Sound detection-based infusion time measurement system for drug delivery devices

Abstract

A real-time drug infusion duration measurement system includes an acoustic transducer, a waveform shaping circuit operably coupled to the acoustic transducer, a pulse clamp circuit operably coupled to the waveform shaping circuit, and a timer operably coupled to the pulse clamp circuit. The acoustic transducer detects a first sound associated with the start of drug delivery and a second sound associated with the completion of drug delivery, and further converts the detected first sound and second sound into a first electronic waveform and a second electronic waveform, respectively. The waveform shaping circuit converts the first waveform and the second waveform into a first pulse and a second pulse, respectively. The pulse clamp circuit is activated upon receiving the first pulse and generates a regeneration pulse. The timer starts upon receiving a regeneration pulse via the pulse clamp circuit and stops upon receiving a subsequent regeneration pulse.

Description

Technical Field

[0001] Cross - Reference to Related Applications Priority is claimed to U.S. Provisional Patent Application No. 63 / 168,491, filed Mar. 31, 2021, the entire content of which is incorporated herein by reference.

[0002] The present disclosure generally relates to drug delivery devices, and more particularly to sound - detection - based techniques for determining infusion duration in drug delivery devices.

Background Art

[0003] Drugs can be administered by use of drug delivery devices such as auto - injectors or on - body injectors (also referred to as wearable injectors). Auto - injectors and on - body injectors can be used to assist in automating the injection and delivery or administration process, thereby simplifying the process for certain patient groups or subgroups for whom the use of a syringe / vial combination or pre - filled syringe system is disadvantageous, regardless of whether the reason is a physical or psychological impairment.

[0004] When testing drug delivery autoinjector devices during manufacturing, infusion time is often measured as the time required for the autoinjector to deliver the amount of drug it contains. Patients rely on consistent infusion time to prevent prematurely lifting and / or removing the autoinjector during injection. For example, if the infusion time is longer than expected, the patient may assume the injection is complete and prematurely remove the autoinjector device before the administration is finished. Infusion time can also be a critical process control parameter used in release testing. In this validation process, it is crucial that the detection circuitry represents the actual variation of the measured autoinjector, rather than artifacts of the measurement system. In some cases, high-speed camera-based imaging systems are used for this purpose. These systems can capture images of the entire autoinjector during the infusion process. The images are later reviewed frame by frame by an operator to identify and measure the total infusion time. However, such systems require extensive human interpretation and can be susceptible to human error and / or bias associated with when the injection is actually completed.

[0005] As will be further detailed below, this disclosure describes a system and method for sound detection-based injection time measurement that embodies a favorable alternative to existing systems and methods, and can address one or more of the challenges or needs described herein, as well as provide other benefits and advantages. [Overview of the Initiative] [Means for solving the problem]

[0006] According to a first embodiment, a real-time drug infusion duration measurement system is provided, comprising an acoustic transducer, a waveform shaping circuit operably coupled to the acoustic transducer, a pulse clamp circuit operably coupled to the waveform shaping circuit, and a timer operably coupled to the pulse clamp circuit. The acoustic transducer is adapted to detect a first sound associated with the start of drug delivery and a second sound associated with the completion of drug delivery, and is further adapted to convert the detected first and second sounds into a first electronic waveform and a second electronic waveform, respectively. The waveform shaping circuit is adapted to convert the first and second waveforms into a first pulse and a second pulse, respectively. The pulse clamp circuit is adapted to be activated upon receiving the first pulse and to generate a regenerative pulse. The timer is adapted to start upon receiving a regenerative pulse via the pulse clamp circuit and stop upon receiving a subsequent regenerative pulse.

[0007] In some examples, a waveform shaping circuit may further filter the high-pitch signal generated by the first and second electronic waveforms. Furthermore, in some examples, a pulse clamping circuit may generate a pulse output having a specified width corresponding to a specified duration, preventing the timer from receiving subsequent regenerative pulses until the specified duration has elapsed. In some examples, the specified duration is approximately 300 milliseconds. In some examples, the pulse clamping circuit includes a monostable vibrator that selectively switches between stable and astable modes. In these examples, in astable mode, the pulse clamping circuit does not respond to subsequent inputs until the specified duration has completed. In these and other examples, the specified duration may be longer than the duration of the detected first sound.

