Drug delivery systems and methods

Abstract

An example drug delivery system and method of the present application includes an injection device for controlling a drug delivery device to deliver a pharmaceutical formulation to a patient, the injection device including a processor and a memory storing instructions executable by the processor. The instructions include instructions to: determine a number of injection steps (h) to be performed within a time window, the time window including a first time window and a second time window, a first number of injection steps (h1) being performed within the first time window and a second number of injection steps (h2) being performed within the second time window; determine a first injection volume for an injection step of the first number of injection steps (h1) using a cumulative delivery volume function; determine a second injection volume for an injection step of the second number of injection steps (h2) using a dose function; and control the drug delivery device such that a first injection volume of fluid is discharged from the drug delivery device during an injection step of the first number of injection steps (h1) and a second injection volume of fluid is discharged from the drug delivery device during an injection step of the second number of injection steps (h2).

Description

[Technical field]

[0001] The present disclosure relates to systems and methods for administering pharmaceutical formulations to a patient.

[0002] The present disclosure is particularly, but not necessarily exclusive to, administration of a pharmaceutical formulation to a patient at a particular test dose for, for example, detecting an adverse reaction during administration of the pharmaceutical formulation, desensitizing the patient to the pharmaceutical formulation, or immuno-testing the patient with the pharmaceutical formulation to determine whether the pharmaceutical formulation is the cause of any adverse reaction in the patient. [Background technology]

[0003] The following discussion of the background art is intended only to facilitate understanding of the present disclosure and is not an admission or acknowledgement that any of the referenced material is or was part of the common general knowledge as of the priority date of this application.

[0004] There are risks associated with administering pharmaceutical preparations, such as intravenous drugs, to patients, particularly those patients who may have drug hypersensitivity reactions to certain intravenous drugs during administration of those particular intravenous drugs.

[0005] Unfortunately, drug hypersensitivity reactions to particular intravenous drugs are typically unpredictable, and in particular the particular dose of a drug that may induce a drug hypersensitivity reaction in a particular patient.

[0006] To reduce the risk that any patient will suffer a fatal reaction to the drug, one way of administering a particular intravenous drug is to give the patient a specific dose (called a test dose) that will cause a submaximal adverse reaction. Upon detection of any submaximal or mild adverse reaction in a particular patient, the process of administering the intravenous drug may be immediately stopped to prevent any further pharmaceutical preparation (drug) from being administered to the patient, preventing the development of a more serious adverse reaction or the eventual death of the patient.

[0007] However, the practice of administering test doses is not routine or recommended, especially for the following reasons:

[0008] Test doses that typically induce submaximal responses are typically on the order of 0.01% or 0.1% of the total therapeutic dose given to the patient, and their preparation is time-consuming and difficult;

[0009] The test dose that will elicit a detectable submaximal response will vary between patients and may be 0.01%, 1%, 10%, or 100% of the therapeutic dose.

[0010] These two reasons, among others, make it difficult or even impossible for clinicians to select the appropriate test dose to carry out the trial, to see whether adverse reactions occur during administration of the full therapeutic dose. In particular, administering a relatively small test dose may not induce or result in detection of adverse reactions in patients. In contrast, a relatively large dose (above a certain threshold specific to each patient) may cause adverse reactions that may lead to life-threatening reactions in patients. This reaction may lead to the death of the patient. Thus, administering the test dose may lead to the life-threatening condition that the provision of the test dose was intended to prevent.

[0011] The process of confirming that a particular drug is responsible for a particular adverse reaction in a particular patient by administering test doses of a particular drug in one or more incremental steps is called drug challenge.

[0012] Another process in which a relatively low dose (test dose) of a drug can be administered to a patient before administering the full dose is called drug desensitization. Drug desensitization is the process of administering a test dose below the threshold that will cause adverse reactions in patients who are hypersensitive or allergic to a particular drug, inducing a state of drug tolerance, allowing the administration of a therapeutic dose while avoiding any adverse reactions or inducing only mild non-fatal reactions.

[0013] Typically, drug desensitization involves first administering a dose (test dose) lower than the actual dose that will induce adverse reactions to the patient. Then, depending on whether the patient's response is favorable to the drug, a larger dose is administered to the patient. Typically, administration is usually performed at intervals of days or weeks, but in some cases, it can be hours, for example, when explicit desensitization is required in emergency situations. The process of drug desensitization continues until it is certain that the actual dose can be safely administered to the patient without adverse reactions. In particular, for intravenous drugs, administration of the drug is performed as a constant infusion rate of a low dose over a certain interval, and then as a constant infusion at a higher rate or higher concentration over an interval until a therapeutic dose is tolerated.

[0014] Unfortunately, due to the difficulty in determining what specific percentage of the total therapeutic dose administered to a patient is the appropriate test dose for that particular patient, the current practice is to administer intravenous drugs via a constant infusion, either for a short period of time ("push") or over a fixed period of time. This has risks, as noted above. Administering a total therapeutic dose of a drug without determining whether the patient is hypersensitive or allergic to that particular may result in administering a lethal drug dose to a particular patient, or cause a serious negative reaction.

[0015] Moreover, currently, any test dose that can be administered to a patient is necessarily administered prior to and separately from the infusion of the therapeutic dose that a particular patient requires. Preparation of separate test doses requires preparation of multiple pharmaceutical formulations for each test dose, and even for the therapeutic dose. This process is cumbersome, and therefore test doses are typically not provided to patients. Instead, therapeutic doses are provided to patients without testing the patient's reaction to the drug. This increases the risk that a particular patient (having a drug hypersensitivity reaction to a particular drug) may suffer a fatal condition while receiving this particular drug. This is especially true because current methods for administering the full therapeutic dose (a constant infusion or "push") provide a relatively large dose at the beginning of the infusion process compared to what is typically required to cause a severe adverse reaction. This does not allow clinicians enough time to detect that a patient receiving an infusion of a pharmaceutical formulation is experiencing a negative (i.e., adverse) reaction to the drug. Summary of the Invention

[0016] According to some examples, a method for delivering an active ingredient to a patient is provided, the method comprising the steps of preparing a pharmaceutical formulation having a specific volume, the pharmaceutical formulation comprising a solvent and a therapeutic dose of the active ingredient, and administering the pharmaceutical formulation to the patient, wherein in a first stage of administration of the pharmaceutical formulation, the pharmaceutical formulation is administered to the patient in a manner such that at least a portion of the therapeutic dose is administered to the patient for detection of a negative reaction in the patient.

[0017] In some instances, the predetermined dose profile is such that the dose rate varies over a predetermined infusion time, hi some instances, the cumulative dose delivered to the patient increases at an exponentially increasing or time-increasing rate over at least a portion of the predetermined infusion time.

[0018] In some examples, the dose profile is such that there is a first period during which the cumulative dose reaches 0.01%-0.1% and a second period during which the cumulative dose reaches 0.1%-1% of the therapeutic dose, and the first period and the second period are selected from the group including at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least the latency of an adverse reaction.

[0019] The processor of the infusion device may control the drug delivery device to deliver the pharmaceutical formulation according to a predetermined profile by controlling an actuator of the infusion device. For example, the actuator may be controlled to drive a plunger or pump of the drug delivery device such that the pharmaceutical formulation is delivered according to a predetermined dose profile. For example, the processor may divide a predetermined infusion time into multiple infusion steps and determine a target flow rate or target output volume for each infusion step such that the predetermined dose profile is achieved when the actuator is controlled according to the target flow rate or target output volume for each infusion step. The target flow rate or target output volume of an infusion step for a predetermined dose profile may be determined by referring to a look-up table stored in the memory. The look-up table may be populated by calculating the target flow rate or target output volume of each infusion step according to the techniques described herein, for example, based on modeling of the predetermined dose profile. In another example, the target flow rate or target output volume of each infusion step may be calculated in real time by the processor.

[0020] Some examples provide an injection device for controlling a drug delivery device to deliver a pharmaceutical formulation to a patient, the injection device including a processor and a memory storing instructions executable by the processor to: determine a number of injection steps (h) to be performed within a time window, the time window including a first time window and a second time window, a first number of injection steps (h_1) will be performed within the first time window and a second number of injection steps (h_2) will be performed within the second time window; determine a first injection volume for an injection step of the first number of injection steps (h_1) using a cumulative delivered volume function; determine a second injection volume for an injection step of the second number of injection steps (h_2) using a dose function; and control the drug delivery device such that a first injection volume of fluid is discharged from the drug delivery device during an injection step of the first number of injection steps (h_1) and a second injection volume of fluid is discharged from the drug delivery device during an injection step of the second number of injection steps (h_2).

[0021] In some instances, the concentration of the active agent in a first injected volume of fluid ejected from the drug delivery device is at least an order of magnitude lower than the concentration of the active agent in a second injected volume of fluid ejected from the drug delivery device.

[0022] In some instances, the rate at which a cumulative dose of an active agent of a pharmaceutical formulation is expelled from a drug delivery device increases over a time window.

[0023] In some examples, the method further includes receiving a plurality of method inputs, at least one of the method inputs being an input of a cumulative delivered volume function and at least one of the method inputs being an input of a dose function.

[0024] In some examples, the instructions further include determining a first target flow rate for an injection step of the first number of injection steps based at least in part on the first injection volume, and determining a second target flow rate for an injection step of the second number of injection steps based at least in part on the second injection volume.

[0025] In some examples, the drug delivery device is controlled such that a first injection volume of fluid is expelled from the drug delivery device at a first target flow rate during an injection step of the first number of injection steps.

[0026] In some examples, the drug delivery device is controlled such that a second injection volume is discharged from the drug delivery device at a second target flow rate during the second injection step.

[0027] In some examples, the instructions further include determining a maximum dose time, the maximum dose time indicating the time when a maximum infusion rate threshold is reached.

[0028] In some examples, the instructions further include determining a transition time, the transition time indicating a point in time separating the first time window and the second time window.

[0029] In some examples, the instructions further include determining that the maximum dose time is within the first time window and controlling the drug delivery device such that a dose rate of fluid ejected from the drug delivery device after the maximum dose time is less than or equal to a maximum injection rate threshold.

[0030] In some examples, the first injection volume is determined by analytically solving the cumulative delivery volume function.

[0031] In some examples, the instructions further include a cumulative delivery volume function defining at least a portion of a dose profile for delivering a therapeutic dose of the pharmaceutical formulation to the patient, the cumulative delivery volume function being such that the cumulative dose delivered to the patient increases exponentially, or at an increasing rate over time, over a period of time between a first time at which 0.1% of the therapeutic dose is delivered to the patient and a second time at which 10% of the therapeutic dose is delivered to the patient.

[0032] In some examples, the cumulative delivered volume function defines at least a portion of a dose profile for delivering a therapeutic dose of the pharmaceutical formulation to a patient, wherein the cumulative delivered volume function is such that there is a first time period during which the cumulative dose reaches 0.01%-0.1% of the therapeutic dose and a second time period during which the cumulative dose reaches 0.1%-1% of the therapeutic dose, and the first time period and the second time period are selected from the group including at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least the latency of an adverse reaction.

[0033] In some examples, an injection device for delivering a pharmaceutical formulation to a patient is provided, the injection device including a processor and a memory storing instructions executable by the processor, the instructions including receiving a concentration input (C ) indicative of a concentration of the pharmaceutical formulation in an active agent chamber of a drug delivery device. p ) and a volume input (V p ) and a dilution chamber volume input (V d), and a time input (i) indicating a time window for delivering the pharmaceutical formulation; determining a number of infusion steps (h) performed within at least a portion of the time window, a first cumulative delivered volume (KV1), where the first cumulative delivered volume (KV1) indicates a cumulative volume of fluid ejected from the drug delivery device between an initial time and an initial infusion step time, where the initial infusion step time corresponds to a start of a target infusion step of the number of infusion steps (h), and a second cumulative delivered volume (KV2), where the second cumulative delivered volume (KV3) indicates a cumulative volume of fluid ejected from the drug delivery device between an initial time and an initial infusion step time, where the initial infusion step time corresponds to a start of a target infusion step of the number of infusion steps (h). 2) is for determining a second cumulative delivery volume (KV2) indicating a cumulative volume of fluid discharged from the drug delivery device between an initial time and a subsequent injection step time, the subsequent injection step time corresponding to the end of the target injection step, and an injection volume, the injection volume being based at least in part on the first cumulative delivery volume (KV1) and the second cumulative delivery volume (KV2) and indicating a volume of fluid discharged from the drug delivery device during the target injection step; and controlling the drug delivery device such that the injection volume of fluid is discharged from the drug delivery device during the target injection step.

