficient gas compression is inferred. It should be noted that such a threshold generally does not apply during the initial acceleration of the plunger, e.g., when there is a current spike well before compression to achieve a high acceleration rate. In practice, this current threshold applies during a phase in which a steady velocity (of either the plunger or the motor driving the plunger) is maintained. Generally, in a steady state, the drive current is expected to remain steady as well. However, as the system transitions from an unloaded state—for example, when uncompressed gas is being compressed in response to plunger advancement but fluid is not being expelled from the syringe—to a loaded or compressed state, the amount of drive current required to maintain a constant velocity will increase. While reference is made herein to a spike that exceeds the threshold, it will be understood that for purposes of this disclosure, a "spike" may include any increase in drive current to a level between the free-running level and the loaded level. As mentioned above, the free-running level used as the lower threshold can be a modeled or predicted current, a threshold provided as a control parameter based on past behavior, or a measurement taken during the current injection, e.g., after the initial current peak and associated acceleration. The upper load level should typically be the current required to drive the motor while ejecting fluid during injection. The threshold for transitioning from the compression state to the injection state can be any value between these upper and lower limits and can be a numerical value or ratio of the drive current (or corresponding control signal) (e.g., relative to the actual steady-state drive current observed upon reaching steady-state velocity during the compression phase).

[0121] Typically, the chamber may be, for example, a removable and replaceable cartridge for a needleless injector as described above. The injectate may include an injectable medication.

[0122] As shown in step 904, method 900 can include operating a plunger of a syringe. For example, this can include using a drive system to operate the plunger at a first speed, moving the plunger in a direction that displaces the injectate from the chamber through the nozzle. Generally, the first speed can be different from the puncture speed and can usefully be greater than the puncture speed. Operating at a higher speed allows for compression of a maximum amount of gas bubbles for a short period of time before the injectate begins to exit the syringe as a coherent or parallel stream. In one embodiment, the first speed can be a maximum speed achievable by the drive system, a speed substantially greater than the puncture speed, or another speed greater than the puncture speed that readily and rapidly compresses trapped gas bubbles to a relatively incompressible state.

[0123] As shown in step 906, method 900 can include estimating a response of the injector, for example, by applying a control signal or other data indicative of an input to the injector to a model that estimates the response of the injector to the input. In the case of an injector, such as one of the needle-free injectors described herein, this can include estimating the response of the needle-free injector with the model during operation of the drive system, thereby providing an estimated response. As discussed above, this estimated response can more specifically be a free-running or no-load response, for example, during movement of the plunger without expelling the injectate from the nozzle. This response can more specifically include linear velocity (e.g., of the plunger), rotational velocity (e.g., of the drive motor), or any other response that can be modeled while also being physically measured during operation of the injector.

[0124] As shown in step 908, method 900 may include measuring a response of the needle-free injector to an input. For example, this may include measuring a response with a sensor during operation of the drive system, thereby providing a measured response. This may include measuring any response suitable for comparison with an estimate provided by the model. This may include a direct comparison, for example, where the model and sensor both provide a linear velocity. This may also or instead include an indirect comparison, for example, where the model provides a linear velocity and the sensor provides a linear position, rotational position, rotational velocity, or any other metric that can be used to calculate or measure a characteristic corresponding to the model output.

[0125] As shown in step 910, the method may include controlling the syringe based on a comparison of the estimated response (from the model) and the actual response (from the sensor). In particular, this may include inferring an uncompressed state of the bubble and maintaining plunger movement at approximately a first speed while the measured response is within a predetermined threshold of the estimated response, and inferring a compressed state of the bubble and changing the plunger speed to a puncture speed when the measured response exceeds the predetermined threshold from the estimated response.

[0126] The first speed may be, for example, greater than the puncture speed and / or may be a variable speed controlled within a predetermined range. In other embodiments, it may include a maximum achievable plunger speed or other threshold greater than the puncture speed selected to transition to the puncture / injection phase as quickly as possible. In other embodiments, the puncture speed may be a speed used to expel the injectate from the chamber at a speed sufficient to puncture the skin of a patient receiving an injection from the needleless injector.

[0127] The predetermined error threshold for the transition to the puncture phase may be any suitable threshold for detecting a physically meaningful deviation between the predicted and actual response of the syringe, including, for example, an empirical threshold obtained by observing physical injections, an analytical threshold determined based on fluid mechanics, syringe dynamics, gas compression, etc., or any other suitable threshold for controlling the operation of a syringe as described herein. Similarly, a compressed state of a bubble may be characterized in multiple ways for purposes of controlling the operation of a syringe as described herein. For example, the compressed state may be a state in which the bubble is compressed to at least the pressure exerted on the chamber when the plunger is operated at the puncture speed for a predetermined period of time. Any other analytic proxy for the compressed state may also be used, or may be used instead. For example, the compression state can be measured in terms of the current compressibility of the gas state (e.g., the bubble has become substantially incompressible within the context of the remainder of the injection process), the change in volume of the bubble, the elasticity of the bubble's response to plunger movement, or any other suitable measurement or surrogate useful for determining when to change from the bubble compression phase of the injection to the liquid ejection phase of the injection. This can additionally or alternatively include measurements that do not have a clearly defined physical meaning, provided that the measurement can be consistently applied to identify when the bubble has been sufficiently compressed to reduce or eliminate control error or variability in switching on the puncture speed.