[0008] According to a second aspect, a method is provided for measuring an infusion duration in a drug delivery device in real time, comprising detecting a first sound associated with the initiation of the drug delivery device via an acoustic transducer. The detected first sound is converted into a first electronic waveform. A waveform shaping circuit operably coupled to the acoustic transducer converts the first waveform into a first pulse. A pulse clamp circuit operably coupled to the waveform shaping circuit is activated upon receiving the first pulse. The pulse clamp circuit then generates a regenerative pulse, and a timer operably coupled to the pulse clamp circuit is started upon receiving the regenerative pulse. The timer terminates upon receiving a subsequent regenerative pulse.

[0009] The above needs can be met, at least partially, through the provision of a system and method for measuring injection duration based on sound detection, as described in the detailed description below, and especially in conjunction with the drawings. [Brief explanation of the drawing]

[0010] [Figure 1] The following are block diagrams illustrating exemplary real-time sound detection-based injection duration measurement systems according to various embodiments. [Figure 2] An exemplary display showing exemplary waveform acquisition of the exemplary real-time sound detection-based injection duration measurement system of Figure 1, according to various embodiments, is shown. [Figure 3] Figure 2 shows an exemplary display illustrating exemplary subsequent waveform acquisitions of exemplary real-time sound detection-based injection duration measurement systems according to various embodiments. [Figure 4] Figures 1 to 3 show schematic diagrams of exemplary real-time sound detection-based injection duration measurement systems according to various embodiments. [Modes for carrying out the invention]

[0011] Those skilled in the art will understand that the elements in the drawings are depicted for simplification and clarity and are not necessarily proportional to the actual size. For example, the dimensions and / or relative positions of some elements in the drawings may be exaggerated relative to others to help improve the understanding of the various embodiments of the invention. Also, common but well-understood elements that are useful or necessary in commercially viable embodiments are often omitted so as not to interfere too much with the drawings of these various embodiments. Furthermore, it will be recognized that certain actions and / or steps may be described or shown in a particular order of occurrence, but those skilled in the art will understand that such specificity regarding order is not actually necessary. It will also be understood that the terms and expressions used herein have the ordinary technical meanings that those skilled in the art would give to such terms and expressions, as described above, unless a different specific meaning is explained herein.

[0012] Generally speaking, these various embodiments provide real-time methods for sound detection-based infusion duration measurement. In some examples, the system can accurately and reliably measure user-synchronized infusion times using transducers and multiple circuits. Furthermore, the system can measure the infusion time of a sample drug delivery device in real time, enabling automation into a testing workflow used to inspect and confirm that the device is ready for distribution to the patient and / or the healthcare facility responsible for drug administration.

[0013] As shown in Figures 1 and 4, the real-time drug infusion duration measurement system 100 is provided for use with a drug delivery device 101 (e.g., an autoinjector). System 100 comprises a computing system 108 having an acoustic transducer 110, a waveform shaping circuit 120 operably coupled to the acoustic transducer 110, a pulse clamp circuit 130 operably coupled to the waveform shaping circuit 120, and a timer / counter 140 operably coupled to the pulse clamp circuit 130. The computing system 108 may further comprise an interface 150 in the form of a display that provides a visual representation of the received signal and / or the processing applied to the received signal. It should be understood that System 100 may comprise any number of additional components, such as a processor, memory modules, programs, and executable instructions, to assist in its operation. Furthermore, the computing system 108 may comprise any number of mechanical and electromechanical components, sub-components, systems, power supplies, measuring devices, processors, controllers, etc., to operate autonomously or semi-autonomously.

[0014] It should be understood that the auto-injector 101 is merely one example of a suitable drug delivery device that can be measured in real time. The auto-injector 101 may include an actuation mechanism 102 (e.g., a button) that initiates injection and drug delivery to the auto-injector 101. In particular, the auto-injector 101 may include an audible notification function that notifies the user of important changes in operating conditions. For example, the auto-injector 101 may generate an audio signal in the form of a short click sound that lasts for a short duration (e.g., about 5 milliseconds to about 50 milliseconds) and is emitted immediately before the start and end of injection. These audio signals may be generated via any number of mechanical and / or electromechanical components and may be captured by the computing system 108 and used as a trigger to control the counter 140 so that the time measurement system can measure the injection time.

