Automatic injector devices and systems for controlled delivery of dosage and associated methods

Auto-injectors and associated assemblies and methods for delivery of liquid medicament in a controlled manner are disclosed herein.

TECHNICAL FIELD

The present technology relates generally to automatic injector devices and associated systems and methods. In particular, several embodiments are directed to automatic injector devices for controlled delivery of a dosage such as a liquid medicament dosage.

BACKGROUND

Auto-injectors are used for parenteral delivery of liquid medicament solutions such as drug solutions, drug suspensions, vaccines, and other medicinal therapies. Many auto-injectors are suitable for the injected delivery of the drug to a patient from pre-filled, disposable cartridges containing the drug. Auto-injectors use an automatic mechanism (e.g., an electrically powered drive unit) to insert a hypodermic needle through the skin of the patient and into the subcutaneous tissue for delivery of the drug. Conveniently, auto-injectors can be used by non-medical users for the subcutaneous administration of drug or by patients for self-administration.

DETAILED DESCRIPTION

The present technology is directed to apparatuses, systems, and methods for parenteral injection of a liquid medicament into a subject in a controlled manner. In particular, embodiments of the present technology relate to electronic injectors and auto-injector assemblies having disposable dose modules suitable to automatically deliver a pre-determined number of dosages (e.g., a single dose volume) of a liquid medicament. Certain embodiments of the present technology deliver a dose in a controlled manner (within a specified amount of time, at a specified drug temperature, etc.) and/or monitor delivery performance of the electronic injector, for example, to audit the state of the drug and device before, during and/or after drug delivery.

In some arrangements, an electronic injector assembly is configured to deliver a single dose of a liquid medicament in a manner that allows for detection and control of various aspects of the delivery process. For example, a user can detect and control the temperature of the liquid medicament prior to injection. In some embodiments, a user can detect and control a rate of injection of the liquid medicament (e.g., within pre-defined ranges). A rate of injection can be calculated within the context of the use of the injector assemblies described herein. In one embodiment, a rate of injection can be determined based on thermodynamic factors such as medicament viscosity, volume, syringe barrel and needle dimensions, etc. In some embodiments, a user can choose, pre-program and save process program settings that initiate and execute injection of the medicament at different temperatures and/or rates of injection (e.g., for different injection sites, for different medications/drugs, etc.).

Specific details of several embodiments of the technology are described below with reference toFIGS. 1A-9. Although many of the embodiments are described below with respect to devices, systems, and methods for controlled automated injection of medicament into a subject, other applications and other embodiments in addition to those described herein are within the scope of the technology. Additionally, several other embodiments of the technology can have different configurations, components, or procedures than those described herein. A person of ordinary skill in the art, therefore, will accordingly understand that the technology can have other embodiments with additional elements, or the technology can have other embodiments without several of the features shown and described below with reference toFIGS. 1A-9.

Selected Examples Automated Injectors and Related Devices

FIGS. 1A and 1Bare a front view and a cross-sectional front view, respectively, of an injection assembly10that can include an injector100and a dose module200inserted into the injector100in accordance with an embodiment of the present technology.FIG. 2is a cross-sectional side view the injector100shown inFIGS. 1A and 1B. Referring toFIGS. 1A-2together, and in several embodiments, the injector100can be a handheld, reusable auto-injector configured to house the dose module200(e.g., disposable drug cartridges) in an internal cavity102(FIG. 1B) and deliver medicament202from a pre-filled hypodermic syringe210within the dose module200to subcutaneous tissue in a subject via a retractable hypodermal needle212(FIGS. 1B and 2).

The internal cavity102of the injector100is operatively coupled to a drive mechanism110housed within the injector100and contained within a drive container112. The drive mechanism110is configured to move the needle220from a retracted position (shown inFIGS. 1A-2) to an extended position beyond a distal end12of the injection assembly10(e.g., for penetrating a subject's skin).