[0128] In one embodiment, method 900 may further include switching to a second model of needleless injector load operation, including syringe-cartridge interaction, when the measured response exceeds a predetermined threshold. At this point, the gas bubble has been effectively compressed, and the injector may be operated to generate a puncture flow of injectate from the cartridge or syringe nozzle. This second phase of operation may be deterministically controlled, for example, by open-loop control of the injector based on a deterministic control signal; thus, the second model may include an open-loop control model of a desired injection profile. In another embodiment, this may include a control model, for example, in which position or other parameters are measured and compared to target parameters of the injection profile to achieve a controlled injection profile in real time, for example, throughout the injection cycle.

[0129] In another embodiment, method 900 may include achieving a biphasic injection profile, such as by slowing the plunger speed from a puncture rate to a drug delivery rate after a predetermined interval. As with the second model, this may include open-loop control of the injection profile, feedback control of the injection profile, or some combination thereof. Additionally or alternatively, other injection profiles may be used, such as a slow and uniform decrease in delivery rate over the course of fluid delivery, or a generally constant delivery rate, for example, within a window and / or due to the control limits of the syringe.

[0130] In another aspect, disclosed herein is a method for performing a needleless injection from a chamber having a plunger and an injection opening, the chamber containing an injectate and a gas bubble, the method including: initiating a first injection phase by operating the plunger of the chamber at a first speed; monitoring compression of the gas bubble during the first injection phase; when the gas bubble reaches a predetermined compression state, decelerating the plunger to a second speed sufficient to force the injectate through the opening at approximately a predetermined injectate speed selected to puncture the target surface; operating the plunger at the second speed for a first period of time; and, after the first period of time, operating the plunger at a third speed less than the second speed until a predetermined amount of injectate is expelled from the chamber through the injection opening.

[0131] Operating the plunger at a first speed may include operating the plunger at maximum speed or maximum acceleration until a predetermined compression speed is reached, so that the bubble can be compressed as quickly as possible or as practical before the syringe begins to expel the injectate from the orifice. Monitoring the compression may include, for example, monitoring deviations from a control model, such as generally described above. Additionally or alternatively, the monitoring may include other techniques for monitoring compression, either directly or through proxies such as plunger backforce. In one embodiment, monitoring the bubble compression may include monitoring the plunger backforce. In another embodiment, monitoring the bubble compression may include monitoring the flow of injectate from the syringe. In another embodiment, monitoring the bubble compression may include estimating a compression time interval of the first injection phase to achieve a predetermined compression state of the bubble, and operating at the first speed for the compression time interval before switching to the second speed. For example, this may involve estimating the compression time interval by capturing an image of the bubble and calculating the volume of the bubble in order to calculate or otherwise estimate the compression time interval. In another embodiment, video data may be acquired to graphically monitor the actual compression state and used to determine when to change the plunger action to a puncture speed.

[0132] In another aspect, a device for injectate delivery contemplated herein includes: a cartridge having a chamber containing a volume of injectate and an outlet port; a linear actuator coupled to a plunger and configured for delivering the injectate from the outlet port of the cartridge by the plunger, the linear actuator including a linkage; a rotary motor mechanically coupled to the linkage; a sensor monitoring the pressure applied to the cartridge by the plunger; and a controller coupled to the rotary motor, the controller being configured to control operation of the device to cause the device to: initiate a first injection phase by operating the plunger of the chamber at a first speed; monitor compression of the air bubble with the sensor during the first injection phase; when the air bubble reaches a predetermined compressed state, change the speed of the plunger to a second speed selected to force the injectate through the opening at approximately the predetermined injectate speed; operate the plunger at the second speed for a first time; and after the first time, operate the plunger at a third speed less than the second speed until a predetermined amount of injectate is expelled from the chamber through the injection opening.

[0133] The device can be a needleless injector. The sensor can include a force sensor. Additionally or alternatively, the sensor can include a pressure sensor for the chamber. Additionally or alternatively, the sensor can include a torque sensor for the rotary motor. In another aspect, the sensor can include a momentary contact force sensor for the linear actuator.

[0134] In another aspect, a needle-free injector contemplated herein includes a cartridge having a chamber containing a volume of injectate and an exit port; a plunger slidably coupled to the chamber, the plunger positioned to hold the volume of injectate in the chamber; a drive system coupled to the plunger, the drive system operable to drive the plunger into the chamber, thereby forcing the injectate out the exit port; a sensor for monitoring pressure exerted on the cartridge by the plunger; a memory storing a model characterizing the response of the needle-free injector to operation of the drive system and plunger in the absence of injectate in the cartridge; and a controller coupled to the drive system, the controller comprising: The system is configured to control operation of the needle-free injector, causing the needle-free injector to perform the following steps: moving the plunger at a first speed with a drive system, the first speed being different from a puncture speed of the injectate; estimating a response of the needle-free injector using a model while the drive system is operating, thereby providing an estimated response; measuring the response of the needle-free injector with a sensor while the drive system is operating, thereby providing a measured response; inferring an uncompressed state of the bubble and maintaining movement of the plunger at approximately the first speed while the measured response is within a predetermined threshold from the estimated response; and inferring a compressed state of the bubble and changing the speed of the plunger to the puncture speed when the measured response exceeds the predetermined threshold from the estimated response.