[0015] In some examples, the acoustic transducer 110 is a sensor capable of detecting an audio signal generated by the auto-injector 101 and converting the audio signal into an electronic waveform drawn by line "A" in Figures 2 and 3. More specifically, in Figure 2, a single detected audio signal corresponding to the start of injection is shown on the display 150, and in Figure 3, a first audio signal and a second audio signal corresponding to the start and completion of injection, respectively, are shown on the display 150. The waveform shaping circuit 120, drawn by line "B" in Figures 2 and 3, filters out high-pitch glitches or undesirable frequencies received by the acoustic transducer 110 and converts them into a series of high or low pulse trains (labeled B') that closely follow the (continuously changing) waveform.

[0016] In some examples, the pulse clamp circuit 130 may be in the form of a monostable vibrator that is operated to produce a regenerative pulse output having a width determined by specified design parameters. In particular, the monostable vibrator may switch between stable and astable modes depending on a particular operating pulse. When entering astable mode, the pulse clamp circuit 130 enters a "recovery" phase, which means it does not respond to any subsequent inputs (i.e., it is automatically locked) until a specified duration or time constant has elapsed. After the completion of the time constant, the pulse clamp circuit 130 may resume its sensing function.

[0017] In some methods, the time constant used by the pulse clamp circuit 130 is significantly longer than the received input pulse train generated when the acoustic transducer 110 senses the first audio signal corresponding to the start of the auto-injector 101. For example, the audio signal generated by the auto-injector 101 may have a duration of about 5 to 50 milliseconds, while the time constant used by the pulse clamp circuit 130 may have a duration of about 300 milliseconds to ensure that the pulse clamp circuit 130 responds only to the first arriving pulse and clamps (or blocks) subsequent arriving pulses. This operation ensures that a single pulse is generated from the pulse train of each audio signal. As shown in Figures 2 and 3, the pulse clamp circuit 130 generates a stable signal drawn by line "C" with pulses drawn by "C'" corresponding to its operation.

[0018] The timer 140 receives the regenerative pulse generated by the pulse clamp circuit 130 and uses it as an activation signal to selectively start or stop the duration measurement. Thus, the timer 140 generates a reliable and accurate measurement of the injection time that is automated and unaffected by artifacts caused by the audio waveform signal generated by the acoustic transducer 110.

[0019] In some examples, a method for measuring the injection duration in an auto-injector 101 in real time involves first using an acoustic transducer 110 to detect a first sound associated with the start of the auto-injector. The detected first sound is converted into a first electronic waveform. A waveform shaping circuit 120 converts the first waveform into a first pulse. A pulse clamp circuit 130 is activated upon receiving the first pulse. The pulse clamp circuit 130 then generates a regeneration pulse, and a timer 140 is started upon receiving the regeneration pulse. The timer 140 is stopped upon receiving a subsequent regeneration pulse. It should be understood that the subsequent regeneration pulse may also be generated, converted into a waveform by the acoustic transducer 110, and then converted into a second pulse by the waveform shaping circuit 120.

[0020] Referring to Figure 2, an exemplary waveform acquisition operation of the computing system 108 is shown on the display 150. As drawn by line A, the acoustic transducer receives a pulse train corresponding to a single click of the audio signal generated by the auto-injector 101. In this example, with a time base of 2 milliseconds per division, a single click generated by the audio signal is approximately 8 divisions, or 16 milliseconds long. As described above, the pulse clamp circuit 130 responds only to the first input pulse and does not respond to subsequent pulses generated by the acoustic transducer 110 until their recovery phase is complete.

[0021] Referring to Figure 3, an exemplary waveform acquisition operation of the computing system 108 is shown on the display 150 with a time base of 200 milliseconds per division, allowing visualization of consecutive clicks and the corresponding audio signals generated by the auto-injector 101. In this example, the injection time from the first audio signal to the second audio signal is 6 divisions, which corresponds to approximately 1.2 seconds. Furthermore, in this example, the time constant of the pulse clamp circuit 130 is adjusted to approximately 1.5 divisions, or approximately 300 milliseconds, so that the pulse clamp circuit 130 fully recovers and is ready to sense subsequent audio signals before receiving the second audio signal corresponding to the completion of injection.