[0034] In some examples, the concentration of the active agent in the target injection volume of fluid ejected from the drug delivery device is at least one order of magnitude higher than the concentration of the active agent in a preceding injection volume of fluid ejected from the drug delivery device prior to the target injection volume of fluid.

[0035] In some examples, the instructions further include determining a target flow rate based at least in part on an injection volume of the target injection step, and the plunger is actuated to expel the target injection volume from the drug delivery device at the target flow rate during the target injection step.

[0036] In some examples, the target flow rate of a target infusion step is equal to a preceding target flow rate of a preceding target infusion step that is performed earlier than the target infusion step within the time window.

[0037] In some examples, the target flow rate of a target infusion step is equal to a subsequent target flow rate of a subsequent target infusion step that is performed later than the target infusion step within the time window.

[0038] In some examples, the first cumulative delivered volume and the second cumulative delivered volume are determined by analytically solving a function that delivers a therapeutic dose of the pharmaceutical formulation to a patient according to a predetermined dose profile.

[0039] In some examples, the dose profile is such that the cumulative dose delivered to the patient increases exponentially, or at an increasing rate over time, over the period between a first time at which 0.1% of the therapeutic dose is delivered to the patient and a second time at which 10% of the therapeutic dose is delivered to the patient.

[0040] In some examples, the dose profile is such that there is a first period during which the cumulative dose reaches 0.01%-0.1% of the therapeutic dose and a second period during which the cumulative dose reaches 0.1%-1% of the therapeutic dose, and the first period and the second period are selected from the group including at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least the latency of an adverse reaction.

[0041] In some examples, an injection device is provided for use with a drug delivery device having an active agent chamber for receiving a pharmaceutical formulation, a dilution chamber for receiving a diluent, and a dilution chamber opening through which the diluted pharmaceutical formulation can be discharged for intravenous delivery to a patient, the injection device comprising: a processor; and a memory storing instructions executable by the processor for causing the drug delivery device to deliver the pharmaceutical formulation to the patient according to a dose profile, the dose profile delivering a therapeutic dose of the pharmaceutical formulation to the patient over an injection time, the dose profile including a first stage and a second stage; during the first stage, the concentration of the pharmaceutical formulation in the dilution chamber increases and a dose rate at which the pharmaceutical formulation is delivered to the patient increases until a maximum dose rate for the pharmaceutical formulation is reached; and during the second stage, the concentration of the pharmaceutical formulation in the dilution chamber increases and a flow rate of the diluted pharmaceutical formulation exiting the dilution chamber decreases such that the maximum dose rate is not exceeded.

[0042] In some instances, the dose rate in the second phase is constant.

[0043] In some instances, the dose rate in the second stage is the maximum dose rate of the pharmaceutical formulation.

[0044] In some examples, the dose profile further comprises a third stage in which the concentration of the pharmaceutical formulation in the dilution chamber is constant.

[0045] In some instances, the dose rate in the third stage is constant, for example, it can be the maximum dose rate of the pharmaceutical formulation.

[0046] In some instances, the dose profile is such that the cumulative dose of the pharmaceutical formulation delivered to the patient increases exponentially over time over at least a portion of a first stage of the dose profile.

[0047] In some examples, the first phase of the dose profile includes a first period during which the cumulative dose reaches 0.01%-0.1% of the therapeutic dose and a second period during which the cumulative dose reaches 0.1%-1% of the therapeutic dose, wherein the first period and the second period are selected from the group including at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least the latency of an adverse reaction.

[0048] In some examples, the drug delivery device comprises a container, a first plunger and a second plunger within the container, the first plunger and the second plunger arranged to define an active agent chamber by a space between the first plunger and the second plunger, and to define a dilution chamber by a space between the second plunger and a distal end of the container; the first and second stages of the dose profile correspond to a first time window, during which the first plunger moves towards the second plunger to expel the pharmaceutical formulation from the active agent chamber to the dilution chamber for mixing with the diluent and for output of the diluted pharmaceutical formulation from the dilution chamber opening.

[0049] In some examples, the third stage of the dose profile corresponds to a second time window, during which the first plunger contacts the second plunger, decreasing the volume of the dilution chamber. And a second plunger is moved toward the distal end of the container to expel the pharmaceutical formulation from the dilution chamber through the dilution chamber opening.

[0050] In some examples, a drug delivery device is provided that includes an activator chamber for receiving a pharmaceutical formulation, a diluent chamber for receiving a diluent, and a diluent chamber opening attached to a conduit of a predetermined volume through which the diluted pharmaceutical formulation can be delivered to a patient by intravenous infusion, wherein the infusion device includes a processor and a memory storing priming instructions executable by the processor for priming the drug delivery device and the conduit of a predetermined volume by controlling the drug delivery device to discharge the pharmaceutical formulation from the activator chamber into the diluent chamber and mix with the diluent and flow out of the diluent chamber opening into a tube of a known volume such that the conduit of a predetermined volume is filled with the diluted pharmaceutical formulation in a manner such that the diluted pharmaceutical in the conduit of a predetermined volume has a concentration profile that follows a desired dose profile over a first portion of the intravenous infusion.

[0051] In some instances, the concentration profile is such that the concentration of the diluted pharmaceutical formulation decreases along the length of the conduit for a given volume.

[0052] In some examples, the memory stores dose delivery instructions executable by the processor that cause the drug delivery device to deliver a pharmaceutical formulation to a patient according to a predetermined dose profile that delivers a therapeutic dose of the pharmaceutical formulation to the patient over an infusion period in a manner that facilitates safe detection of an adverse reaction of the patient to the pharmaceutical formulation or desensitization of the patient to the pharmaceutical formulation.

[0053] In some instances, the dose profile is such that over at least a portion of a first stage of the dose profile, the cumulative dose of the pharmaceutical formulation delivered to the patient increases exponentially over time.

[0054] In some examples, the first phase of the dose profile includes a first period during which the cumulative dose reaches 0.01%-0.1% of the therapeutic dose and a second period during which the cumulative dose reaches 0.1%-1% of the therapeutic dose, wherein the first period and the second period are selected from the group including at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least the latency of an adverse reaction.

[0055] In some instances, the infusion rate used to prime the drug delivery device and the conduit for a given volume is greater than the initial infusion rate for a given dose profile.

[0056] In some examples, an injection device for use with a drug delivery device including a syringe with an active agent chamber for receiving a pharmaceutical formulation, a diluent chamber for receiving a diluent, and a diluent chamber opening through which the diluted pharmaceutical formulation can be discharged for intravenous delivery to a patient, the injection device comprising: a processor; and a memory storing dose delivery instructions executable by the processor, the dose delivery instructions for causing the drug delivery device to deliver the pharmaceutical formulation to the patient according to a dose profile that delivers a therapeutic dose of the pharmaceutical formulation to the patient over an injection time in a manner that facilitates safe detection of an adverse reaction of the patient to the pharmaceutical formulation or desensitization of the patient to the pharmaceutical formulation, the dose delivery instructions including instructions for causing the injection device to move a plunger of the syringe toward the diluent chamber opening in multiple injection steps that implement the dose profile, wherein a maximum injection rate is reached after 50% of the injection time has elapsed, and for injection steps that occur after the first 3% of the injection time and before the maximum dose rate is reached, each injection step has a higher dose rate than the preceding injection step.

[0057] In some examples, a drug delivery system includes an injection device as described in any of the preceding claims together with a drug delivery apparatus as described in any of the preceding claims, wherein the injection device is a pump, a peristaltic pump, a vacuum pump or a syringe driver.

[0058] In some embodiments, there is provided a method of delivering a pharmaceutical formulation to a patient, the method comprising: determining a number of injection steps (h) to be performed within a time window, the time window comprising a first time window and a second time window, a first number of injection steps (h1) being performed within the first time window and a second number of injection steps (h2) being performed within the second time window; determining a first injection volume for an injection step of the first number of injection steps (h1) using a cumulative delivered volume function; determining a second injection volume for an injection step of the second number of injection steps (h2) using a dose function; actuating a plunger of a drug delivery device such that a first injection volume of fluid is expelled from the drug delivery device during an injection step of the first number of injection steps (h1); and actuating a plunger such that a second injection volume of fluid is expelled from the drug delivery device during an injection step of the second number of injection steps (h2).

[0059] In some embodiments, the concentration of the active agent in a first injected volume of fluid ejected from the drug delivery device is at least an order of magnitude lower than the concentration of the active agent in a second injected volume of fluid ejected from the drug delivery device.

[0060] In some embodiments, the rate at which the cumulative dose of the active agent of the pharmaceutical formulation is expelled from the drug delivery device increases over the time window.

[0061] In some embodiments, the method further includes receiving a plurality of method inputs, at least one of the method inputs being an input of a cumulative delivered volume function and at least one of the method inputs being an input of a dose function.

[0062] In some embodiments, the method further includes determining a first target flow rate for an injection step of the first number of injection steps based at least in part on the first injection volume, and determining a second target flow rate for an injection step of the second number of injection steps based at least in part on the second injection volume.

[0063] In some embodiments, the plunger is actuated such that a first injection volume of fluid is expelled from the medication delivery device at a first target flow rate during an injection step of the first number of injection steps.

[0064] In some embodiments, the plunger is actuated during the second injection step such that a second injection volume is expelled from the drug delivery device at a second target flow rate.

[0065] In some embodiments, the method further includes determining a maximum dose time, the maximum dose time indicating the time at which a maximum infusion rate threshold is reached.

[0066] In some embodiments, the method further comprises determining a transition time, the transition time indicating a point in time separating the first time window and the second time window.

[0067] In some embodiments, the method further includes determining that the maximum dose time is within the first time window and actuating the plunger such that a dose rate of fluid ejected from the drug delivery device after the maximum dose time is less than or equal to a maximum injection rate threshold.

[0068] In some embodiments, a pharmaceutical formulation is provided to a patient, and the method includes receiving a concentration input (C ) indicating a concentration of the pharmaceutical formulation in an active agent chamber of the drug delivery device. p ) and a volume input (V p ) and a dilution chamber volume input (V dreceiving a time input (i) indicating a time window for delivering the pharmaceutical formulation, the time window including a first time window and a second time window; determining a number of injection steps (h) to be performed within the time window, wherein a first number of injection steps (h1) are performed within the first time window and a second number of injection steps (h2) are performed within the second time window; determining a first cumulative delivered volume (KV1) for an injection step of the first number of injection steps (h1), the first cumulative delivered volume (KV1) indicating a cumulative volume of fluid ejected from the drug delivery device between an initial time and an initial injection step time, the initial injection step time corresponding to a start of an injection step of the first number of injection steps (h1). determining a second cumulative delivered volume (KV2), the second cumulative delivered volume (KV2) indicating a cumulative volume of fluid ejected from the drug delivery device between an initial time and a subsequent injection step time, the subsequent injection step time corresponding to an end of an injection step of the first number of injection steps (h1); determining a first injection volume based at least in part on the first cumulative delivered volume (KV1) and the second cumulative delivered volume (KV2), the first injection volume indicating a volume of fluid ejected from the drug delivery device during an injection step of the first number of injection steps (h1); determining a first pharmaceutical dose (Dose) for an injection step of the second number of injection steps (h2). c1 determining a first pharmaceutical dose, c1 ) indicates a cumulative pharmaceutical formulation dose output by the drug delivery device between the initial time and an initial infusion dose time, the initial infusion dose time corresponding to a start of an infusion step of a second number of infusion steps (h2); c2 determining a second pharmaceutical dose (Dose c2 ) indicates a cumulative pharmaceutical formulation dose output by the drug delivery device between the initial time and the subsequent injection dose time, the subsequent injection dose time corresponding to an end of an injection step of the second number of injection steps (h2); c1 ) and the second pharmaceutical dose (Dose c2determining a dose target based at least in part on the dose target and the concentration estimate, where the dose target indicates a pharmaceutical formulation dose output by the drug delivery device during an injection step of the second number of injection steps (h2); determining a concentration estimate, where the concentration estimate indicates a pharmaceutical formulation concentration of the fluid during an injection step of the second number of injection steps (h2); determining a second injection volume based at least in part on the dose target and the concentration estimate, where the second injection volume indicates a volume of fluid ejected from the drug delivery device during an injection step of the second number of injection steps (h2); actuating a plunger of the drug delivery device such that a first injection volume of fluid is ejected from the drug delivery device during an injection step of the first number of injection steps (h1); and actuating the plunger such that a second injection volume of fluid is ejected from the drug delivery device during an injection step of the second number of injection steps (h2).