[0135] Figure 10 shows a comparison of two control techniques. Generally, one method does not use bubble detection, and the other method uses bubble detection as described herein. In Figure 10, it can be seen that the bubble detection method generally avoids integrator windup errors and the associated undershoots and overshoots that increase the time to reach the target velocity for fluid injection.

[0136] Figure 11 is a model of the unloaded operation of a syringe powered by a rotary motor. Typically, this model runs in parallel with the physical device, e.g., on the device's processor, to estimate the expected behavior of the syringe.

[0137] Figure 12 is a time continuous equation that estimates the operation of the system of Figure 11. When a load is imposed on the syringe, such as the physical ejection of fluid, the actual system behavior will deviate from this continuous estimate in a manner that can be detected with sensors (e.g., for plunger velocity, plunger force, rotational motor speed, or any other detectable variable) and used to determine when a gas bubble in a fixed volume of ejection becomes compressed.

[0138] While the techniques described above may be advantageously used to improve control of needle-free injectors and the like, it will be appreciated that the insights from this analytical approach (particularly that before controlling volume or rate, any trapped air bubbles or other gases in the syringe chamber should be sufficiently compressed so that linear motion of the plunger is directly and mechanically translated into displacement of the injectate from the device) can also be used in other ways to improve control of needle-free injectors.

[0139] For example, in one embodiment, the syringe can be operated at a higher pre-injection speed until a volume of fluid is detected at the syringe exit orifice that indicates sufficient gas compression to displace the fluid from the chamber. In another embodiment, for example, if the volume of gas forms a discrete, visible bubble at a known location within the chamber, an image of the uncompressed bubble can be used to estimate the bubble volume and calculate an appropriate estimated duration of initial high-speed operation for bubble compression. In another embodiment, the plunger back force is expected to increase as the bubble compresses. This back force may be measured directly or via a proxy, such as a reduction in plunger speed (or an increase in drive current required to maintain a target speed), and can be used to detect the appropriate time to reduce the plunger speed from gas compression speed to puncture speed, e.g., when the plunger speed has decreased by a predetermined absolute or relative amount or threshold that indicates an appropriate compression state. This threshold may be empirically derived or otherwise estimated, calculated, or measured prior to injection to provide a target value for detection during injection. It will be appreciated that these techniques may be varied according to, for example, the viscosity of the injectate, the diameter of the injection orifice, or other factors that may affect the amount of bubble compression appropriate for transitioning to a puncture speed.

[0140] According to one or more embodiments, a needle-free injector is provided and may include a housing, a cartridge disposed within the housing, a plunger slidably coupled to and disposed within the chamber, and a motor operatively coupled to the plunger to actuate the plunger within the chamber.

[0141] The cartridge may include an outlet port and a chamber for holding a volume of injectate. The plunger may be positioned to expel the volume of injectate through the outlet port when slid within the chamber. The needle-free injector may further include a controller operatively coupled to the motor. The controller may be operable to selectively operate the plunger according to one of a first delivery profile, a second delivery profile, and a third delivery profile.

[0142] One embodiment of a needle-free injector is shown in Figure 13. Referring to Figure 13, and using in part the numbering conventions of Figure 1, the needle-free injector 100 includes a chamber 106 having an exit port or nozzle 108 at one end with an axis of flow 101 through the chamber, depicted as a dashed arrow. The chamber 106 contains an injectate 150, as described herein, and a volume of gas 151. The volume of gas 151 may form bubbles within or adjacent to the injectate 150, or may be distributed throughout the injectate 150 as any number of smaller bubbles, or may be dissolved within the injectate 150, any of which are referred to interchangeably herein as a volume of gas or bubbles, unless a more specific meaning is expressly stated or otherwise apparent from the context. The volume of gas 151 may be introduced during the manufacturing process used to encapsulate the injectate 150 within the chamber 106. This may be, for example, a manufacturing artifact or an intentionally included volume of gas specified by regulatory or operational requirements for the needle-free injector 100. When the needle-free injector 100 is oriented such that the volume of gas 151 rises to the top of the injectate 150 and adjacent to the plunger 120, the volume of gas 151 can form a headspace above the injectate 150.

[0143] The needle-free injector 100 further includes a plunger 120 disposed within the chamber 106 prior to the volume of gas 151. The needle-free injector 100 further includes a motor (not shown) using a nib 121 operatively coupled to the motor. The nib 121 is disposed adjacent to the plunger 120 and is configured to move along the flow axis 101 when the motor is actuated.

[0144] Continuing with reference to FIG. 13 , prior to injection, plunger 120 may be spaced from tip 121 by gap 121 a. The presence of gap 121 a between plunger 120 and tip 121 allows tip 121 to accelerate to a high speed when the motor is activated, potentially allowing tip 121 to reach a higher speed before movement of plunger 120 begins, allowing plunger 120 to move along flow axis 101 within chamber 106. After tip 121 impacts plunger 120 (or immediately upon actuation, for a plunger 120 without gap 121 a), plunger 120 and the volume of gas 151 within chamber 106 are compressed, thus pressurizing injectate 150 within cartridge 106. Under these conditions, the velocity of plunger 120 can rapidly cause compression of injectate 150 and the volume of gas 151 within cartridge 106.