[0022] Timer 140 measures the elapsed time between the playback pulses generated by the pulse clamp circuit 130 corresponding to the start and completion of drug delivery. By measuring the time between voice signals, the measurement is synchronized with the same trigger that the user receives for the start and end of injection. As described above, this measurement can be performed in real time, and there is no need for a human to retrospectively interpret a series of captured scenes. The method described herein is cost-effective and less prone to operator errors compared to conventional systems that require an operator to determine when the start and / or completion of drug delivery occurred. Further, by measuring these signals in real time, production efficiency can be grasped, thereby enabling automation and integration with a series of inspections.

[0023] If the timing data is different from the tolerance value or outside the allowable range of values, additional inspections may be required. More specifically, a difference in time may indicate that the autoinjector 101 (and / or autoinjectors manufactured in the same group or lot) deviates from the specifications regarding the expected parameters. Therefore, inspections of the device and components may be required to confirm that all components of the autoinjector 101 (and / or other autoinjectors assembled in the same group or lot) were manufactured and assembled within tolerances. In some examples, the system 100 can perform a "destructive" test, i.e., it should be understood that the actual autoinjector 101 being tested is not shipped to the consumer for use. In such examples, other devices in the same group or lot can be inferred from the test results.

[0024] With this configuration, the system described herein ensures that the autoinjector delivers the drug within an acceptable time frame. The autoinjector can include instructions indicating that the patient should hear a click sound to notify the start and end, and thus the system can provide confirmation that the measured injection time matches the time described in the instructions.

[0025] In the above description, various devices, assemblies, components, subsystems, and methods for use in connection with drug delivery devices have been described. The devices, assemblies, components, subsystems, methods, or drug delivery devices may further include, or be used with, drugs including, but not limited to, the drugs specified below and their generic and biosimilar equivalents. As used herein, the term "drug" can be used interchangeably with other similar terms and is used to refer to any kind of drug or therapeutic material including traditional and non-traditional pharmaceuticals, nutraceuticals, supplements, biological agents, biologically active agents and compositions, macromolecules, biosimilars, biological equivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic drugs. Non-therapeutic injectable materials are also included. The drug can be in liquid form, lyophilized form, or reconstituted from lyophilized form. The following list of exemplary drugs should not be considered exhaustive or limiting.

[0026] The drug will be contained within a reservoir. In some cases, the reservoir is a primary container that is either filled or pre-filled with the drug for treatment. The primary container can be a vial, cartridge, cartridge vial, bag, pre-filled syringe, or any suitable drug container, drug product container, bulk drug container, or other drug-related container.

[0027] In some embodiments, the reservoir of the drug delivery device can be filled with, or the device can be used with, colony stimulating factors such as granulocyte colony stimulating factor (G-CSF). Such G-CSF formulations include, but are not limited to, Neulasta® (pegfilgrastim, PEGylated filgrastim, PEGylated G-CSF, PEGylated hu-Met-G-CSF) and Neupogen® (filgrastim, G-CSF, hu-MetG-CSF).

[0028] In other embodiments, the drug delivery device may contain, or may be used with, an erythropoiesis-stimulating agent (ESA), which may be in liquid or lyophilized form. An ESA is any molecule that stimulates erythropoiesis. In some embodiments, the ESA is an erythropoiesis-stimulating protein. As used herein, “erythropoiesis-stimulating protein” means any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to the receptor and causing dimerization of the receptor. Examples of erythropoiesis-stimulating proteins include erythropoietin and its variants, analogs, or derivatives that bind to and activate the erythropoietin receptor; antibodies that bind to and activate the erythropoietin receptor; or peptides that bind to and activate the erythropoietin receptor. Examples of erythropoiesis-stimulating proteins include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol-epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), and Binocrit® (epoetin a). Examples include, but are not limited to, epoetin alpha (alpha), epoetin alpha Hexal, Abseamed® (epoetin alpha), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alpha, epoetin beta, epoetin iota, epoetin omega, epoetin delta, epoetin zeta, epoetin theta, and epoetin delta, PEGylated erythropoietin, carbamylated erythropoietin, and their molecules, variants, or analogues.