[0069] In some embodiments, the method further includes determining a first target flow rate based at least in part on the first injection volume; and determining a second target flow rate based at least in part on the second injection volume; wherein the plunger is actuated to eject the first injection volume of fluid from the drug delivery device at the first target flow rate during an injection step of the first number of injection steps (h1), and the plunger is actuated to eject a second injection volume of fluid from the drug delivery device at the second target flow rate during an injection step of the second number of injection steps (h2).

[0070] In some embodiments, determining the number of injection steps (h) comprises: g×i where g is the number of injection steps performed per minute and i is the time input.

[0071] In some embodiments, determining the number of injection steps (h) includes receiving the number of injection steps (h) as an injection step input.

[0072] In some embodiments, the first cumulative delivered volume (KV1) is determined by the initial injection step time of an injection step of the first number of injection steps (h1), the time input (i), the dilution chamber volume input (V d ), volume input (V p ), and is determined at least in part based on the principal branch of the Lambert W function (W0).

[0073] In some embodiments, determining the first cumulative delivered volume (KV1) comprises:

number

[0074] In some embodiments, the second cumulative delivered volume (KV2) is determined by the subsequent injection step time of an injection step of the second number of injection steps (h2), the time input (i), the dilution chamber volume input (V d ), volume input (V p ), and is determined at least in part based on the principal branch of the Lambert W function (W0).

[0075] In some embodiments, determining the second cumulative delivered volume (KV2) comprises:

number

[0076] In some embodiments, determining the first infusion volume includes determining a difference between the second cumulative delivered volume (KV2) and the first cumulative delivered volume (KV1).

[0077] In some embodiments, an injection step of the first number of injection steps (h1) is performed for a first injection step duration.

[0078] In some embodiments, determining the first target flow rate includes dividing the first infusion volume by the first infusion step duration.

[0079] In some embodiments, the first injection step duration is different from the injection step duration of another injection step of the first number of injection steps (h1).

[0080] In some embodiments, the first injection step duration is shorter than the injection step duration of another injection step of the first number of injection steps (h1), and an initial injection step time of an injection step of the first number of injection steps (h1) is closer to an initial time than an initial injection step time of another injection step of the first number of injection steps (h1).

[0081] In some embodiments, the first pharmaceutical dose c1 ) is the concentration input (C p ), and is determined at least in part based on the value of the flow rate function at the time of the initial infusion dose.

[0082] In some embodiments, the first pharmaceutical dose c1 ) is determined by

number

number

[0083] In some embodiments, the second pharmaceutical dose c2 ) is the concentration input (C p ), and the value of the flow rate function at the subsequent infusion dose time.

[0084] In some embodiments, the second pharmaceutical dose c2 ) is determined by

number

number

[0085] In some embodiments, determining the dose target includes determining the second pharmaceutical dose. c2 ) and the first pharmaceutical dose (Dose c1)

[0086] In some embodiments, determining the concentration estimate comprises:

number

[0087] In some embodiments, determining the second infusion volume includes dividing the dose target by the concentration estimate.

[0088] In some embodiments, an injection step of the second number of injection steps (h2) is performed for a second injection step duration.

[0089] In some embodiments, the second injection step duration is different from the injection step duration of another injection step of the second number of injection steps (h2).

[0090] In some embodiments, the second injection step duration is shorter than the injection step duration of another injection step of the second number of injection steps (h2), and an initial injection step time of an injection step of the second number of injection steps (h2) is closer to an initial time than an initial injection step time of another injection step of the second number of injection steps (h2).

[0091] In some embodiments, determining the second target flow rate includes dividing the second infusion volume by the second infusion step duration.

[0092] In some embodiments, the method further comprises determining a transition time, the transition time indicating a point in time separating the first time window and the second time window.

[0093] In some embodiments, the method further comprises a transition injection step (h t ), the transition injection step (h t a transition injection volume indicating the volume of fluid expelled from the medication delivery device during a first portion of the Transition injection step (h t determining a second transition infusion volume indicative of a volume of fluid ejected from the drug delivery device during a second portion of the first transition infusion volume; a transition step infusion volume by summing the first transition infusion volume and the second transition infusion volume; and a transition target flow rate based at least in part on the transition step infusion volume.

[0094] In some embodiments, the transition injection step (h t ) is performed for the transition injection step duration including the transition time.

[0095] In some embodiments, the method further comprises a transition injection step (h t ), and actuating the plunger such that the fluid transfer step volume is expelled from the medication delivery device.

[0096] In some embodiments, the transition injection step (h t ) is between an injection step of the first number of injection steps (h1) and an injection step of the second number of injection steps (h2).

[0097] In some embodiments, the method further includes determining a maximum dose time indicating the time when a maximum injection rate threshold is reached, determining that the maximum dose time is within a first time window, determining a cumulative volume of fluid delivered between the initial time and the maximum dose time, and actuating the plunger such that the dose rate of the injection is less than or equal to the maximum injection rate threshold over the remainder of the first time window and over a second time window.

[0098] In some embodiments, the rate at which the cumulative dose of the active agent of the pharmaceutical formulation is expelled from the drug delivery device increases over the time window.

[0099] In some embodiments, a method of delivering a pharmaceutical formulation to a patient includes the step of: p ) and a volume input (V p ) and a dilution chamber volume input (V d receiving a time input (i) indicating a time window for delivering the pharmaceutical formulation; a number of infusion steps (h) to be performed within at least a portion of the time window; a first cumulative delivered volume (KV1) indicating a cumulative volume of fluid expelled from the drug delivery device between an initial time and an initial infusion step time, the initial infusion step time corresponding to a start of a target infusion step of the number of infusion steps (h); and a second cumulative delivered volume (KV2) indicating a cumulative volume of fluid expelled from the drug delivery device between an initial time and an initial infusion step time, the initial infusion step time corresponding to a start of a target infusion step of the number of infusion steps (h). The method includes determining an injection volume, which is based at least in part on the first cumulative delivery volume (KV1) and the second cumulative delivery volume (KV2), and indicates a cumulative volume of fluid ejected from the drug delivery device between the first cumulative delivery volume (KV1) and the second cumulative delivery volume (KV2), where the subsequent injection step time corresponds to the end of the target injection step; and an injection volume, which is based at least in part on the first cumulative delivery volume (KV1) and the second cumulative delivery volume (KV2), and indicates a volume of fluid ejected from the drug delivery device during the target injection step; and actuating a plunger of the drug delivery device such that the injection volume of fluid is ejected from the drug delivery device during the target injection step.

[0100] In some embodiments, the concentration of the active agent in the target injection volume of fluid ejected from the drug delivery device is at least one order of magnitude higher than the concentration of the active agent in a preceding injection volume of fluid ejected from the drug delivery device prior to the target injection volume of fluid.

[0101] In some embodiments, the method further includes determining a target flow rate based at least in part on an injection volume of the target injection step, and the plunger is actuated to expel the target injection volume from the drug delivery device at the target flow rate during the target injection step.

[0102] In some embodiments, the target flow rate of a target infusion step is equal to a preceding target flow rate of a preceding target infusion step that is performed earlier than the target infusion step within the time window.

[0103] In some embodiments, the target flow rate of a target infusion step is equal to the subsequent target flow rate of a subsequent target infusion step that is performed later than the target infusion step within the time window.

[0104] In some embodiments, determining the first cumulative delivered volume (KV1) comprises:

number

[0105] In some embodiments, determining the second cumulative delivered volume (KV2) comprises:

number

[0106] In some embodiments, determining the first cumulative delivered volume (KV1) comprises:

number

[0107] In some embodiments, determining the second cumulative delivered volume (KV2) comprises:

number

[0108] In some embodiments, the volume parameter (β) is

number

[0109] In some embodiments, the method comprises:

number

[0110] In some embodiments, determining the injection volume includes determining a difference between the second cumulative delivered volume (KV2) and the first cumulative delivered volume (KV1).

[0111] In some embodiments, determining the target flow rate comprises dividing the infusion volume by the infusion step duration of the target infusion step.

[0112] In some embodiments, the rate at which the cumulative dose of the active agent of the pharmaceutical formulation is expelled from the drug delivery device increases over the time window.

[0113] In some embodiments, there is provided a method of delivering a pharmaceutical formulation to a patient, the method comprising: determining a number of injection steps (h) to be performed within a time window, the time window comprising a first time window and a second time window, a first number of injection steps (h1) being performed within the first time window and a second number of injection steps (h2) being performed within the second time window; determining a first injection volume for an injection step of the first number of injection steps (h1) using a first cumulative delivery volume function; determining a second injection volume for an injection step of the second number of injection steps (h2) using a second cumulative delivery function; actuating a plunger of a drug delivery device such that a first injection volume of fluid is expelled from the drug delivery device during an injection step of the first number of injection steps (h1); and actuating a plunger such that a second injection volume of fluid is expelled from the drug delivery device during an injection step of the second number of injection steps (h2).

[0114] In some embodiments, the concentration of the active agent in a first injected volume of fluid ejected from the drug delivery device is at least an order of magnitude lower than the concentration of the active agent in a second injected volume of fluid ejected from the drug delivery device.

[0115] In some embodiments, the rate at which the cumulative dose of the active agent of the pharmaceutical formulation is expelled from the drug delivery device increases over the time window.

[0116] In some embodiments, the method further includes receiving a plurality of method inputs, at least one of the method inputs being an input for a first cumulative delivery volume function and at least one of the method inputs being an input for a second cumulative delivery volume function.

[0117] In some embodiments, the method further includes determining a first target flow rate for an injection step of the first number of injection steps based at least in part on the first injection volume; and determining a second target flow rate for an injection step of the second number of injection steps based at least in part on the second injection volume.

[0118] In some embodiments, the plunger is actuated such that a first injection volume of fluid is expelled from the medication delivery device at a first target flow rate during an injection step of the first number of injection steps.

[0119] In some embodiments, the plunger is actuated during the second injection step such that a second injection volume is expelled from the drug delivery device at a second target flow rate.

[0120] In some embodiments, the method further includes determining a maximum dose time, the maximum dose time indicating the dose time point at which a maximum infusion rate threshold is reached.

[0121] In some embodiments, the method further comprises determining a transition time, the transition time indicating a point in time separating the first time window and the second time window.

[0122] In some embodiments, the method further includes determining that the maximum dose time is within the first time window; and actuating the plunger such that a dose rate of fluid ejected from the drug delivery device after the maximum dose time is less than or equal to a maximum injection rate threshold.