[0145] It will be appreciated that various techniques can be used to measure plunger velocity and load on the plunger 120 and / or motor. For example, the motor may include a rotary encoder that provides a signal corresponding to the angular position of the motor. This can be provided as an input to a controller indicating a change in angular position, which can then calculate a change in linear position of the plunger. Simultaneously, the controller can provide a drive current to the motor, for example, according to a drive profile for the syringe. The drive current provided by (or in response to a control signal from) the controller can be used to estimate the load on the motor. While encoder position and drive current are useful and readily available control signals, it will be appreciated that various other sensors and / or techniques can be used to measure position and load as described herein. For example, position can be measured optically, electronically, acoustically, etc. Similarly, the load on the plunger may be measured using a force sensor located within the device or by measuring the drive current actually output to the motor (as distinguished from the drive current the controller attempts to provide to the motor).

[0146] It will also be appreciated that various pre-injection control profiles may be used, for example, where a cartridge of fluid (and gas) is inserted into the syringe and a tip 121 coupled to a motor is moved to engage the plunger 120. In one aspect, the tip 121 may be engaged with the plunger 120 before the injection is initiated. In another aspect, the tip 121 is positioned near the plunger 120 but is not mechanically engaged therewith. For example, in some embodiments, the distance 121a between the tip 121 and the plunger 120 may be about 1 mm to about 10 mm, e.g., about 2 mm to about 8 mm, about 3 mm to about 7 mm, or about 5 mm, e.g., about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm.

[0147] As disclosed herein, in one embodiment, the needle-free injector may operate according to three or more separate delivery profiles corresponding to multiple phases of the injection delivery process: for example, a first delivery profile (e.g., a gas compression profile) that accelerates the motor before engaging the plunger 120 and initiates the injection by detecting an initial compression of the gas within the cartridge; a second delivery profile (e.g., a puncture profile) that rapidly transitions to an initial injection velocity while the injectate is expelled from the cartridge at a velocity sufficient to penetrate the permeable barrier; and a third delivery profile (e.g., a delivery profile) that maintains an injectate velocity sufficient to deliver the injectate to the subject. Transitions between each of the three profiles can be performed using the needle-free injector's controller. In some embodiments, transitions between each of the first, second, and third delivery profiles may be a function of the load on the motor and / or plunger. In some examples, the load may be measured, for example, by receiving a signal from a circuit that measures the current supplied to the motor. In another embodiment, the load may be inferred based, for example, on the drive current the controller requests or outputs for the motor.

[0148] In the first delivery profile, the plunger is initially accelerated from zero to a first speed (although not necessarily a high speed greater than the target speed in the puncture profile, e.g., at or near the maximum (rotational) speed of the motor). This initial acceleration will typically be accompanied by an initial spike in current supplied to the motor. Once the first speed is reached, the drive current is reduced to approximately the steady-state current required to drive the plunger at the first speed. During this phase, the tip coupled to the motor engages the plunger as described above, allowing the plunger to begin advancing within the chamber. However, as the gas in the chamber becomes more compressible, the drive current required to maintain the plunger's velocity increases. For example, as soon as the gas in the chamber is compressed (e.g., to a state where the gas cannot be further compressed during injection or where the compressibility of the gas is approximately equal to that of the fluid), the load on the motor will be approximately equal to the load applied by driving the fluid through the injection opening. As soon as a spike in the drive current occurs indicating that the contents of the chamber are approaching this state (e.g., indicating gas compression above a predetermined threshold), the controller may transition to a second delivery profile (while maintaining plunger velocity) to eject fluid from the syringe.

[0149] In practice, the first delivery profile may use a target speed at or near the maximum speed of the motor, or operate the plunger at maximum acceleration. Once the volume of gas is sufficiently compressed in the first delivery profile, the speed of the needle-free syringe plunger may be adjusted according to a second delivery profile for delivery of the injectate to the target. That is, while a substantially constant drive current is being supplied (e.g., during constant speed operation), upon detection of gas compression, indicated by a spike in the measured current supplied to the motor and / or a decrease in speed, the operation of the plunger may be transitioned from the first delivery profile to the second delivery profile.

[0150] A significant advantage is that by measuring the compression state and waiting for sufficient compression before beginning to execute the injection profile, changes in compression state can be prevented from interfering with the control of the injectate rate during injection. Detecting the compression of this fixed volume of gas prior to injectate delivery in this manner can control the injectate flow to more closely replicate the target injection profile, and can mitigate artifacts such as integrator windup and overshoot.

[0151] In some embodiments, operating according to the first delivery profile can cause the plunger to operate at a speed of between about 300 m / s and about 500 m / s. For example, the first delivery profile may move the plunger at about 300 m / s to about 500 m / s, about 320 m / s to about 480 m / s, about 340 m / s to about 460 m / s, about 360 m / s to about 440 m / s, about 380 m / s to about 420 m / s, or about 400 m / s, e.g., about 300 m / s, about 310 m / s, about 320 m / s, about 330 m / s, about 340 m / s, about 350 m / s, about 360 m / s, about 370 m / s, about 380 m / s, about 390 m / s, about 400 m / s, about 410 m / s, about 420 m / s, about 430 m / s, about 440 m / s, about 450 m / s, about 460 m / s, about 470 m / s, or about 480 m / s. The actuator may be operated at a speed of about 480 m / s, about 490 m / s, about 500 m / s, or greater than 500 m / s.