[0029] Certain exemplary proteins, including their fusions, fragments, analogs, variants, or derivatives, are described below: fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies (also known as RANKL-specific antibodies, peptide bodies, etc.), OPGL-specific antibodies, peptide bodies, and related proteins; myostatin-specific peptide bodies, myostatin-binding proteins, peptide bodies, and related proteins; in particular, IL-4 receptor-specific antibodies, peptide bodies, and related proteins that suppress the activity mediated by the binding of IL-4 and / or IL-13 to their receptors; interleukin-1 receptor 1 ("IL1-R1")-specific antibodies, peptide bodies, and related proteins; Ang2-specific antibodies, peptide bodies, and related proteins; NGF-specific antibodies, peptide bodies, and related proteins; CD22-specific antibodies, peptide bodies, and related proteins, particularly human-mouse monoclonal hLL2 Human CD22-specific antibodies, including but not limited to human CD22-specific IgG antibodies such as human CD22-specific fully humanized antibodies such as human CD22-specific fully humanized antibodies for epratuzumab (CAS registry number 501423-23-0), human-mouse monoclonal hLL2 γ-chain disulfide dimers bound to the κ chain; human CD22-specific antibodies, including but not limited to human CD22-specific fully human antibodies such as human CD22-specific fully humanized antibodies for epratuzumab (CAS registry number 501423-23-0); human CD22-specific antibodies, including but not limited to human CD22-specific antibodies; IGF-1 receptor-specific antibodies, peptide bodies, and related proteins, including but not limited to anti-IGF-1R antibodies; B7RP-specific fully human monoclonal antibodies This includes, but is not limited to, IgG2 antibodies, fully human IgG2 monoclonal antibodies that bind to the epitope of the first immunoglobulin-like domain of B7RP-1, and antibodies that suppress the interaction between B7RP-1 and ICOS, the innate receptor for B7RP-1 on activated T cells, such as B-7-related protein 1 specific antibodies, peptide bodies, and related proteins (also referred to as "B7RP-1", B7H2, ICOSL, B7h, and CD275); HuMax IL-15 antibodies and related proteins, such as 146B7, and are not limited to those mentioned above, particularly humanized monoclonal antibodies, such as IL-15 specific antibodies, peptide bodies, and related proteins; and human IFNIFN γ-specific antibodies, peptide bodies, and related proteins, including but not limited to γ-specific antibodies, and fully human anti-IFN γ antibodies; TALL-1 specific antibodies, peptide bodies, and related proteins, as well as other TALL-specific binding proteins; parathyroid hormone ("PTH") specific antibodies, peptide bodies, and related proteins; thrombopotiene receptor ("TPO-R") specific antibodies, peptide bodies, and related proteins; and HGF / SF:cMet axis antibodies such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / dispersion factor (HGF / SF). Hepatocyte growth factor ("HGF")-specific antibodies, peptide bodies, and related proteins, including those targeting (HGF / SF:c-Met); TRAIL-R2-specific antibodies, peptide bodies, and related proteins; Activin A-specific antibodies, peptide bodies, and proteins; TGF-β-specific antibodies, peptide bodies, and related proteins; Amyloid-β protein-specific antibodies, peptide bodies, and related proteins; and those that bind to c-Kit and / or other stem cell factor receptors. c-Kit-specific antibodies, peptide bodies, and related proteins, including but not limited to proteins; OX40L-specific antibodies, peptide bodies, and related proteins, including but not limited to proteins that bind to OX40L and / or other ligands of the OX40 receptor; Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon β-1a), Bexxar® (tositumomab, anti-CD22 monoclonal antibody), Betaseron® (interferon-β), Campath® (aremtuzumab, anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-α4β7)mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), Vectibix® (panitumumab), Xgeva( (Registered Trademark) (Denosumab), Prolia (Registered Trademark) (Denosumab), Enbrel (Registered Trademark) (Etanercept, TNF receptor / Fc fusion protein, TNF blocker), Nplate (Registered Trademark) (Romiplostim), Rilotumumab, Ganitumumab, Conatumumab, Brodalumab, Insulin in Solution, Infergen (Registered Trademark) (Interferon alfacon-1), Natrecor (Registered Trademark) (Nesiritide), Recombinant Human Type B Natriuretic Peptide (hBNP), Kineret (Registered Trademark) (Anakinra), Leukine (Registered Trademark) (Sargamostim, rhuGM-CSF), LymphoCide (Registered Trademark) (Epratuzumab, anti-CD22 mAb), Benlysta (trademark) (lymphostat B, belimumab, anti-BlyS mAb), Metalyse (registered trademark) (tenecteplase, t-PA analog), Mircera (registered trademark) (methoxypolyethylene glycol-epoetin beta), Mylotarg (registered trademark) (gemtuzumab ozogamicin), Raptiva (registered trademark) (efalizumab), Cimzia (registered trademark) (certolizumab pegol, CDP 870), Soliris (trademark) (eculizumab), pexerizumab (anti-complement C5), Numax (registered trademark) (MEDI-524), Lucentis (registered trademark) (ranibizumab), Panorex (registered trademark) (17-1A, edrecolomab), Trabio (registered trademark) (reldelimumab), TheraCimhR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem (registered trademark) (IDM-1), OvaRex (registered trademark) (B43.13), Nuvion (registered trademark) (vizilizumab), cantuzumab meltansine (huC242-DM1), NeoRecormon (registered trademark) (epoetin beta), Neumega (registered trademark) (oprelbequin, human interleukin-11), Orthoclone OKT3 (registered trademark) (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit (registered trademark) (epoetin alfa), Remicade (registered trademark) (infliximab, anti-TNFα monoclonal antibody), Reopro (registered trademark) (absiximab, anti-GP) (Ib / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanorimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon α-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax®, Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor co-protein)), VEGF trap (IgG1 VEGFR1 Ig domain fused with Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimabe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO 148 (golimumab, anti-TNFα mAb), HGS-ETR1 (mapatuzumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (saltumumab), M200 (boroxiximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb, and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin BC mAb MDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adecatumumab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF fibrogen for idiopathic pulmonary fibrosis stage 1 (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2 mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12 mAb (ABT-874), anti-IL12 / IL23 mAb (CNTO 1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO 95), anti-IP10 ulcerative colitis mAb (MDX-1100), BMS-66513, anti-mannose receptor / hCGβ mAb (MDX-1307), anti-mesothelin dsFv-PE38 conjugate (CAT-5001), anti-PD1 mAb (MDX-1106(ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβmAb(GC-1008), TRAIL-2 mAb (HGS-ETR2), TWEAK mAb, VEGFR / Flt-1 mAb, ZP3 mAb (HuMax-ZP3)