FIG. 3is a cross-sectional side view of the dose module200in accordance with an embodiment of the present technology.FIG. 4illustrates a side view of the various components of the dose module200shown inFIG. 3and separated from each other component in accordance with an embodiment of the present technology. In the embodiment illustrated inFIGS. 3 and 4, the dose module200includes the syringe210(e.g., primary container) configured to contain the liquid medicament202, a cassette230(e.g., secondary container) configured to house the syringe210and to operably couple with the drive mechanism110within the injector100, and a stand250configured to shield the needle212inside the cassette230and to vertically support the cassette230for convenient insertion into the injector100. Referring toFIGS. 3 and 4together, the cassette230can include a closable access232configured to provide a plunger214on an upper portion of the syringe210access to the drive mechanism110when the dosage module is received in the injector100(seeFIGS. 1B and 2). In some embodiments, the closable access232may be one or more moveable doors234. The cassette230can also have a window236for viewing the liquid medicament202when the cassette230is housing the syringe210(FIGS. 3 and 4). In one embodiment the window236can be clear such that, for example, a person administering the liquid medicament202with the injector assembly10can view the contents (e.g., volume, etc.) and characteristics (e.g., clarity, precipitation formation, etc.) of the medicament202prior to administration. In such embodiments, the syringe210can be clear or, in other embodiments, a portion211of the syringe210aligning with the window236is clear such that the viewing person can visualize the syringe contents (FIG. 3).

In some embodiments, the cassette230can also include identification information. such as lot number and/or dimensions of the hypodermic syringe210. lot number of the cassette230, drug batch and/or expiry date, etc. In one embodiment, the identification information can be stored on an RFID tag238. In one example, the RFID tag238can be a passive tag. In other embodiments, the cassette230can include a thermal coupling element or transducer240(FIG. 3) in contact with the syringe210for transducing the thermal state of the liquid medicament202to a thermal sensor160located within the inner interior cavity102of the injector100(shown inFIG. 2).

The dose module200, as assembled, is illustrated inFIG. 3. As shown, the hypodermic syringe210is retained and housed within an interior of the cassette230. In this embodiment, retention of the syringe210is facilitated by a syringe support242coupled to the interior of the cassette230. The syringe support can be a collar or a plurality of shoulder supports configured to retain the syringe210at a pre-determined distance from a lower surface244(e.g., a surface suitable for contact with a subject's skin) of the cassette230. Attached to the syringe support242and resting against the interior lower surface244of the cassette230is a spring246configured to apply resistance against the syringe210in a direction away from the lower surface244and suitable to assist in retraction of the needle212following injection and dose delivery. An upper portion of the cassette210can include an indentation248configured to be mated with a retention collar103within the interior cavity102of the injector100when the injector assembly is loaded (FIGS. 1A-2).

The stand250can be configured to vertically support the cassette230and hypodermic syringe210within a cradle or cavity252in a manner that facilitates transfer to the internal cavity102of the injector100(FIGS. 3 and 4). The stand250can also include a needle sheath254to surround and protect the tip of the needle212affixed to the hypodermic syringe210. When cradled in the stand250, the needle sheath254extends past lower cassette doors249at the lower surface244and into a lower portion of the cassette230housing the syringe210and needle212. The stand250can further include a cassette latch256configured to releasably retain the cassette230onto the stand250in the vertical orientation. When assembled, the dose module200is configured to be received into the internal cavity102of the injector100.

FIG. 5is cross-sectional, side view of the injector100without the dose module200in accordance with an embodiment of the present technology. In referring toFIGS. 1B, 2 and 5together, the drive mechanism110can be operatively coupled to and/or driven by one or more motors for (a) moving the hypodermal needle212from a retracted position to an extended position beyond the lower surface244of the cassette230(e.g., through a needle aperture243), and (b) providing force to the plunger214in order to expel the liquid medicament202from the hypodermic syringe210through the needle212in a controlled manner. In one arrangement, a motor120, such as an electronic motor with motion control (e.g., a servo motor), can facilitate both the movement of the hypodermal needle212as well as force against the plunger214. In another embodiment (not shown), a first motor can be configured for a first actuation event of moving the syringe210forward within the cassette230for the purpose of penetrating the needle212into the subject's skin. In such an embodiment, a second motor120b(e.g., a servo motor) can be configured for a second actuation event of driving the plunger214through the syringe210at a controlled rate for expelling the liquid medicament202into the subject. In various embodiments, the motor(s)120may be connected to an actuator122comprising a lead screw124(e.g., drive piston) and lead nut126. The actuator122can translate the rotational motion of an output shaft128into linear motion of the lead nut126. In some embodiments, a set of gears130may be positioned between the output shaft128and the actuator122for reducing the speed of the motor120band/or increasing the torque output. In various embodiments, the gear set130can be optimized for delivery of liquid medicaments202having varying viscosity.