[0152] Once the volume of gas is compressed by the plunger in a detectable manner as described herein, the syringe can transition to a second delivery profile to generate a high-velocity injectate flow. As described herein, the second delivery profile targets a high injectate velocity for a short duration sufficient to generate an injectate velocity capable of penetrating a permeability barrier, such as a subject's skin. This can include, for example, rapid acceleration to a velocity suitable for puncture. An example of the above is shown in FIG. 14, where a high plunger velocity is maintained for a short duration and then decreased once the injectate penetrates the permeability barrier, with the decreased plunger velocity resulting in an increase in injectate or flow rate. Note that in FIG. 14, the drive current may be momentarily decreased to near zero, to zero, or even negative (to apply a brake or counter force to the plunger) before accelerating to the target injection velocity. This can advantageously mitigate overshoot of the initial target velocity and prevent large initial fluctuations in the velocity of the fluid ejected from the device.

[0153] Note that the initial target speed and speed range in this second phase may be significantly smaller than during the first phase. For example, the injectate velocity generated during operation according to the second delivery profile is about 150 m / s to about 250 m / s, e.g., about 150 m / s to about 250 m / s, about 160 m / s to about 240 m / s, about 170 m / s to about 230 m / s, about 180 m / s to about 220 m / s, about 190 m / s to about 210 m / s, or about 200 m / s, e.g., about 150 m / s, about 160 m / s, about 170 m / s, about 180 m / s, about 190 m / s, about 200 m / s, about 210 m / s, about 220 m / s, about 230 m / s, about 240 m / s, about 250 m / s, or greater than about 250 m / s. More generally, any speed or combination of speeds suitable for delivery of injectate in a needle-free injection may be used in the second and third profiles.

[0154] As part of the transition from operation with the first delivery profile to operation with the second delivery profile, one consideration is controlling the current supplied to the motor to avoid over-penetration of the injectate through the permeability barrier. To better control the velocity during the second phase, particularly early in the injection when the fluid is penetrating the tissue, the second delivery profile may begin with little or no current supplied to the motor. As shown in Figure 14 (at approximately 5 milliseconds along the x-axis), the flow rate can continue to increase despite this momentary decrease in drive current, and the flow rate can continue to smoothly accelerate as the plunger velocity rapidly decreases toward the target initial velocity for the second phase. In this configuration, backpressure from the compression of the fixed volume of gas in the chamber can slow the plunger velocity.

[0155] Under these conditions, the current supplied to the motor, and therefore the force on the plunger, should increase inversely to the decrease in plunger velocity until both the plunger velocity and the current supplied to the motor reach a steady-state condition. That is, by controlling the current and plunger velocity together in a power-controlled mode (illustrated in FIG. 15C, where the product of plunger velocity and current is used as a proxy for the mechanical power supplied to the plunger), a second delivery profile can be achieved, allowing for power control to the needle-free injector until the plunger velocity, the current applied to the motor, and the power supplied to the needle-free injector reach a steady-state condition where the plunger velocity, the current applied to the motor, and the power supplied to the needle-free injector are relatively stable for the duration of the injection. For example, the device can employ a slow, monotonically decreasing injection rate as the injectate is physically delivered from the device.

[0156] The above is illustrated in Figures 14 and 15A-15C, which show the change in plunger velocity (Figure 15A), measured motor current (Figure 15B), and power measured as the product of plunger velocity and measured motor current (Figure 15C) as the delivery profile changes from a first delivery profile to a second delivery profile and then to a third delivery profile after detecting a steady-state condition between the measured current and plunger velocity.

[0157] In some embodiments, the average velocity of the plunger during operation with the first delivery profile is greater than the average velocity of the plunger during operation with the second delivery profile. An example of this is shown in Figure 14. Referring to Figure 14, the velocity of the plunger, represented by the dotted line, is highest in the first delivery profile and decreases shortly after impact with the plunger in the second delivery profile until a steady-state plunger velocity is reached during the third delivery profile.

[0158] In some embodiments, operating according to the second delivery profile can cause the plunger to operate at a velocity of about 60 m / s to about 150 m / s. For example, the second delivery profile can cause the plunger to operate at a velocity of about 60 m / s to about 150 m / s, about 70 m / s to about 140 m / s, about 80 m / s to about 130 m / s, about 90 m / s to about 120 m / s, or about 110 m / s, e.g., about 60 m / s, about 70 m / s, about 80 m / s, about 90 m / s, about 100 m / s, about 100 m / s, about 120 m / s, about 130 m / s, about 140 m / s, 150 m / s, or greater than 150 m / s.

[0159] The transition from the second delivery profile to the third delivery profile can occur in response to detecting a steady-state condition between the measured current and plunger velocity until a predetermined amount of injectate is delivered from the chamber through the exit port. One consideration regarding this transition is the uniform deceleration reduction while the injectate velocity remains above a lower velocity limit. That is, after penetrating the permeability barrier during operation with the second delivery profile, the plunger velocity, and therefore the injectate velocity, must be maintained during operation with the third delivery profile to achieve efficient and complete delivery of the appropriate volume of injectate to the subject's tissue. To achieve control and maintenance of injectate velocity, the third delivery profile can include control of plunger velocity, and therefore plunger deceleration, by reducing the current applied to the motor. By performing this deceleration in a slow, monotonically decreasing pattern, the target flow rate can be maintained in direct proportion to the supplied control current. Graphical representations of this control of the plunger are shown in Figures 16A and 16B.