[0030] In some embodiments, the drug delivery device may contain, or may be used with, sclerostin antibodies such as romosozumab, brosozumab, or BPS 804 (Novartis), and in other embodiments, monoclonal antibodies (IgG) that bind to human proprotein convertase subtilisin / kexin type 9 (PCSK9). Examples of such PCSK9-specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab). In other embodiments, the drug delivery device may contain, or may be used with, rilotumumab, bixalomer, trevananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the drug delivery device reservoir may be filled with IMLYGIC® (Tarimogene Laharpa Lepbec) or another oncolytic HSV for the treatment of melanoma or other cancers, including but not limited to OncoVEXGALV / CD;OrienX010;G207, 1716;NV1020;NV12023;NV1034; and NV1042, or the device may be used in conjunction with them. In some embodiments, the drug delivery device may contain or be used with endogenous tissue inhibitors of metalloproteinases (TIMPs), such as but not limited to TIMP-3. Antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor, such as erenumab and bispecific antibody molecules targeting the CGRP receptor and other headache targets, but not limited to them, may also be delivered using the drug delivery device of this disclosure. In addition, bispecific T cell activators with extended half-life containing an antibody Fc region (BiTE®), such as BLINCYTO® (blinatumomab), and other BiTE antibodies, not limited to those described herein, can be used in or with the drug delivery device of this disclosure. In some embodiments, the drug delivery device may contain or be used with APJ macromolecule agonists, such as but not limited to Apelin or its analogues.In some embodiments, a therapeutically effective amount of anti-thymocrine interstitial lymphocyte generating factor (TSLP) or TSLP receptor antibody is used in or in conjunction with the drug delivery device of the present disclosure.

[0031] Drug delivery devices, assemblies, components, subsystems, and methods have been described in terms of exemplary embodiments, but are not limited to exemplary embodiments. The detailed descriptions should be interpreted merely as examples and do not describe all possible embodiments of the Disclosure. Many alternative embodiments can be carried out using either the current art or art developed after the filing date of this patent application, but such embodiments are still included within the scope of the claims described herein that define the invention disclosed herein.

[0032] Those skilled in the art will understand that various modifications, changes, and combinations of the above embodiments can be made without departing from the spirit and scope of the invention disclosed herein, and that such modifications, changes, and combinations are to be interpreted as falling within the scope of the concept of the invention.