Referring toFIG. 5, the injector100also includes a control system150, such as a processor (e.g., microprocessor), having instructions for controlling the rate of an injection. In operation, the control system150can be based on feedback from one or more sensors (described further below), or from input received from a user via a user interface152(e.g., touch screen, buttons). For example, the injector100can include an RFID reader154for wirelessly reading the identification information on the RFID tag238on the cassette230(FIG. 4A). In one embodiment, the user interface152can be simple with higher-function control available remotely through a mobile and/or web application. The injector100can have a radio transceiver156, such as a Bluetooth Low Energy chip, for sending and receiving information, such as receiving injection instructions from the subject, or sending injection data to a remote database. In some embodiments, the injector100can communicate wirelessly with a corresponding application running on a subject's mobile device or computer.

In some arrangements, the injector100can have a thermal sensor160on the wall of the interior cavity102oriented such that the thermal sensor will be in contact with the thermal coupling element240(FIG. 3) on the cassette230when the cassette is inserted properly into the internal cavity102. In one embodiment, the thermal sensor160can transmit data related to the temperature of the liquid medicament202to the control system150via a thermoresistor circuit161. In such arrangements, the control system150can alert the user (e.g., subject, patient) when the liquid medicament202is at an optimal temperature for injection. A skin sensor162(e.g., pressure sensor, contact/touch sensor, temperature sensor, position sensor, etc.) can be positioned on a distal tip163of the injector100(e.g., a surface aligned with the lower surface244of the cassette230). The skin sensor162can indirectly detect contact between the lower surface244of the cassette230and the subject's skin. In some embodiments, the control system150includes memory for storing data related to doses received, injections performed, user-generated injection parameter, etc. For example, the memory can store programs specific for a medicament's rheology. The control system150can use input from sensors, such as the thermal sensor160, in combination with the stored rheology programs in order to calculate a medicament's viscosity. The memory also stores programs for operating the injector100, such as injection force calculation and corresponding motor speed. The control system's processor can be a master control unit for calculating and performing parameters of a desired injection. The injector100can include a power source170such as a rechargeable battery for powering the control system150. The power source170may be charged, for example, through a micro-USB port.

Movement of the lead screw124can be determined through information received from first and second piston sensors164a,164b. The speed of the lead nut126can be detected via data received via a rotational sensor166and a rotary encoder168can measure the speed of the motor120. When injection instructions are calculated and/or determined, the drive mechanism can engage the plunger214of the dose module200via contact of a piston head114through the closable access232of the cassette210. In some arrangements, a plunger adapter216can be positioned between the piston head114and the plunger214(FIG. 2). Injection of liquid medicament202can be initiated by engagement of an injection button116on the injector100.

Selected Embodiments of Methods Associated with Injection Assemblies

Several suitable methods are disclosed herein and discussed further below: however, one of ordinary skill in the art will recognize a plurality of methods suitable to operate injection assemblies and to deliver a dose of liquid medicament in a controlled manner. With respect to the embodiment illustrated inFIGS. 1A-5, the injector can be used in combination with the dose module for automated delivery of a liquid medicament to a subject. Further methods include steps for delivering a dose of liquid medicament in a controlled manner within a specified time and/or a specified delivery rate. Additional methods include steps for monitoring delivery performance of an injector assembly (e.g., the injector assembly10shown inFIGS. 1A-2).

FIG. 6is a flow diagram illustrating a method600for automated delivery of a liquid medicament in accordance with an embodiment of the present technology. The method600can begin with sending a first notification reminder (e.g., set by a patient, a healthcare provider, etc.) to a user (e.g., patient) to remind the user to inject a dose of liquid medicament at a predetermined time (block602). The reminder may be sent by the application, either natively through a software application or by text message to the user's phone. Upon notification, a user can remove a dose module containing a dose of the liquid medicament out of refrigerated storage (if necessary) in order to raise a temperature of the medicament to room temperature, for example. An injector may be loaded with a dosage module cassette containing the syringe by placing the injector over the vertically aligned cassette and moving the injector in a downward motion. The method600can continue with sending a second notification reminder to the user when the temperature of the medicament reaches a threshold temperature (e.g., reaches desired injection temperature) (block604). The method600continues with setting an injection speed of the injector (block606). In some embodiments, and prior to injection of the dosage, the user may select a desired injection speed via the user interface on the injector or wirelessly through a software application. In another embodiment, the injection speed can be a speed selected based on the characteristics of the medicament and/or a manufactures's preference.