[0160] In some embodiments, operating according to the third delivery profile can cause the plunger to move at a velocity of about 80 m / s to about 120 m / s. For example, the second delivery profile can cause the plunger to move at a velocity of about 80 m / s to about 120 m / s, about 85 m / s to about 115 m / s, about 90 m / s to about 110 m / s, about 90 m / s to about 104 m / s, or about 100 m / s, e.g., about 80 m / s, about 85 m / s, about 90 m / s, about 95 m / s, about 100 m / s, about 105 m / s, about 110 m / s, about 115 m / s, or about 120 m / s. In one embodiment, the second delivery profile targets a constant velocity (of either the injectate or the plunger), and the third delivery profile targets a slow, monotonically decreasing velocity. In another embodiment, the second delivery profile targets a decreasing rate (eg, a slow, monotonically decreasing rate) and no third delivery profile is used.

[0161] According to one or more embodiments, a needle-free injector is provided. The needle-free injector may include a plunger arranged to pressurize fluid and gas within a cartridge having an exit port, and a motor operatively coupled to the plunger. As described herein, the plunger may be arranged to contact the gas within the chamber, and the motor may be operable to actuate the plunger in a linear motion along the axis of the cartridge to expel the fluid from the exit port of the cartridge. Actuation of the motor in a first delivery profile may cause the plunger to compress the gas within the chamber and pressurize the injectate within the chamber. In response to detecting compression of the gas within the cartridge above a predetermined threshold, the needle-free injector may operate in a second delivery profile, such as a biphasic profile including a puncture phase and a delivery phase. As described herein, the puncture phase may generate an injectate velocity sufficient to puncture the permeability barrier, but is controlled so that the injectate is not delivered deeper than required into the subject's tissue. The delivery phase may generate an injectate velocity sufficient to deliver a constant volume of injectate to the subject. The delivery phase is further controlled, for example, by controlling the current supplied to the motor of the needle-free injector to achieve complete delivery of the appropriate volume of injectate into the subject's tissue. In some embodiments, as described herein, the plunger velocity during the penetration phase is decreased as a function of time. This decrease in plunger velocity reduces the resulting injectate velocity to a magnitude that is unlikely to result in over-penetration of the injectate into the subject.

[0162] The needle-free injector may further include a controller operatively coupled to the motor, which may be operable to operate the plunger according to a first delivery profile to compress gas in the cartridge in response to an injection start signal, and to operate the plunger according to a second delivery profile in response to detecting compression of gas in the cartridge above a predetermined threshold.

[0163] In some embodiments, detecting compression of gas within the cartridge beyond a predetermined threshold includes detecting a deviation in motor current between a free-running drive current predicted by the model and a measured current supplied to the motor. In some embodiments, detecting compression of gas within the cartridge includes detecting an increase in motor current above a predetermined threshold to maintain the velocity of the plunger within the first delivery profile. In some embodiments, detecting compression of gas within the cartridge may include detecting a decrease in plunger velocity below a predetermined threshold. In some embodiments, detecting compression of gas within the cartridge includes simultaneously detecting a decrease in plunger velocity and an increase in drive current to the motor. For example, the measured current supplied to the motor may be measured by an encoder operatively coupled to the motor that indicates the rotational position of the motor, and feedback from the encoder can be used by the controller to actuate the plunger.

[0164] In accordance with one or more embodiments, a method of delivering an injectate using a needle-free injector is provided. The method may include providing a needle-free injector as described herein. The needle-free injector may include a housing having a cartridge for holding a chamber, a plunger constructed and arranged to expel the injectate from the chamber, and a motor operatively coupled to the plunger. The method includes, in response to initiating an injection using the needle-free injector, causing the needle-free injector to operate the plunger according to a first delivery profile, monitoring a current supplied to the motor during the first delivery profile, transitioning from the first delivery profile to a second delivery profile in response to detecting compression of gas in the chamber by the plunger based at least in part on a spike in the current supplied to the motor, operating the plunger according to the second delivery profile, transitioning from the second delivery profile to a third delivery profile in response to detecting a steady-state condition between the measured current and the velocity of the plunger, and operating the plunger according to the third delivery profile until a predetermined amount of injectate is delivered from the chamber through the outlet port.

[0165] In some embodiments of the method of delivering an injectate, transitioning from the first delivery profile to the second delivery profile may include transitioning from the first delivery profile to the second delivery profile upon detecting a spike in measured current supplied to the motor concurrent with compression of the gas. In some embodiments of the method of delivering an injectate, transitioning from the first delivery profile to the second delivery profile may include reducing the current supplied to the motor to within a range of 0 A to about 10 A.

[0166] In some embodiments of the present methods of delivering an injectate, operating the plunger according to the second delivery profile can include operating the plunger while maintaining compression of the gas in the chamber. In some embodiments of the present methods of delivering an injectate, operating the plunger according to the second delivery profile can result in the velocity of the injectate being sufficient to penetrate a permeability barrier. For example, as described herein, the permeability barrier can be the subject's skin.