[0123] In some embodiments, a method of delivering a pharmaceutical formulation to a patient includes the step of: p ) and a volume input (V p ) and a dilution chamber volume input (V d), and a time input (i) indicating a time window for delivering the pharmaceutical formulation, the time window including a first time window and a second time window; determining a number of injection steps (h) performed within the time window, wherein a first number of injection steps (h1) are performed within the first time window and a second number of injection steps (h2) are performed within the second time window; determining a third cumulative delivered volume (KV3) for an injection step of the second number of injection steps (h2), the third cumulative delivered volume (KV3) indicating a cumulative volume of fluid ejected from the drug delivery device between an initial time and a second initial injection step time, the second initial injection step time corresponding to a start of an injection step of the second number of injection steps (h2); determining a fourth cumulative delivered volume (KV determining a fourth cumulative delivery volume (KV4) indicating a cumulative volume of fluid ejected from the drug delivery device between an initial time and a second subsequent injection step time, the second subsequent injection step time corresponding to an end of an injection step of the second number of injection steps (h2); determining a second injection volume based at least in part on the third cumulative delivery volume (KV3) and the fourth cumulative delivery volume (KV4), the second injection volume indicating a volume of fluid ejected from the drug delivery device during an injection step of the second number of injection steps (h2); and actuating a plunger of the drug delivery device such that the second injection volume of fluid is ejected from the drug delivery device during an injection step of the second number of injection steps (h2).

[0124] In some embodiments, the method further includes determining a second target flow rate based at least in part on the second injection volume, and the plunger is actuated during the second injection step such that the second injection volume is expelled from the drug delivery device at the second target flow rate.

[0125] In some embodiments, the rate at which the cumulative dose of the active agent of the pharmaceutical formulation is expelled from the drug delivery device increases over the time window.

[0126] In some examples, a non-transitory machine-readable storage medium is provided that stores instructions executable by a processor to perform any of the above methods or instructions for any of the functions described above with respect to the infusion device and drug delivery apparatus. Any one or more features of any of the examples, methods, devices and systems described herein may be combined unless expressly stated or logically apparent.

[0127] Further features of the present disclosure will be more fully described in the following description of some non-limiting embodiments thereof. This description is included solely for the purpose of illustrating the present disclosure. As stated above, it should not be understood as a limitation on the broad overview, disclosure, or description of the present disclosure. This description is made with reference to the attached drawings. [Brief description of the drawings]

[0128] [Figure 1a] FIG. 1 is a perspective view of a particular configuration of a drug delivery device for delivery of a pharmaceutical formulation according to a first embodiment of the present disclosure. [Figure 1b] 1 is a block diagram of a particular configuration of a drug delivery device for delivery of a pharmaceutical formulation, according to some embodiments. [Diagram 2] 1A-1D are perspective views of particular configurations of devices for delivery of pharmaceutical formulations (drug delivery devices), according to some embodiments. [Fig.3-11e] It has been deleted. Therefore, the next figure after Figure 2 is Figure 12a. [Figure 12a] 1 depicts a flow chart illustrating a method for delivering a therapeutic dose of a drug, sometimes referred to as the Tansy method, according to some embodiments. [Figure 12b] 1 depicts a flowchart illustrating the Tansy method, including a process for programming an infusion pump, according to some embodiments. [Figure 13a] 1 depicts a flow chart illustrating a method for delivering a therapeutic dose of a drug, sometimes referred to as the Sadleir method, according to some embodiments. [Figure 13b]1 depicts a flowchart illustrating the Sadleir technique, including a Sadleir function configured to allow calculation of injection rates and delivered volumes at various times during the Sadleir technique, according to some embodiments. [Figure 13c] 13 depicts a flowchart illustrating a method for approximating the infusion rate and volume calculated in FIG. 13b using an infusion pump, according to some embodiments. [Figure 13d] For example, the use of the flowchart of Figure 13b is illustrated when the Sadleir method is used for each interval n in the first 0.04 minutes of a 30 minute infusion of a 50 mL pharmaceutical formulation, where each interval n is in the first 0.04 minutes of the infusion. The following values ​​are illustrated: the target dose delivered (modified Tansy function dose), the flow rate (infusion rate) determined by the Sadleir function, the concentration in the dilution chamber, and the % dose delivered in each interval n. [Figure 14a] FIG. 14a (logarithmic y-axis scale) illustrates the rate of drug administration comparing the constant infusion method with the Tansy method over a 30 minute infusion duration. [Figure 14b] 14a (logarithmic y-axis scale) and 14b (linear y-axis scale) illustrate the rate of drug administration comparing the constant infusion method with the Tansy method over a 30 minute infusion duration. [Figure 15a] FIG. 15a (logarithmic y-axis scale) illustrates the difference in cumulative dose administered at each stage of a 30 minute infusion with an infusion method according to a first embodiment of the present disclosure (referred to as the Tansy method) versus a constant infusion method. [Figure 15b] FIG. 15b (linear y-axis scale) illustrates the difference in cumulative dose administered at each stage of a 30 minute infusion with an infusion method according to a first embodiment of the present disclosure (referred to as the Tansy method) versus a constant infusion method. [Figure 16] The infusion time and cumulative percentage of total dose delivered to the patient for a 30 minute infusion of 50 mL of pharmaceutical formulation using the constant infusion, Tansy, and Sadleir methods are shown in the table (τ=1200 / min using the same initial pharmaceutical formulation concentration and 10 ml dilution chamber). [Figure 17a] FIG. 17a (calculating the Sadleir function using an integral interval of 60 per minute, i.e., τ=60) illustrates the variation in flow rate for different cases of the second embodiment of the present disclosure, each of which differs as a result of the selection of different start interval rates (30 minute injection duration, 10 ml dilution chamber, 50 ml pharmaceutical formulation volume). [Figure 17b] 17a and 17b illustrate the difference in minimum flow rate for the Sadleir function as a result of different starting interval velocities in FIG. [Figure 17c] FIG. 17C (calculating the Sadleir function using an integral interval of 1200 per minute, i.e., τ=1200) illustrates the variation in flow rate for different cases of the second embodiment of the present disclosure, each of which differs as a result of the selection of different start interval rates (30 minute injection duration, 10 ml dilution chamber, 50 ml pharmaceutical formulation volume). [Figure 17d] 17c illustrates the difference in minimum flow rate for the Sadleir function as a result of different starting interval velocities. [Figure 17e] A graph is shown plotting the minimum flow rate values ​​for each of the Sadleir method cases (shown in FIG. 17d) that differ from each other in start-up interval speed. [Figure 18] Illustrates the volume of drug administered during the first minute of the Sadleir method with different precision calculations (number of integral intervals per minute, or tau), with or without the volume of the start interval. [Figure 19a] FIG. 19a (linear y-axis scale) illustrates the rate of infusion of pharmaceutical formulation liquid from the dilution chamber into the patient when using the Tansy method for a 50 ml injection over various exemplary injection durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes). [Figure 19b]FIG. 19b (logarithmic y-axis scale) illustrates the rate of infusion of pharmaceutical formulation liquid from the dilution chamber into the patient when using the Tansy method for a 50 ml injection over various exemplary injection durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes). [Fig. 20a-21c] Since it has been deleted, the next figure after Figure 19b is Figure 22a. [Figure 22a] 1 is a table of calculated instantaneous rate, cumulative volume delivered, and cumulative dose delivered for the Tansy and Sadleir methods in 45 second intervals over a 30 minute infusion of 50 mL of pharmaceutical formulation. In this particular example, the Sadleir function values ​​were calculated using an integration interval of 50 millisecond duration (τ=1200 / min) and a dilution chamber of 10 mL volume. [Figure 22b] FIG. 22b illustrates the difference in injection or infusion rate (ml / min) of pharmaceutical formulation liquid when using a first (Tansy) embodiment of the present disclosure for a 50 ml infusion over 30 minutes, with FIG. 22b illustrating the first 15 minutes of the 30 minute infusion. [Figure 22c] 1 illustrates the difference in injection or infusion rate (ml / min) of pharmaceutical formulation liquid when using a second (Sadleir with 10 ml dilution chamber) embodiment of the present disclosure for a 50 ml infusion over 30 minutes. [Fig. 22d] FIG. 22c illustrates the difference in cumulative volume injected from a pharmaceutical formulation liquid syringe or container over the course of a 30 minute injection when using either the presently disclosed or second (Sadleir with 10 ml dilution chamber) embodiment for a 50 ml injection, with FIG. 22d illustrating the first 15 minutes of the 30 minute injection. [Figure 22e] 1 illustrates the difference in cumulative volume injected from a pharmaceutical formulation liquid syringe or container over the course of a 30 minute injection when using a second (Sadleir with 10 ml dilution chamber) embodiment of the present disclosure for a 50 ml injection. [Fig. 23a-29] It has been deleted. [Diagram 30] 1 shows a side view of a drug delivery device according to some embodiments. [Diagram 31]Illustrates a process for filling a drug delivery device according to some embodiments. [Diagram 32] Shows a side perspective view of a drug delivery device filled with an active agent and a diluent according to some embodiments, as shown in FIG. 30. [Diagram 33] Is a perspective view of a drug delivery device shown in FIG. 32 during attachment to an infusion driver in the form of a syringe driver according to some embodiments. [Figure 34a] Illustrates a process for mixing an active agent and a diluent in a dilution chamber according to some embodiments. [Figure 34a(i)] Shows a block diagram of a drug delivery system of FIGS. 30 - 34a according to some embodiments. [Figure 34b] Illustrates a method of operating a drug delivery device according to some embodiments. [Fig. 34c] Is a block diagram for calculating a method of delivering a therapeutic dose of a drug, which may be referred to as the Diocles infusion protocol or the Diocles method. The Diocles method is used during operation of the drug delivery device depicted in FIGS. 30 - 41 while attached to an infusion device in the form of a syringe driver. [Fig. 34d] Is a flowchart illustrating a method of approximating an infusion rate and volume calculated in FIG. 34c using an infusion pump according to some embodiments. [Figure 35-41] Deleted. [Diagram 42] Shows a side view of a drug delivery device filled with an active agent and a diluent according to some embodiments. [Diagram 43] Shows a side view of a drug delivery device filled with an active agent and a diluent, where the active agent is supplied remotely from a syringe driver, according to some embodiments. [Figure 43b] Illustrates a method of operating a drug delivery device depicted in FIG. 43a according to some embodiments. [Figure 43c]A block diagram illustrating a method of delivering a therapeutic dose of a drug according to some embodiments. This method may be for calculating the Sadleir infusion protocol used during the operation of the dilution chamber depicted in FIG. 43a. [Fig. 43d] A flowchart illustrating a method of approximating the infusion rate and volume calculated in FIG. 43c using an infusion pump according to some embodiments. [Figure 44-48] Deleted. [Figure 49-1] a) - d) illustrate the results of exemplary infusions performed according to the Diocles method. [Figure 49-2] e) - h) illustrate the results of exemplary infusions performed according to the Diocles method. [Figure 50-54] Deleted. [Figure 55] A process flow diagram of method 5500 for delivering a pharmaceutical formulation to a patient according to some embodiments. [Figure 56] A process flow diagram of method 5600 for delivering a pharmaceutical formulation to a patient according to some embodiments. [Figure 57] A process flow diagram of method 5700 for delivering a pharmaceutical formulation to a patient according to some embodiments. [Figure 58] Charts of infusion rate over infusion, cumulative volume delivered over infusion, concentration of active agent in the dilution chamber of a drug delivery device over infusion, and drug administration rate of an exemplary infusion of vancomycin are shown according to some embodiments. [Figure 59] Charts of infusion rate over infusion, cumulative volume delivered over infusion, concentration of active agent in the dilution chamber of a drug delivery device over infusion, and drug administration rate of an exemplary infusion are shown according to some embodiments. [Figure 60]1 shows a chart of infusion rate over an infusion, a chart of cumulative volume delivered over an infusion, a chart of concentration of active agent in a dilution chamber of a drug delivery device over an infusion, and drug administration rates for an exemplary infusion, according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0129] It should be noted that the figures are only schematic and that the location and arrangement of components may vary according to the particular configuration of the embodiment of the disclosure and the particular application of the disclosure.