The user can remove the injection assembly from the stand (e.g., the dose module stand). In various arrangements, removal of the cassette/syringe portion of the dose module from the stand results in removal of the needle sheath, unsheathing the needle tip within the cassette housing. The lower surface of the cassette and skin sensor on the distal tip of the injector can be positioned at an injection site with the device held at an approximate 90° angle relative to the injection surface. In other embodiments, the lower surface of the cassette can be positioned at other angles relative to the injection surface (e.g., between about 80°-90°, between about 70°-90°, between about 60°-90°, etc.). The method600also includes initiating an injection of the medicament when an injection button is engaged (block608). The button may be activated by compression, or in another embodiment, can be touch sensitive. In certain embodiments, the button may require a prolonged depression (e.g., 2 seconds or longer) in order to prevent misfiring of the injector. In other embodiments, the skin sensor can relay a signal to the processor in conjunction with the activation of the inject button in order for the injection to occur.

Once an injection is initiated, the method600includes pushing the syringe forward within the cassette with a first drive mechanism, resulting in the protrusion of the needle beyond the lower surface of the cassette and through a needle aperture into the subject's skin (block610). The method600further includes applying force to the plunger using a second drive mechanism to expel the liquid medicament through the needle at a controlled rate (block612). In various arrangements, the motor speed can be actively controlled by the control system through, for example, a closed loop feedback mechanism in order to maintain a smooth flow rate at the specified injection speed. The method600can also include sensing an end of a dosage injection (block614). For example, a photodiode/photoreceptor located at a distal end of the drive piston chamber can be disrupted when a drive piston reaches a pre-determined terminal distance, thereby signaling an end of an injection. In such embodiments, the injector may signal to the subject that the injection is complete. In various arrangements, a reverse motor rotation can be used to retract the needle out of the patient and back into the protective housing of the cartridge. In some embodiments, a user does not see the needle during the injection process. The cassette and used syringe can be released and/or removed from the injector for disposal. In various embodiments, data related to the injection (average motor speed, injection speed, sensory data such as kinetic temperature profile, dose module identification information, injection performance, etc.) can be manually or automatically uploaded wirelessly through the application into a secure database.

FIG. 7is a flow diagram illustrating a method for delivering a dose of a biologic solution in a controlled manner in accordance with an embodiment of the present technology. The method700can begin with receiving input from a user, feedback from one or more sensors and/or calculations made by programs stored on the processor memory for defining parameters for an injection of medicament at a specific and/or controlled flow rate (block702). For example, calculation of an appropriate injection force profile can include receiving information regarding injection speed. Injection speed may be selected by a user (e.g., patient), or alternatively, a standard speed setting may be selected. For injection at a specific flow rate, an appropriate injection force can be calculated. Injection force can depend on multiple parameters, including length of the needle, gauge of the needle, diameter of the syringe barrel, shear rate, and viscosity of the liquid medicament. Viscosity can be unique to each medicament (e.g., drug solution) and dependent on such characteristics as concentration, shear rate and temperature. In some embodiments, drug-specific rheology programs can be stored within the processor's internal memory and can be used in combination with the concentration of the dose, temperature of the syringe, and selected flow rate in order to calculate viscosity. Data for calculating injection force stored on the cassette's identification element and translated by the RFID radar may include, for example, length of the needle, needle gauge, diameter of the syringe barrel and concentration of the dose. The method700can also include transmitting all of the inputs/data and sensory information received to the processor (block704), and calculating an injection force profile (block706). In various embodiments, the calculations can be performed and the programs can be executed in a specific order at the time the user activates the inject button.