[0167] In some embodiments of the present methods of delivering injectate, operating the plunger with the third delivery profile can include adjusting the velocity of the plunger as the injectate is delivered. For example, during delivery of the injectate, the third delivery profile can be configured to decrease the velocity of the plunger to decrease the velocity of the injectate.

[0168] According to one or more embodiments, a method for facilitating needle-free injection of an injectate is provided. The method can include providing a needle-free injector as described herein, such as a needle-free injector including a motor operatively coupled to a plunger and a controller. The controller provided with the needle-free injector can be a controller described herein, which can operate the plunger at a first delivery profile, monitor current supplied to the motor during the first delivery profile, transition from the first delivery profile to a second delivery profile in response to detecting compression of gas in a chamber by the plunger based at least in part on a spike in current supplied to the motor, operate the plunger at the second delivery profile, transition from the second delivery profile to a third delivery profile in response to detecting a steady-state condition between the measured current and the velocity of the plunger, and operate the plunger according to the third delivery profile until a predetermined amount of injectate is delivered from the chamber via the outlet port.

[0169] In some embodiments of the facilitating method, the method may further include providing instructions to the user for loading the injectate cartridge into the needle-free injector.In some embodiments of the facilitating method, the method may further include providing instructions to the user for operating the needle-free injector.

[0170] The above-described systems, devices, methods, processes, etc. may be implemented in hardware, software, or a combination thereof suitable for a particular application. This hardware may include a general-purpose computer and / or a special-purpose computing device. This includes implementation in one or more microprocessors, microcontrollers, embedded microcontrollers, programmable digital signal processors, or other programmable devices or processing circuits, along with internal and / or external memory. Additionally or alternatively, this may include one or more application-specific integrated circuits, programmable gate arrays, programmable array logic circuits, or any other device that can be configured to process electronic signals. It will be further understood that implementations of the above-described processes or devices may include computer-executable code created using a structured programming language such as C, an object-oriented programming language such as C++, or any other high- or low-level programming language (including assembly language, hardware description languages, database programming languages and techniques) that can be stored, compiled, or interpreted to run on any of the above-described devices, or on heterogeneous combinations of processors and processor architectures, or on different hardware and software combinations. In alternative embodiments, the methods may be embodied in the system that performs the steps, or may be distributed in some manner among multiple devices. At the same time, the processing may be distributed across multiple devices, such as the various systems described above, or all of the functionality may be integrated into a dedicated stand-alone device or other hardware. In alternative embodiments, the means for performing the steps associated with the processing described above may include any of the hardware and / or software described above. All such permutations and combinations are intended to fall within the scope of the present disclosure.

[0171] The embodiments disclosed herein may include a computer program product including computer-executable or computer-usable code that, when executed on one or more computing devices, performs any and / or all of its steps. This code may be stored in a non-transitory manner in computer memory, such as memory from which the program executes (such as random access memory associated with a processor) or storage such as a disk drive, flash memory, or any other optical, electromagnetic, magnetic, infrared, etc. device or combination of devices. In another aspect, any of the above-described systems and methods may be embodied in any suitable transmission or propagation medium that carries the computer-executable code and / or any input or output therefrom.

[0172] The elements described and illustrated herein, including the flowcharts and block diagrams in the figures, imply logical boundaries between the elements. However, depending on the software or hardware engineering implementation, the illustrated elements and their functionality may be implemented as a monolithic software structure, as a standalone software module, as a module using external routines, code, services, etc., or any combination thereof, through a computer-executable medium on a machine having a processor capable of executing stored program instructions, and all such implementations may be within the scope of the present disclosure. Examples of such machines may include, but are not limited to, personal digital assistants, laptops, personal computers, mobile phones, other handheld computing devices, medical equipment, wired or wireless communication devices, transducers, chips, calculators, satellites, tablet PCs, e-books, gadgets, electronic devices, devices with artificial intelligence, computing devices, networking devices, servers, routers, etc. Furthermore, the elements illustrated in the flowcharts and block diagrams or other logical components may be implemented in a machine capable of executing program instructions.

[0173] Thus, while the foregoing drawings and description illustrate functional aspects of the disclosed system, the specific configuration of software for implementing those functional aspects should not be inferred from those descriptions unless explicitly stated or apparent from the context. Similarly, it will be understood that the various steps identified and described above may be varied, and the order of those steps may be adapted to particular applications of the techniques disclosed herein. All such variations and modifications are intended to fall within the scope of the present disclosure. As such, the illustration and / or description of the order of various steps should not be understood as stipulating that a particular order of performance of those steps is essential, unless required by a particular application or unless explicitly stated or apparent from the context. Unless expressly indicated to the contrary, the disclosed steps may be modified, supplemented, omitted, and / or reordered without departing from the scope of the present disclosure.