[0130] The methods and systems according to the present embodiments of the present disclosure allow for the administration of a therapeutic dose of a particular drug together with a test dose in a single injection process. These methods and systems are particularly useful because they do not require multiple test doses for a given patient prior to the injection of the therapeutic dose. Instead, the test dose is given during the injection of the full therapeutic dose, due to the test dose being a part of the therapeutic dose. Providing a test dose without using the embodiments of the present embodiments of the present disclosure requires (1) preparing multiple pharmaceutical formulations (including the test dose) with different concentrations, and (2) injecting the multiple pharmaceutical formulations with each test dose for each of the pharmaceutical formulations into the patient. This process of injecting multiple pharmaceutical formulations with test doses (pre-injection of a therapeutic dose) can be cumbersome and time-consuming, and may not be suitable in situations where, for example, the injection of a therapeutic dose must be performed immediately to sustain the life of the patient.

[0131] These methods and systems according to the present disclosure are particularly useful because they increase the likelihood that an adverse reaction will be recognized before the patient is administered a particular dose (a particular amount of drug) that will induce a more severe negative reaction (see Figures 15a and 15b). Thus, these methods and systems are adapted to safely provide a therapeutic dose to a patient when the particular dose or doses that will cause a submaximal reaction in the patient are not known.

[0132] The present embodiment of the disclosure provides a method and system for providing a test dose of a drug to a particular patient who may suffer from a hypersensitivity reaction (hypersensitivity, or allergic or other adverse reaction), preferably with a short latency period.

[0133] It will be understood that the term "active agent" used in the description may correspond to or may be referred to as an "active ingredient" or "drug". That is, throughout this disclosure, the terms "active ingredient", "active agent", and "drug" are used to describe the active agent that will be administered to the patient. In some embodiments, a pharmaceutical formulation may be delivered to the patient. The pharmaceutical formulation may include an active agent. The pharmaceutical formulation may also include one or more other ingredients. For example, the pharmaceutical formulation may include a solvent. That is, in some embodiments, the pharmaceutical formulation may include an active agent and a solvent. The pharmaceutical formulation may include a particular concentration of the active agent. This may be referred to as the active agent concentration. The pharmaceutical formulation may be a solution. It will be understood that the term "drug" used in the description may correspond to the active agent of the "pharmaceutical formulation".

[0134] The method and system according to the first embodiment of the present disclosure uses a specific function (Tansy function) for sequentially delivering (infusing) a wide range of test doses of a pharmaceutical formulation to a patient, the doses increasing during the duration of the infusion. This has the purpose of overcoming the problem of sensitivity to a particular drug in a patient, when the threshold of this sensitivity is not known before the administration of the particular drug. In some embodiments, a full therapeutic dose is provided during the total duration of the infusion, using a portion of this therapeutic dose as one or more test doses. In this way, for example, by providing a test dose contained in a particular pharmaceutical formulation in a first stage, it is not necessary to interrupt the administration of the therapeutic dose, and then continue to infuse the pharmaceutical formulation to the patient after confirming that the patient will not have a negative reaction to the drug. Thus, according to the first embodiment of the present disclosure, only a single pharmaceutical formulation is needed to provide a full therapeutic dose, including any test doses.

[0135] The method and system according to the second embodiment of the present disclosure also allows for a single pharmaceutical formulation to be administered to the patient to provide a full therapeutic dose, including a test dose. However, as described below, the method and system according to the second embodiment of the present disclosure allows for increased accuracy with which the pharmaceutical formulation is provided to the patient. This is done by allowing an increase in the initial flow rate of the pharmaceutical formulation driven by the infusion driver 14, when compared to the flow rate of the pharmaceutical formulation when using the method and system according to the first embodiment of the present disclosure (Tansy method). In some embodiments, the infusion driver 14 can be a syringe driver, or a peristaltic pump, or a similar drug infusion pump. In some embodiments, the infusion driver is in the form of an infusion device. In some embodiments, the infusion device comprises an infusion driver.

[0136] Because it is known that the infusion driver 14 does not accurately deliver the pharmaceutical formulation at relatively low rates, such as those that occur when using a Tansy function, increasing the flow rate at which the pharmaceutical formulation exits the infusion driver 14 when the flow rate is relatively low increases the accuracy of the pharmaceutical formulation administration process.

[0137] However, the method and system according to the second embodiment of the present disclosure uses another function (the Sadleir function) to control the rate at which the pharmaceutical formulation is delivered (injected) to the patient. Injecting the pharmaceutical formulation according to the Sadleir function allows the pharmaceutical formulation to be given at a higher initial flow rate (relative to the Tansy method) as a result of the use of a dilution chamber 32 located between the active agent chamber and the patient. The pharmaceutical formulation flows through the dilution chamber 32 before entering the patient. The dilution chamber 32 contains a diluent for mixing with the pharmaceutical formulation entering the dilution chamber 32. The dilution chamber 32 is adapted to ensure rapid mixing of the pharmaceutical formulation with the diluent in the dilution chamber 32. Mixing is first performed by repeatedly varying the flow rate between low and high values ​​during a second priming step (performed when the first mixed pharmaceutical formulation is injected from the dilution chamber 32 through the conduit 30b into the patient's intravenous access point). Subsequent mixing and dilution are performed in the dilution chamber 32 during the course of delivery of the Sadleir function infusion program. This may involve the use of an infusion catheter in the dilution chamber 32 that includes a flexible sleeve to allow dynamic adjustment of resistance depending on flow rate.

[0138] In particular, the use of the Sadleir method allows for a reduced concentration of the pharmaceutical formulation entering the patient at the beginning of the infusion process when compared to the Tansy method. Thus, the Sadleir method requires a higher initial flow rate and a higher minimum infusion rate to provide a dosing profile similar to that of the Tansy function. It is important to note that the pharmaceutical dosing profile with the Sadleir method is the same as that delivered by the Tansy method, except that the dose in the Sadleir method at any point during the infusion is reduced by a fixed fraction to compensate for the amount of drug remaining in the dilution chamber 32 at the end of the infusion process. However, it is important to note that the use of either the Tansy or Sadleir method results in an order of magnitude of cumulative dose of the active ingredient of the pharmaceutical formulation.

[0139] Figures 22b and 22c illustrate the difference in injection or infusion rate (ml / min) of pharmaceutical formulation liquid when using the first (Tansy) or second (Sadleir with 10 ml dilution chamber) embodiment of the present disclosure for a 50 ml infusion over 30 minutes. Figure 22b illustrates the first 15 minutes of a 30 minute infusion, where early in the infusion the infusion rate (in ml / min) of pharmaceutical formulation is greater for the Sadleir method, and the Tansy method has a higher flow rate at the end of the infusion.

[0140] Figures 22d and 22e illustrate the difference in cumulative volume injected from a pharmaceutical formulation liquid syringe or container over the course of a 30 minute injection when using a first (Tansy) or second (Sadleir with 10 ml dilution chamber) embodiment of the present disclosure for a 50 ml injection. Figure 22d illustrates the first 15 minutes of a 30 minute injection. The cumulative volume injected at a given time is intended to mean the total volume of pharmaceutical formulation injected into the patient from the start of the injection to that time.

[0141] According to a first embodiment of the present disclosure, a method and system for providing a pharmaceutical formulation to a patient is provided. The flow rate of the pharmaceutical formulation follows the curve of a Tansy function (see Figures 19a and 19b). This method (referred to as the Tansy method) includes providing a drug at a specific flow rate determined by the Tansy function.

[0142] Drug Delivery Systems The drug delivery system 1 comprises a drug delivery device 10 for providing a pharmaceutical formulation, sometimes referred to herein as device 10. The drug delivery device 10 is configured to provide the pharmaceutical formulation at or near a flow rate determined by a Tansy function.

[0143] The drug delivery system 1 comprises an infusion device. The infusion device may be in the form of an infusion driver 14. In some embodiments, the apparatus 10 may comprise an infusion driver 14 (such as a syringe driver, a peristaltic pump, a plum pump, or a similar drug infusion pump). The infusion device may include or be in the form of a vacuum infusion device. The infusion device may apply an infusion pressure (i.e., vacuum pressure) to the dilution chamber opening 110 of the drug delivery device. The infusion pressure may be a negative pressure.

[0144] The infusion driver 14 comprises a control unit for controlling the rate at which the infusion driver 14 delivers the drug (pharmaceutical formulation) from a syringe or bag through a common length of tubing to a patient. The control unit comprises hardware and software for controlling the infusion driver 14 to deliver the drug at a flow rate established by a Tansy function. The software includes instructions for executing an algorithm designed to calculate the flow rate determined by the Tansy function.

[0145] FIG. 1b shows a block diagram of an apparatus 10 for controlling the flow rate at which an infusion driver 14 delivers medication from a syringe or bag through a standard length of tubing to a patient.

[0146] The apparatus 10 comprises a computer system 12. The drug delivery apparatus 10 comprises an injection driver 14. The injection driver 14 may be referred to as an injection device. The injection driver 14 comprises a syringe 15 and a syringe driver 17. The syringe 15 defines an injection container 19. The syringe 15 comprises a plunger 21. The injection container is configured to receive at least a portion of the plunger 21. The plunger 21 and the injection container together define an active agent chamber 98. The active agent chamber 98 may be referred to as a first chamber. The active agent chamber 98 is configured to receive an active agent. In particular, the active agent chamber 98 is configured to receive a pharmaceutical formulation. The pharmaceutical formulation includes an active agent.

[0147] The activator chamber 98 includes an activator chamber opening 23 configured to receive at least a portion of the plunger 21. The activator chamber opening 23 may be considered an activator chamber inlet. The activator chamber 98 includes an activator chamber outlet 25.

[0148] The plunger 21 is configured to be displaced relative to the longitudinal axis of the infusion container. Displacement of the plunger 21 along the longitudinal axis of the infusion container displaces the pharmaceutical formulation in the activator chamber through the activator chamber outlet 25. The pharmaceutical formulation is displaced into the conduit 30a.

[0149] In some embodiments, the injection driver 14 comprises a computer system 12 and a syringe driver 17. The injection driver 14 comprises a drive mechanism. In particular, the syringe driver 17 comprises a drive mechanism. The drive mechanism is controlled by the computer system 12 (control unit 12). In particular, the control unit 12 is adapted to control the drive mechanism of the syringe driver 17 to deliver the drug (contained in the syringe 15) to the patient in a specific manner, for example according to either a Tansy function or a Sadleir function.

[0150] The computer system 12 includes computer components such as a processor 16, a random access memory (RAM) 18, an external memory drive 20, and a user interface 22, such as a display 24 and a keyboard 26. These computer components are connected to each other and to the infusion driver 14 via a system bus 28.

[0151] In some embodiments, the infusion device comprises at least one infusion device processor in communication with the infusion device memory. The at least one infusion device processor comprises or may be in the form of processor 16. The infusion device memory may comprise one or more of random access memory 18 and external memory drive 20. The at least one infusion device processor is configured to execute infusion device program instructions stored in the infusion device memory to cause the infusion device to function as described herein. In other words, the infusion device program instructions are accessible by at least the infusion device processor and are configured to cause the at least one infusion device processor to function as described herein.

[0152] In some embodiments, the infusion device program instructions are in the form of program code. At least one infusion device processor comprises one or more microprocessors, central processing units (CPUs), application specific instruction set processors (ASIPs), application specific integrated circuits (ASICs), or other processors capable of reading and executing program code.

[0153] The infusion device memory may comprise one or more volatile or non-volatile memory types. For example, the infusion device memory may include one or more of a random access memory (RAM), a read only memory (ROM), an electrically erasable programmable read only memory (EEPROM), or a flash memory. The infusion device memory is configured to store program code accessible by the at least one infusion device processor. The program code may include executable program code modules. In other words, the infusion device memory is configured to store executable code modules configured to be executable by the at least one infusion device processor. The executable code modules, when executed by the at least one infusion device processor, cause the at least one infusion device to perform a particular function, as described herein.