FIG. 8is a flow diagram illustrating a method800for monitoring delivery of a dose of a liquid medicament in accordance with another embodiment of the present technology. The method800begins with detecting disparities between a calculated flow rate and injection duration with an actual injection duration, given a constant drug delivery force (block802). In some embodiments, the control system's processor may use feedback from sensors and a program stored in the memory in order to detect disparities between calculated flow rate and injection duration with actual injection duration. The method800can also include calculating a true viscosity of the liquid medicament (block804). In one example, the actual injection duration may be used in combination with motor performance to calculate a true viscosity of the medicament. Such a disparity between calculated injection duration, based on calculated drug viscosity, and actual injection duration and drug viscosity, may be stored on the device and/or communicated wirelessly through the corresponding application to a remote database. The diagnostic accuracy and sensitivity of the injection audit can further be improved using aggregated data. Accordingly, the method800further includes analyzing aggregated injection data (block806), including the injection audits, which may be wirelessly communicated to a remote database.

FIG. 14. depicts a representative analysis of aggregate injection audits from multiple doses performed by multiple injectors in the hands of different users, which can signal the source of a quality issue (e.g., disparity between expected drug delivery performance and recorded drug delivery performance). Drug delivery performance refers to either drug delivery force (given a constant delivery speed), or drug delivery speed (given a constant delivery force). For example, cluster1shows multiple injection audits with performance metric disparities from a single injector over multiple doses with no common variable between the dose, which indicates an injector malfunction. Alternatively, injection audits with performance metric disparities reported from multiple injectors with doses that share a common variable stored in the dose ID can reveal the potential source of the quality issue. For example, cluster2shows multiple injection audits from different injectors that share a common geographic region where they were administered, suggesting a quality issue such as counterfeiting may have occurred in that location. Cluster3shows multiple injection audits with performance metric disparities that derive from the same drug batch, suggesting a production error for that batch of liquid medicament. Cluster4shows a single distributor with which multiple injection audits were correlated with, suggesting another quality issue such as improper storage or handling during distribution. Thus, one benefit of the injection audit is quality control over multiple aspects of a treatment (e.g., drug, syringe, injector, distributor, etc.) at the point of care.

Additional Embodiments

Features of the injection assembly components described above and illustrated inFIGS. 1A-5can be modified to form additional embodiments configured in accordance with the present technology. The memory and storage devices (e.g., remote databases, remote servers, etc.) are computer-readable media that may store instructions that implement at least portions of the described technology. In various arrangements, the data structures (e.g., memory associated with the injector's internal processor. remote server(s), remote database, etc.) and message structures may be stored or transmitted via a data transmission medium, such as a signal on a communications link. Various communications links may be used, such as the Internet, local area network, a wide area network, etc.

For example, in a further embodiment, the injection assembly components described above and illustrated inFIGS. 1A-5can be assembled in a manner such that all the methods and features described above are achieved in a bolus injection device.FIG. 9is a front view of a bolus injection device300for automated delivery of a liquid medicament to a subject301in accordance with an embodiment of the present technology.FIG. 10is a perspective view of the bolus injection device300ofFIG. 9. The bolus injection device300includes features generally similar to the features of the injection device10described above with respect toFIGS. 1A-5. In particular, the bolus injection device300includes a bolus injector310and a disposable dose module320receivable in the bolus injector310for delivery of the liquid medicament (e.g., visible through a window312) to a subject301. With reference toFIGS. 9 and 10together, and in some embodiments, the bolus injector310is wearable by the subject301, for example, by attaching the device300to the clothing of the subject301, or in another arrangement, by attaching the device300to the skin302of the subject301. In a particular example, the lower surface of the disposable dose module320(e.g., the cassette) can be configured to stick or adhere to the skin302of the subject301, for example, via an adhesive surface322(FIG. 10) or the like. When the disposable dose module320is properly inserted into the bolus injector310, the adhesive surface322of the dose module320may serve as a base for the injection device300.

In some embodiments, the bolus injection device300is capable of delivering large volumes of high viscosity biological drugs. For example, the total delivered volume of medicament can be between about 1 mL and about 20 mL. In certain arrangements, the drive mechanism (not shown) for delivering the liquid medicament in a controlled manner is similar to the drive mechanism110described above and illustrated inFIGS. 1B, 2 and 5. In other embodiments, the rate of injection from a bolus injection device300described herein can be slower than conventional bolus injectors. For example, a maximum rate of delivery can be approximately 100 mL/hr. In certain arrangements, the rate of delivery is controllable by the user. In further embodiments, the rate of delivery can be recorded by the device300from the time the delivery of the liquid medicament begins to the completion of delivery. In yet a further embodiment, the bolus injection device300may be capable of stopping and restarting delivery. For example, the bolus injection device300may stop delivery based on improper flow rate, which can be indicative of a change in the viscosity of the liquid medicament. In additional arrangements, the subject301may stop delivery based on discomfort.