[0174] The method steps of the implementations described herein are intended to include any suitable manner of causing such method steps to be performed, consistent with the patentability of the following claims, unless a different meaning is expressly stated or apparent from the context. Thus, for example, performing step X includes any suitable manner of causing another party, such as a remote user, a remote processing resource (e.g., a server or cloud computer), or a machine, to perform step X. Similarly, performing steps X, Y, and Z may include any manner of directing or controlling any combination of such other individuals or resources to perform steps X, Y, and Z to obtain the benefit of such steps X, Y, and Z. Thus, the method steps of the implementations described herein are intended to include any suitable manner of causing one or more other parties or entities to perform those steps, consistent with the patentability of the following claims, unless a different meaning is expressly stated or apparent from the context. Such parties or entities need not be under the direction or control of any other party or entity, nor need they be located within any particular jurisdiction.

[0175] It will be understood that the above-described methods and systems are described by way of example and not by way of limitation. Numerous variations, additions, omissions, and other modifications will be apparent to those skilled in the art. Furthermore, the order or presentation of method steps in the above description and drawings is not intended to require an order for performing the described steps unless a particular order is expressly required or is otherwise apparent from the context. Thus, while particular embodiments have been shown and described, it will be apparent to those skilled in the art that various changes and modifications in form and detail can be made without departing from the spirit and scope of the disclosure, which are intended to form a part of the present invention as defined by the following claims.

Claims

1. 1. A needleless injector comprising: a plunger positioned to pressurize fluid and gas within a cartridge having an outlet port; a motor operatively coupled to the plunger, the motor operable to actuate the plunger in a linear motion along the axis of the cartridge to expel the fluid from the cartridge; a controller operatively coupled to the motor, the controller operable to operate the plunger according to a first delivery profile to compress the gas in the cartridge in response to an injection start signal, and to operate the plunger according to a second delivery profile in response to detecting compression of the gas in the cartridge above a predetermined threshold, wherein detecting the compression of the gas in the cartridge comprises simultaneously detecting a decrease in the velocity of the plunger and an increase in drive current to the motor.

2. 10. The needle-free injector of claim 1, wherein detecting the compression of the gas within the cartridge further comprises detecting a deviation in motor current between a free-running drive current predicted by a model and a measured current supplied as the drive current to the motor.

3. 10. The needle-free injector of claim 1, wherein detecting the compression of the gas within the cartridge further comprises detecting an increase in motor current above a predetermined current threshold to maintain the velocity of the plunger within the first delivery profile.

4. 10. The needle-free injector of claim 1, wherein detecting the compression of the gas within the cartridge further comprises detecting a decrease in the velocity of the plunger below a predetermined velocity threshold.

5. 10. The needle-free injector of claim 1, wherein the controller actuates the plunger in response to feedback from an encoder operatively coupled to the motor.

6. 10. The needle-free injector of claim 1, wherein the first delivery profile has a first target velocity that is greater than a second target velocity of the second delivery profile.

7. 7. The needle-free injector of claim 6, wherein the second delivery profile is a biphasic profile comprising a puncturing phase and a delivery phase.

8. 8. The needle-free injector of claim 7, wherein the plunger speed during the puncture phase decreases as a function of time.

9. 10. The needle-free injector of claim 1, wherein the fluid comprises at least one of an injectable pharmaceutical formulation, an injectable nutritional supplement formulation, and a high viscosity biological formulation.

10. 10. The needle-free injector of claim 1, wherein the plunger speed of the second delivery profile generates an injectate velocity of the fluid exiting the exit port sufficient to penetrate the skin of a human subject.

11. 1. A needleless injector comprising: a plunger positioned to pressurize fluid and gas within a cartridge having an outlet port; a motor operatively coupled to the plunger, the motor operable to actuate the plunger in a linear motion along the axis of the cartridge to expel the fluid from the cartridge; a controller operatively coupled to the motor, the controller operable to operate the plunger according to a first delivery profile to compress the gas in the cartridge in response to an injection start signal, and to operate the plunger according to a second delivery profile in response to detecting compression of the gas in the cartridge above a predetermined threshold, the first delivery profile having a first target speed that is greater than a second target speed of the second delivery profile.

12. 12. The needle-free injector of claim 11, wherein detecting the compression of the gas in the cartridge exceeding the predetermined threshold comprises detecting a deviation in motor current between a free-running drive current predicted by a model and a measured current supplied as the drive current to the motor.

13. 12. The needle-free injector of claim 11, wherein detecting the compression of the gas within the cartridge comprises detecting an increase in motor current above a predetermined current threshold to maintain the plunger velocity within the first delivery profile.

14. 12. The needle-free injector of claim 11, wherein detecting the compression of the gas within the cartridge alternatively comprises detecting a decrease in the velocity of the plunger below a predetermined velocity threshold.

15. 12. The needle-free injector of claim 11, wherein the controller actuates the plunger in response to feedback from an encoder operatively coupled to the motor.

16. 12. The needle-free injector of claim 11, wherein the second delivery profile is a biphasic profile comprising a puncturing phase and a delivery phase.

17. 17. The needle-free injector of claim 16, wherein the plunger speed during the puncture phase decreases as a function of time.

18. 12. The needle-free injector of claim 11, wherein the injectate comprises an injectable pharmaceutical drug.

19. 12. The needle-free injector of claim 11, wherein the fluid comprises a high viscosity biological product.

20. 12. The needle-free injector of claim 11, wherein the plunger speed of the second delivery profile generates an injectate velocity of the fluid exiting the exit port sufficient to penetrate the skin of a human subject.

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