[0154] The computer system 12 may optionally include a drug library and database containing a maximum allowable drug administration rate for each particular drug that may be infused into a patient. If the expected drug delivery rate during use of the infusion driver 14 (e.g., during execution of the Tansy or Sadleir method) exceeds the maximum allowable drug administration rate, the infusion rate is increased by 100% by increasing the dilution chamber (C d ) is reduced according to the maximum allowable infusion rate so that the concentration of drug leaving the infusion port does not exceed the maximum allowable drug administration rate. This may result in an infusion time that is longer than intended for the infusion, but ensures that the maximum allowable or suggested drug administration rate is not exceeded.

[0155] During the method of injecting a pharmaceutical formulation according to the method of the present disclosure, the drug library may be accessed by the computer system 12 to ascertain whether the drug delivery rate exceeds the maximum allowable drug administration rate, and if so, the infusion rate will be reduced according to the maximum allowable infusion rate to provide the maximum allowable drug administration rate.

[0156] The processor 16 may execute instructions for controlling the drive mechanism of the syringe driver 17 to deliver the drug according to, for example, either the Tansy or Sadleir function. The code executed by the processor 16 may be stored in the RAM 18 of the computer system 12 or may be provided from an external source via the external memory drive 20. This software would include instructions for controlling the drive mechanism of the infusion driver 14 (e.g., the syringe driver 17) to cause the pharmaceutical formulation to exit the syringe 15 at a particular flow rate that matches or approximates an infusion rate of the pharmaceutical formulation as determined by Tansy, Sadleir, or another function that specifies the rate at which the pharmaceutical formulation is to be infused into the patient. According to a first embodiment of the present disclosure, the infusion driver 14 delivers the drug directly to the patient via the conduit 30a (such as a minimum volume tube with a three-way stopcock to allow priming of the tube with the pharmaceutical formulation prior to starting the program), and the processor 16 executes the code for driving the syringe driver 17 to deliver the drug (contained in the syringe 15) to the patient according to the Tansy function. The software code (eg, FIG. 27) executed by the processor 16 includes instructions for executing an algorithm for calculating an injection rate determined by a Tansy function in order to control the flow rate using the syringe driver 17.

[0157] 2, there is shown a drug delivery device 10 according to a second embodiment of the present disclosure, and may also be referred to as device 10. The device 10 according to the second embodiment is similar to the device 10 according to the first embodiment, and like reference numbers are used to identify like parts.

[0158] As described with reference to FIG. 1 , the drug delivery device 10 comprises an injection container and a plunger 21. The injection container and plunger 21 may form at least a portion of a syringe. The injection container is configured to receive at least a portion of the plunger 21. The plunger 21 and the injection container together define an active agent chamber 98. The active agent chamber 98 is configured to receive a pharmaceutical formulation. The pharmaceutical formulation includes an active agent, as previously described. The active agent chamber 98 comprises an active agent chamber opening 23. The active agent chamber opening 23 is configured to receive at least a portion of the plunger 21. The active agent chamber 98 comprises an active agent chamber outlet 25.

[0159] One of the differences of the device 10 of the second embodiment of the present disclosure is that the infusion driver 14 delivers the pharmaceutical formulation to the dilution chamber 32 before the pharmaceutical formulation is delivered to the patient. Thus, the drug delivery device 10 comprises a dilution chamber 32. The dilution chamber 32 is fluidly connected to the infusion container. The dilution chamber 32 is configured to receive a diluent. The dilution chamber 32 is configured to receive the pharmaceutical formulation from the activator chamber 98. In particular, the dilution chamber 32 is configured to receive the pharmaceutical formulation from the activator chamber outlet 25. The dilution chamber 32 comprises a dilution chamber outlet 27.

[0160] The plunger 21 is configured to be displaced relative to the longitudinal axis of the infusion container. Displacement of the plunger 21 along the longitudinal axis of the infusion container displaces the pharmaceutical formulation in the activator chamber 98 through the activator chamber outlet 25. The pharmaceutical formulation is displaced into the conduit 30a. The pharmaceutical formulation is displaced through the conduit 30a to the dilution chamber 32. The pharmaceutical formulation is diluted in the dilution chamber 32. Displacement of the plunger 21 displaces the diluted pharmaceutical formulation from the dilution chamber 32 through the second conduit 30b to the patient.

[0161] The software code executed by the processor 16 includes instructions for executing an algorithm to calculate an injection rate determined by a Sadleir function to control the flow rate of the syringe driver 17. Delivery of the pharmaceutical formulation from the injection driver 14 (i.e., the activator chamber 98) to the dilution chamber 32 and subsequently to the patient occurs via conduits 30a and 30b. Conduits 30a and 30b comprise minimum volume extension tubing. Conduit 30a may be referred to as a first conduit. Conduit 30b may be referred to as a second conduit. Conduit 30a is configured to fluidly connect the activator chamber outlet 25 and the dilution chamber inlet 29.

[0162] As noted above, the apparatus 10 according to the second embodiment of the present disclosure includes a dilution chamber 32. An exemplary arrangement of the dilution chamber 32 is shown in operation in FIG.

[0163] There are two different disposable consumable systems that are particularly suitable for clinical use, one with a 10 ml dilution chamber 32 and one with a 20 ml dilution chamber 32, although the method includes arrangements with dilution chambers 32 of other volume sizes (an example of a method with a 10 ml chamber volume is equivalent to the Tansy method. The 20 ml dilution chamber 32 allows for a higher minimum injection rate and a lower maximum injection rate than the 10 ml chamber 32, but at a cost. This cost is due to the fact that the fraction of drug delivered to the patient at any given time of injection is

number

[0164] Alternatively, (1) the concentration of the active ingredient in the pharmaceutical formulation can be increased ("increased concentration Sadleir method"), or (2) the volume and infusion rate of the pharmaceutical formulation can be increased ("increased volume Sadleir method"), either (1) or (2) being done to deliver the same dose as the equivalent Tansy method at the end of the infusion period (i). In both of these alternative methods, once the infusion process is completed, any drug remaining in the dilution chamber 32 is discarded.

[0165] For infusions lasting more than 25 minutes, approximately 80% of the total dose is given before the final bolus, so a dilution chamber volume of 1 / 5 the infusion volume (i.e., 10 ml for a 50 ml infusion, 20 ml for a 100 ml infusion) is appropriate. For infusions over 20-25 minutes, a ratio of 2 / 5 (i.e., 20 ml dilution chamber for a 50 ml primary infusion volume) ensures that the infusion rate does not exceed 20 ml / min for a 50 ml infusion.

[0166] Clinically, a 30-minute infusion with a 50 ml volume and a 10 ml dilution chamber is appropriate in view of the competing interests of (1) achieving the full therapeutic dose infusion in a relatively short period of time, and (2) allowing detection of submaximal adverse reactions in patients. For infusions not witnessed by a physician (i.e., left on the ward), it may be more appropriate to use a Sadleir function over 60-120 minutes and with a 100 ml volume and a 20 ml dilution chamber.

[0167] However, the infusion duration may be limited by several factors. The first factor is the maximum infusion rate that a typical size intravenous cannula (i.e., 22g) can tolerate. The second factor is that the maximum infusion rate of 20ml / hour on most infusion drivers 14 results in a commonly used minimum Sadleir function infusion duration of 20 minutes for a 50ml infusion volume and a 20ml dilution chamber 32.

[0168] According to a second embodiment of the present disclosure, the injection driver 14 delivers the drug via conduit 30a to the dilution chamber 32 and then to the patient via conduit 30b fluidly connected to the patient (see FIG. 3). The processor 16 also executes code that executes a specific algorithm for the driving of the syringe driver 17 to deliver the pharmaceutical formulation (contained in the syringe 15) to the patient, as determined by the Sadleir function.

[0169] The device 10 may be used to administer a full therapeutic dose of any drug (active ingredient such as a drug) diluted in a diluent to form a diluted pharmaceutical formulation that can be administered slowly to a patient to reduce the occurrence of severe hypersensitivity reactions and avoid death in any hypersensitive patient.

[0170] In particular, the device 10 according to the first and second embodiments of the present disclosure is intended to be used, for example, in one of the following three scenarios:

[0171] A drug test dose in a patient not suspected of being hypersensitive to the drug administered to the patient, where the device 10 is used to administer therapeutic doses of the drug in a particular manner (e.g., by providing incremental test doses) that increases the chances that an unexpected hypersensitivity will be detected, allowing the infusion process to be stopped before the dose that will cause a more severe reaction in the patient is administered. In this particular scenario, a patient who would otherwise have an unexpected reaction to the drug will not have a negative reaction because tolerance has been induced in the patient using the particular manner in which the therapeutic dose is administered. Thus, this particular scenario typically produces what is referred to as unintended acute desensitization.

[0172] A drug challenge in a patient suspected of having a hypersensitivity reaction due to a particular drug, and in which it is deemed advantageous to confirm that the particular drug administered was the cause of the reaction, the device 10 is used to administer a therapeutic dose of the drug in a particular manner that increases the ability or probability that, in the event of a hypersensitivity reaction, the infusion can be stopped before a particular amount of drug reaches a dose that will cause a more severe reaction in the patient. This scenario is particularly useful in confirming that the drug administered to the patient was the cause of the patient's hypersensitivity reaction.

[0173] Drug desensitization in a patient known to be hypersensitive to a particular drug, where a therapeutic dose of the particular drug is administered in a particular manner using device 10 (e.g., providing a relatively low dose at the beginning of the infusion process) such that tolerance to the drug is induced. This scenario is particularly useful for desensitizing a patient to a particular drug.

[0174] Methods for delivering pharmaceutical formulations

[0175] Tansy method

[0176] 12a and 13a broadly illustrate steps for the delivery of a therapeutic dose of a drug contained in a pharmaceutical formulation delivered by an infusion driver 14. FIG.

[0177] 12a and 12b illustrate a method according to a first embodiment of the present disclosure. In the first embodiment of the present disclosure, a method of delivering a pharmaceutical formulation to a patient is provided. The pharmaceutical formulation is delivered directly to the patient according to a flow rate determined by a Tansy function according to equation (1) introduced below. In some embodiments, the pharmaceutical formulation is delivered according to an infusion modeling function. In some embodiments, the Tansy function is an infusion modeling function.

[0178] According to a first embodiment of the present disclosure, there is provided a method for delivering a therapeutic dose of a particular drug to a patient using a device 10 according to the first embodiment of the present disclosure and depicted in Figure 1. This method is referred to as the Tansy method.

[0179] As noted above, the device 10 according to the first embodiment of the present disclosure uses a Tansy function to control the flow rate for delivering a therapeutic dose of a particular drug directly to a patient (without the use of a dilution chamber 32).

[0180] The particular drug to be administered is prepared in a syringe 15 containing a solvent (sterile water or saline) and delivered to the patient via an injection driver 14.

[0181] As shown in FIG. 12a, the operator enters via keyboard 26 of injection driver 14 the following: a) The volume (V) of a pharmaceutical formulation to be administered to a patient in ml containing a quantity of drug (active ingredient in units of mass) and a volume of solvent for mixing with the drug (active ingredient). p ), and b) The time period over which the pharmaceutical formulation will be administered in minutes (also referred to as the duration of infusion); c) Optionally, the identity of a specific drug (drug name), the dose of the drug, and / or the maximum drug administration rate (doses / min) for a specific drug to ensure that the maximum drug administration rate is not exceeded during the infusion process.

[0182] The operator then provides the pharmaceutical formulation to the patient's entry point, this step being referred to as the priming step.

[0183] The operator then activates the injection driver 14 via a command through the keyboard 26 .