Claims

1. A real-time drug infusion duration measurement system, An acoustic transducer adapted to detect a first sound associated with the commencement of drug delivery and a second sound associated with the completion of drug delivery, wherein the acoustic transducer is further adapted to convert the detected first sound and the second sound into a first electronic waveform and a second electronic waveform, respectively. A waveform shaping circuit operably coupled to the acoustic transducer, wherein the waveform shaping circuit is adapted to filter the first electronic waveform and the second electronic waveform to convert the first electronic waveform and the second electronic waveform into a first pulse and a second pulse, respectively. A pulse clamp circuit operably coupled to the waveform shaping circuit, wherein the pulse clamp circuit is configured to be activated upon receiving the first pulse and to generate a regenerative pulse, A timer operably coupled to the pulse clamp circuit, wherein the timer is adapted to start upon receiving the regeneration pulse via the pulse clamp circuit and stop upon receiving a subsequent regeneration pulse. Equipped with, A real-time drug infusion duration measurement system wherein the regeneration pulse has a specified width corresponding to a specified duration, and prevents the timer from receiving the subsequent regeneration pulse until the specified duration has elapsed.

2. The real-time drug infusion duration measurement system according to claim 1, wherein the waveform shaping circuit is further adapted to filter out high-pitch signals or undesirable frequencies generated by the first and second electronic waveforms.

3. The real-time drug infusion duration measurement system according to claim 1 or 2, wherein the timer is adapted to measure the elapsed time between the regeneration pulse and the subsequent regeneration pulse, and the measured elapsed time corresponds to the infusion duration.

4. A real-time drug infusion duration measurement system according to any one of claims 1 to 3, wherein the specified duration is 300 milliseconds.

5. The real-time drug infusion duration measurement system according to any one of claims 1 to 4, wherein the pulse clamp circuit comprises a monostable vibrator adapted to selectively switch between a stable mode and an astable mode, and in the astable mode, the pulse clamp circuit does not respond to subsequent inputs until the specified duration is completed.

6. The real-time drug infusion duration measurement system according to any one of claims 1 to 5, wherein the specified duration has a duration longer than the duration of the detected first sound.

7. A method for measuring the infusion duration in a drug delivery device in real time, wherein the method is To detect a first sound related to the initiation of the drug delivery device via an acoustic transducer, Converting the detected first sound into a first electronic waveform, By filtering the first electronic waveform, the first electronic waveform is converted into a first pulse via a waveform shaping circuit operably coupled to the acoustic transducer, Upon receiving the first pulse, the pulse clamp circuit, which is operably coupled to the waveform shaping circuit, is activated. The regeneration pulse is generated via the aforementioned pulse clamp circuit, Upon receiving the aforementioned regeneration pulse, the timer operably coupled to the pulse clamp circuit is started, The timer terminates upon receiving a subsequent regeneration pulse. Includes, A method wherein the regeneration pulse has a specified width corresponding to a specified duration, and prevents the timer from receiving the subsequent regeneration pulse until the specified duration has elapsed.

8. The steps include detecting a second sound related to the completion of administration of the drug delivery device via the acoustic transducer, The steps include converting the detected second sound into a second electronic waveform, The steps include: filtering the second electronic waveform to convert it into a second pulse via the waveform shaping circuit; The steps include generating the subsequent regenerative pulse via the pulse clamp circuit and The method according to claim 7, further comprising:

9. The method according to claim 8, further comprising measuring the elapsed time between the regeneration pulse and the subsequent regeneration pulse, wherein the measured elapsed time corresponds to the injection duration.

10. The method according to any one of claims 7 to 9, wherein the specified duration is 300 milliseconds.

11. The method according to any one of claims 7 to 10, further comprising the step of activating the pulse clamp circuit by selectively switching between a stable mode and an astable mode via a monostable vibrator, wherein in the astable mode, the pulse clamp circuit does not respond to subsequent inputs until the specified duration is completed.

12. The method according to any one of claims 7 to 11, wherein the specified duration has a duration longer than the duration of the detected first sound.

13. The method according to any one of claims 7 to 12, wherein the waveform shaping circuit is further adapted to filter out high-pitch signals or undesirable frequencies generated by the first electronic waveform and / or the second electronic waveform.

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