In some embodiments, the bolus injection device300is a programmable electronic device. For example, the electronic drive mechanism can be preprogrammed to deliver the liquid medicament at a specific flow rate. In certain embodiments, the bolus injector310(FIGS. 9 and 10) can become activated when a disposable dose module320(FIG. 10) is properly inserted into the base of the injector310. In another embodiment, the bolus injector310can become activated when an activation button314on the injector is engaged by a user. In a further embodiment, the bolus injection device300alerts the user when the dose module320reaches an appropriate injection temperature by wirelessly sending a notification to a software application running on a user's device or computer. In yet further arrangements, the bolus injection device300can alert the user at the end of delivery, thereby indicating it is safe to remove the device. In another embodiment, the bolus injection device300can automatically upload the data related to the injection wirelessly to a software application.

In some embodiments, the drive path of the drive mechanism of the bolus injector310and the syringe (not shown) in the dose module320are aligned, and the direction of movement may be parallel to a base of the device300. In some embodiments, the dose module320includes a hypodermic needle324and a needle release mechanism (not shown) for inserting the needle324through a needle aperture326disposed in the lower and/or adhesive surface322of the dose module320and into the skin302of the subject301. In another embodiment, the direction of movement of the hypodermic needle324may be perpendicular to the base of the device300. For example, the needle324may be inserted into the recipient's skin302at about a 90 degree angle. In other examples, the needle324may be inserted into the recipient's skin302at an angle less than about 90°. In some arrangements. the needle release may be synchronized to the injector's drive mechanism.

FIG. 1Iis a block diagram illustrating the control system environment900in which aspects of the injector technology may operate in various embodiments. The environment900includes the sensors and controlled components discussed above with respect toFIGS. 1A-5. For example, the environment can include a processor and associated memory retaining instructions for one or more processes. Operative programs can include, for example, a hydrodynamic force program902, a motor control program904, proportional-integral-derivative (PID) controller instructions906, and a rheology program908. As discussed above, these processes can be based on injection data and other feedback data, such as data collected from an RFID reader910, a thermal sensor912, a rotary encoder914and a user interface916. Instructions for operatively injecting a dosage into a patient can include instructions for determining the appropriate force provided by the motor to achieve a user-controlled injection time.

Table 1 describes a plurality of variables that can affect drug delivery force (Ftotal).

EXAMPLES

The viscosity of a drug dose is primarily dependent on the drug concentration and the solution temperature. Therefore, in one example, it is possible to detect changes to the drug concentration based on drug delivery force, given a constant primary containment system and drug solution temperature. Specifically, drug delivery force measurement may be used to detect counterfeit drug doses (e.g. low or no drug concentration). For example, an experiment was performed to determine how the viscosity of a drug dose effects the drug delivery force of the injection. The experiment used a 27G×0.5″ needle, a BD Tuberculin Syringe, 1 mL, Lure Slip Tip with a 57 mm syringe travel, an injection speed of 5 seconds and the GammaGard (1 g/10 ml) biologic. The experiment varied the concentration of the biologic to distilled water at 100 mg/mL (100%), 50 mg/mL (50%), and 0 mg/mL (0%) and was run at room temperature (average 26° C.) and refrigerator temperature (average 5° C.). Five samples for 100 mg/mL, 50 mg/mL, and 0 mg/mL concentrations at both refrigerator and room temperatures were tested, equaling a total of 30 test runs. After parsing the data, and averaging over the5trials, the average and standard deviation for each concentration for both room temperature and refrigerator temperature were obtained.

The bars inFIGS. 12 and 13indicate the average drug delivery force relative to concentration, and the error bars indicate one standard deviation in either direction from the average. The different concentrations vary substantially with the average drug delivery force. Thus, drug viscosity determined by measuring drug delivery force of the drug dose actually administered compared to a standard benchmark performance of the drug dose can be used to detect whether the quality of a drug dose has been compromised.