[0184] The processor 16 of the infusion driver 14 then executes corresponding instructions to calculate the flow rate (ml / min) of the pharmaceutical formulation at each time point during the duration of the infusion as determined by the Tansy function according to the following equation (1):

number

[0185] The Tansy method for a 30 minute infusion duration has the following unique features: a) The Tansy method delivers 0.01% of the dose after 14%, 0.1% after 34%, and 1% after 56% of the period corresponding to the duration of the infusion process (see Figures 15 and 16). This increases the likelihood that a negative reaction will be detected and that the infusion process can be stopped before a more severe negative reaction occurs. (In contrast, when using traditional methods based on constant infusion, 0.01%, 0.1%, and 1% of the total dose would all be administered within the first 1% of the infusion process.) b) Throughout the infusion, the flow rate increases continuously, doubling every 2 minutes for a 30 minute infusion - see Figures 14a and 14b.

[0186] In relation to unique feature (a.) listed above, Figure 15 shows the difference in cumulative dose administered over a 30 minute infusion period for the Tansy method compared to the conventional constant infusion method. The total dose delivered over 30 minutes is the same in both methods (Tansy method and conventional (constant infusion over 30 minutes) method).

[0187] Furthermore, Figures 15a and 15b illustrate the clear demarcation in time of the clinically relevant magnitude of cumulative drug administration when using the Tansy method.

[0188] However, using a constant infusion over 30 minutes would result in 0.01%, 0.1%, 1%, and 1% of the dose being administered over only the first 18 seconds of the infusion, as shown in Figure 15. If a patient were to have a minor reaction to 0.01% of the dose and a maximal reaction at 10 or 100 times 0.01% when using a constant infusion, the clinician would be unlikely to recognize that the patient is hypersensitive to the drug and would not stop the infusion process before the dose that would induce the maximal reaction resulting in injury and potential death to the patient is administered.

[0189] In contrast, the Tansy method starts with a relatively low infusion rate and increases the infusion rate continuously. In particular, using the Tansy method would result in the patient receiving 0.01% of the dose at 4.18 minutes and 0.1% of the dose after 5.97 minutes. This approximately 6 minute interval increases the ability to detect a reaction and allows the infusion to be stopped before the patient receives a supramaximal dose, thus minimizing complications. Similarly, a cumulative 1% dose is achieved after another 6 minutes, as is a 10% cumulative dose. The approximately 6 minute interval (for a 30 minute infusion) of the order of magnitude of the cumulative dose is a particular feature of the device 10 according to the first and second embodiments of the present disclosure. This is illustrated in Figures 15 and 16.

[0190] In relation to unique feature (b) listed above, Figure 14a illustrates the rate of drug administration using a logarithmic scale comparing a conventional constant infusion method to the Tansy method. This illustrates that when using the Tansy method for a 30 minute infusion, the rate of drug administration changes every 2 minutes (in this particular configuration, this rate doubles). In particular, the Tansy method has the property that the rate of drug administration is 0.01% of the final infusion rate at 3.425 minutes into the infusion, 0.1% of maximum at 10.07 minutes, 1% at 16.71 minutes, 10% at 23.36 minutes, and 100% at 30 minutes. The total drug administered is 0.01% after 4.18 minutes, 0.1% after 10.15 minutes, 1% after 16.72 minutes, 10% after 23.35 minutes, and 100% after 30 minutes (see Figure 16).

[0191] As shown above, for a 30 minute injection, the flow rate doubles every 2 minutes. However, the variation in flow rate can be adjusted by varying the injection duration (see Figures 19a and 19b). As shown in Figure 19b, as the duration of the injection increases, the rate variation decreases, and as the duration of the injection decreases, the flow rate variation increases.

[0192] Outlined below is a general formula for the cumulative volume of pharmaceutical formulation provided at each time point during an infusion according to a first embodiment (i.e., using the Tansy method).

[0193]

number

[0194] As mentioned, the drug delivery system 1 may comprise the drug delivery device 10 described above. The drug delivery system 1 may also comprise an infusion device. The infusion device comprises at least one infusion device processor and an infusion device memory storing program instructions accessible by the at least one infusion device processor. The program instructions are configured to cause the at least one infusion device processor to actuate an infusion device actuator (e.g., infusion driver 14) to control the drug delivery device 10 to deliver a drug according to the Tansy method.

[0195] In particular, the program instructions may include programming at least one infusion device processor to receive a volume input (V p ), which may be the volume of the pharmaceutical formulation in the active agent chamber. p ) may be received via user-provided input. For example, a volume input (Vp ) may be input using the user interface 22. Alternatively, a volume input (V p ) may be obtained from the infusion device memory. Throughout this disclosure, volume input (V p ) may correspond to the volume of the pharmaceutical formulation.

[0196] The program instructions are further configured to cause the at least one infusion device processor to receive a time input (i) indicating a time at which the pharmaceutical formulation is to be administered. The time input (i) may be received via an input provided by a user. For example, the time input (i) may be entered using the user interface 22. Alternatively, the time input (i) may be obtained from an infusion device memory.

[0197] The program instructions are further configured to cause the at least one infusion device processor to determine a number of infusion steps to be performed during the time the pharmaceutical formulation is to be administered. Although referred to herein as "infusion steps," it will be understood that the infusion steps may also be considered or referred to as pump steps. Determining the number of infusion steps may include receiving an infusion step input indicating the number of infusion steps. Determining the number of infusion steps may include retrieving the number of infusion steps from an infusion device memory.

[0198] The program instructions are further configured to cause the at least one infusion device processor to determine a pharmaceutical formulation output volume for each of the number of infusion steps. Each pharmaceutical formulation output volume corresponds to a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective infusion step. Determining the pharmaceutical formulation output volume for each of the number of infusion steps may include integrating a Tansy function from a first time corresponding to a start of an associated infusion step to a second time corresponding to an end of the associated infusion step.

[0199] The Tansy function T(t) may be defined by:

number

[0200] In the formula, V p is the volume input, t is the time, and i is the time input.

[0201] Determining the pharmaceutical formulation output volume for each of a number of infusion steps includes calculating:

number

[0202] The program instructions are further configured to cause the at least one infusion device processor to determine a target flow rate for each infusion step. Each target flow rate indicates a target flow rate of the pharmaceutical formulation output by the drug delivery device during the respective infusion step. Each target flow rate is determined based at least in part on the pharmaceutical formulation output volume of the respective infusion step. Determining the target flow rate for each infusion step may include dividing the pharmaceutical formulation output volume of the respective infusion step by the length of that infusion step. Determining the target flow rate for each infusion step may include determining an initial target flow rate and a final target flow rate for each infusion step. The initial target flow rate for each infusion step may be equal to the final target flow rate of the preceding infusion step. The final target flow rate for each infusion step may be equal to the initial target flow rate of the following infusion step.

[0203] The program instructions are further configured to cause the at least one infusion device processor to receive a pharmaceutical formulation input. The pharmaceutical formulation input indicates one or more of an identity of the pharmaceutical formulation, a dose of the pharmaceutical formulation, and a maximum pharmaceutical formulation administration rate. The target flow rate may be limited to the maximum pharmaceutical formulation administration rate such that the target flow rate does not exceed the maximum pharmaceutical formulation administration rate during the infusion.

[0204] The program instructions are further configured to cause the at least one injection device processor to actuate the injection device actuator to displace the plunger 21 within the active agent chamber 98 so that the pharmaceutical formulation is output by the drug delivery device 10 at a respective target flow rate during each injection step.

[0205] Sadleir method According to a second embodiment of the present disclosure, there is provided a method for delivering a therapeutic dose of a particular drug to a patient using the device 10 according to the second embodiment of the present disclosure.

[0206] As noted above, the device 10 according to the second embodiment of the present disclosure uses the Sadleir function to control the flow rate of the pharmaceutical formulation exiting the infusion driver 14 for delivery of the pharmaceutical formulation to the dilution chamber 32 and from the dilution chamber 32 to the patient.

[0207] The method according to the second embodiment of the present disclosure improves the precision of the manner in which the drug is delivered by delivering the drug at a variable rate similar to the first embodiment of the present disclosure, but in contrast to the first embodiment of the present disclosure, the drug when using the second embodiment of the present disclosure is delivered at (1) a minimum flow rate that is greater than the minimum flow rate of the first embodiment of the present disclosure, and (2) a maximum infusion rate that is less than the maximum flow rate of the first embodiment of the present disclosure. See Figures 22a, 22b, and 22c.

[0208] Improved accuracy (i.e., being able to deliver a higher flow rate of the pharmaceutical formulation during the initial phase of the injection process) is achieved by delivering the pharmaceutical formulation to the dilution chamber 32. The dilution chamber 32 contains a fixed volume of diluent (saline or the like) with which the pharmaceutical formulation will be mixed during the course of the injection. Thus, by directing the pharmaceutical formulation to the dilution chamber 32, a diluted pharmaceutical formulation is provided.

[0209] However, dilution of the pharmaceutical formulation in the dilution chamber 32 results in a reduction in the drug concentration in the dilution chamber 32 compared to the drug concentration of the pharmaceutical formulation contained in the syringe 15 (i.e., the activator chamber 98). This causes the pharmaceutical formulation exiting the dilution chamber 32 to have a lower concentration than the pharmaceutical formulation contained in the syringe 15 (activator chamber 98) of the injection driver 14. The concentration of the pharmaceutical formulation exiting the dilution chamber 32 will be lowest at the beginning of the injection and increases throughout the duration of the injection (see FIG. 26c for an example using a 10 ml dilution chamber with an injection of 50 mL over 30 minutes). Compared to that provided by the first embodiment of the present disclosure (Tansy method), the flow rate of the pharmaceutical formulation is adjusted to a higher flow rate to compensate for the reduction in the pharmaceutical formulation (drug) concentration (due to dilution in the dilution chamber 32).

[0210] Furthermore, because the pharmaceutical formulation is delivered to the dilution chamber 32 and not directly to the patient, at the end of the process of administering the pharmaceutical formulation, a remainder of the pharmaceutical formulation will remain in the conduit 30 and the dilution chamber 32. The remainder of the pharmaceutical formulation (contained in the dilution chamber 32) can be administered, for example, either by reducing the volume of the dilution chamber 32 or by flushing the conduit 30 and the dilution chamber 32 with saline or other suitable solution. To this end, as previously mentioned, according to the second embodiment of the present disclosure, in the arrangement shown in the figure, the dilution chamber 32 comprises a syringe that allows the reduction of the volume of the dilution chamber 32 by pressing the plunger of the syringe. The dilution chamber 32 may comprise a second plunger (i.e., part of the syringe).

[0211] The dose in the dilution chamber 32 at the end of the injection process (V r ) is the amount of the remaining drug in the p ) and the volume of the dilution chamber (V d In particular, the volume of the remaining dose in the dilution chamber 32 at the end of the drug administration process (V r ) is given by:

number

[0212] Comparing the Tansy and Sadleir methods, the specific amount of drug remaining in the dilution chamber 32 (at the end of the injection process) and not delivered for the dose delivered via the Sadleir method is less than the full therapeutic dose, or the dose delivered by the Tansy method. In particular, at any point during the drug administration process, the dose delivered using the Sadleir function is calculated using Equation 3 below:

number

[0213] The variation in the administration rate of drug (active ingredient) for the Tansy and Sadleir methods is similar, but the amount per unit time and total dose (of drug) delivered to the patient is reduced by a fixed fraction (by multiplying by a "correction factor") that depends on the volume of the dilution chamber 32 relative to the total injection volume, see Figure 22a.

[0214] In particular, for a 10 ml dilution chamber with a 50 ml primary drug injection (or a 20 ml dilution chamber with a 100 ml primary drug injection), at the end of the injection, 19.865% of the dose remains in the dilution chamber 32, and therefore only 80.135% of the total therapeutic dose is administered to the patient.

[0215] The volume of the dose remaining in the dilution chamber 32 can be delivered to the patient by reducing the volume of the dilution chamber 32 (by depressing the plunger in the dilution chamber) or by flushing the system with saline and delivering it to the patient so that 19.865% of the final dose can be given to the patient as a push.

[0216] An advantage of the Sadleir technique used in conjunction with the device 10 incorporating the dilution chamber 32 is that the minimum flow rate of pharmaceutical formulation exiting the infusion driver 14 is an order of magnitude greater than that of the Tansy technique, thereby improving the ability to accurately administer a drug and reducing the total amount of pharmaceutical formulation. As noted above, the infusion driver 14 is unable to provide adequate infusion rates at relatively low flow rates, such as the initial infusion rate using the Tansy technique. The Sadleir technique also reduces the maximum flow rate required, reducing the required size of the patient's intravenous cannula size and improving patient tolerance.

[0217] The Sadleir method accomplishes this through the use of dilution chamber 32 of apparatus 10 in accordance with the second embodiment of the present disclosure.

[0218] The accuracy of the Sadleir function's estimation of the volume administered in the first minute achieves a significant three figures when the algorithm used to calculate the volume operates on a time interval of 1 / 600th of a minute, or shorter (see Figure 16 for the volume in the first minute of a 30 minute injection from a 50 ml syringe with a 10 ml dilution chamber).

[0219] The Sadleir method delivers a known fraction of the Tansy protocol dose that increases proportionately at a similar rate when the same pharmaceutical formulation concentration is used. The Sadleir function is calculated by numerical approximation of a nonlinear function, the calculation of which is detailed below.

[0220] Figures 13a, 13b and 13c illustrate a method according to a second embodiment of the present disclosure, where a pharmaceutical formulation is delivered to a patient via a dilution chamber 32 according to a variation in flow rate determined by a Sadleir function according to equation (6) introduced below. Figure 13d illustrates, for each interval n (with interval duration of 1 / 1200 min), values ​​of flow rate, concentration in the dilution chamber and % dose determined by the Sadleir function.

[0221] According to a second embodiment of the present disclosure, a method for delivering a therapeutic dose of a particular drug to a patient uses a device 10 according to the second embodiment of the present disclosure and depicted in Figures 2 and 3. This method is referred to as the Sadleir method.

[0222] As noted above, the device 10 according to the second embodiment of the present disclosure uses the Sadleir function to indicate to the syringe driver 17 at what flow rate the pharmaceutical formulation is to be delivered to the patient using the dilution chamber 32.

[0223] The particular drug to be administered to the patient is prepared in a syringe 15 containing a diluent (sterile water or saline) and delivered to the patient via an injection driver 14. The diluent may also be referred to as a solvent.

[0224] Referring to FIG. 13 a , the operator provides input via the keyboard 26 of the infusion driver 14 . a) The volume of the pharmaceutical formulation in mL (V) delivered to the patient, consisting of the volume of solution to give the correct therapeutic dose of drug (active ingredient). p ), b) the volume of the dilution chamber 32; c) drug concentration in the primary syringe (e.g., percent of therapeutic dose / ml); d) the time period (i) over which the pharmaceutical formulation is to be administered in minutes (also referred to as the duration of infusion); e) the number of intervals per minute (τ) (as explained below, the injection process is divided into intervals over which the algorithm (executed by the processor 16 of the injection driver 14 and used to calculate the flow rate value determined by the Sadleir function) is repeated); and f) Optionally, the identity of the specific drug (drug name), the dose of the drug, and / or the maximum drug administration rate (doses / min) for the specific drug to ensure that the maximum drug administration rate is not exceeded during the infusion process.

[0225] The processor 16 of the infusion driver 14 then calculates the parameters required to calculate the flow rate at which the infusion driver 14 needs to drive the pharmaceutical formulation from the syringe 15 (pharmaceutical formulation) with the syringe driver 17 in order to comply with the Sadleir function, these parameters being: 1. The number of intervals during the injection process (the number of intervals per minute (τ) multiplied by the duration of the injection in minutes (i)) for which the dilution chamber concentration value is calculated, and 2. The flow rate S(0) of the pharmaceutical formulation that establishes a specific concentration of drug in the dilution chamber 32 initiating This interval occurs before the drug is delivered to the patient, begins 1 / τ minutes before the infusion, is 1 / τ minutes in duration, and ends at time 0. The following formula provides the rate of the starting dose in ml / min:

number

[0226] The processor 16 executes instructions to execute an algorithm for calculating the rate or volume of the start interval, as well as the rate or volume of the τ×i intervals during the injection process, according to the algorithm illustrated in FIG. 13b, which is performed by python3 software instructions (software) shown in FIG. 28.

[0227] The processor 16 executes instructions that perform an algorithm to calculate a start interval velocity using equation (4) above, for delivery of the pharmaceutical formulation to the dilution chamber 32 during the time period -1 / τ~0. The deduction of equation 4 is presented in a later step below.

[0228] The initiation step occurs during the period −1 / τ~0, during which the concentration of the active ingredient is established in the dilution chamber 32.

[0229] To calculate the flow rate at which the pharmaceutical formulation must exit the syringe driver 17 according to the Sadleir method during each subsequent interval after the start interval, it is necessary to calculate the concentration in the dilution chamber 32 before each subsequent interval.

[0230] For example, at time 0 and prior to the start of the injection process, in order to calculate the flow rate of the first subsequent interval occurring after the start step, it is necessary to calculate the concentration of the pharmaceutical formulation contained in the dilution chamber 32. Equation 12 shown in Figure 13b provides the concentration in the dilution chamber 32 at time 0.

[0231] Once the concentration in the dilution chamber 32 at time 0 has been calculated, the flow rate during the first interval (n=1) is calculated by the processor 16 via equation 13 shown in FIG. 13b. This means that the same pharmaceutical formulation properties (concentration of drug, volume of pharmaceutical formulation to be administered (V p ), and the total duration of the infusion (i). This particular dose (as it will be administered using the Tansy function) is then multiplied by a correction factor

number

[0232] The dose obtained by this multiplication is called the modified Tansy function dose, or D mtf and is defined in FIG. 13b.

[0233] After the flow rate for interval n=1 has been calculated by processor 16, the concentration of drug in dilution chamber 14 at the end of this interval (time 1 / τ minutes) is calculated using equation 14 in FIG. 13b. This equation estimates the concentration of drug in dilution chamber 14 at the end of interval n (n=1 in this example) which is the amount of drug in the dilution chamber divided by the volume of dilution chamber 32. The amount of drug in dilution chamber 32 is estimated from the amount of drug present in dilution chamber 32 at the start of the previous interval (n-1, at this point n=0 or the start interval), the particular dose that entered dilution chamber 32 during interval n, and the particular dose that left dilution chamber 32 during interval n.

[0234] At this stage, the flow rate during each subsequent interval n after the first interval occurring from time 0 to 1 / τ minutes is calculated by processor 16 by sequentially calculating the flow rate for each interval n via equation 15 shown in Figure 13b, and then calculating the concentration of drug in the dilution chamber at the end of each interval n via equation 14 shown in Figure 13b.

[0235] In particular, the flow rate between each successive interval (S n ) results in the same dose being given to the patient as if the Tansy method were used, but is modified by reducing the flow rate of the Tansy function to account for the amount of drug remaining inside the dilution chamber 32 at the end of the injection. The injection rate is calculated using the formula

number

[0236] Deduction of the equation for the onset rate of the priming dose

[0237] The initial rate of the theoretical Sadleir function is undefined (since the concentration in the dilution chamber is zero, the initial rate is equal to the dose(0) divided by the concentration(0) of the Tansy function, i.e. 0 / 0).

[0238] The Sadleir function follows a concave curve that starts from a particular value at t=0, decreases to a minimum value, and then increases to a final value after reaching the minimum value. Figure 17, particularly Figures 17b and 17d, illustrate the flow rate as determined by the Sadleir function over a particular period of a 30 minute injection duration for different values ​​of τ (60 and 1200, respectively).

[0239] For example, as shown in Figures 17a and 17b, the flow rate starts at a particular rate and slows until a minimum flow rate is reached, after which the flow rate increases continuously until the completion of the injection process.

[0240] The optimal starting infusion flow rate (for the Sadleir infusion process) is that particular flow rate that results in the greatest minimum infusion rate over the course of the infusion process. The reason this particular flow rate is the optimal flow rate is that, as discussed above, it is known that the infusion driver 14 does not accurately deliver the pharmaceutical formulation at relatively low flow rates, such as those that occur when using the Tansy function, and therefore increasing the flow rate at which the pharmaceutical formulation leaves the infusion driver 14 (i.e., the active agent chamber 98) increases the accuracy of the pharmaceutical formulation administration process.

[0241] Figure 17a (tau = 60, i = 30 min, V p = 50 mL, V d As can be seen from Fig. 17b, the lowest starting section rate (17.2) results in a lower concentration in the dilution chamber at the end of the section, which results in a higher S1 rate, but a lower subsequent rate. In Fig. 17b, it can be seen that the starting rate that results in an equal S1 rate will result in the largest flow minimum (17.1).

[0242] Figures 17c and 17d show graphs plotting the flow rate as determined by the Sadleir function over a particular time period for a number of cases with different starting flow rates than cases 17a and 17b, but with tau = 1200. As shown in Figure 17d, line 17.1 has a starting flow rate of approximately 2.26 ml / min and the highest minimum flow rate (as shown in Figure 17d), while line 17.2 has the lowest flow rate compared to all other cases.

[0243] Figure 17e shows a graph plotting the minimum flow rate values ​​for each particular flow rate for a number of flow rates from Figures 17c and 17d. As shown in Figure 17e, the highest minimum flow rate occurs at a starting flow rate of approximately 2.26 ml / min. This particular flow rate is selected as the starting flow rate due to having the highest minimum flow rate.

[0244] The ideal priming (starting) dose would have a flow rate of the starting flow rate of line 17.3 due to the fact that this line 17.3 has the greatest minimum flow rate as can be seen in FIG. 17e. The ideal starting dose or rate before the infusion process is started would be the starting step (S(0)) which is equal to the infusion rate of the first leg (S(1st leg)) such that the rate of S(0)=S(1). initiating ) injection rate.

[0245] When the size of the interval over which the Sadleir function is repeated (1 / τ) is larger, the sensitivity of the Sadleir function to variations in the flow rate of the start step increases, as illustrated in Figures 17a and 17b, as well as Figures 17c and 17d. Indeed, in Figures 17a and 17b, a value of τ of 60 / min is used, and the change in the minimum flow rate is larger. Also, as shown in Figures 17c and 17d, when a value of τ of 1200 / min is chosen, the change in the minimum flow rate is smaller. Reducing the size of the interval (increasing τ) reduces the sensitivity to changes in the start interval speed.

[0246] Furthermore, after the start-up interval the injection process will commence.

[0247] The flow rate during the first interval of the Sadleir function is calculated based on the concentration in the dilution chamber 32 after the start dose is delivered during the first interval. mtf (t)1 (as defined above).

[0248] The infusion time is divided into τ×i intervals, where i is the number of minutes the infusion is delivered and τ is the number of intervals per minute. Each interval is 1 / τ minutes in duration.

[0249] The volume given by the modified Tansy function for interval n (between time=(n-1) / τ and n / τ minutes) is given by the integral of the tansy rate function multiplied by a correction factor that accounts for the amount of drug remaining in the dilution syringe at the end of the Sadleir injection (the second embodiment of the present disclosure), or by:

number

number

number

number

[0250] The modified tangent function dose for interval n (Dmtf(t)n) is calculated by (1) multiplying the volume (Vmtf(t)n) given over the interval by (2) the concentration of drug from the primary drug container (C p ) or given by:

number

number

number

[0251] The speed of the starting interval (S(0)) should be equal to the speed of the first interval (S(1)), as explained earlier.

[0252] The rate of the first interval (S(1)) is the equivalent interval of the injection (from time zero to time 1 / τ minutes) and the dilution chamber V d Concentration in C d(0) and the dose of a modified Tansy function of: The rate is equal to the given volume divided by the time interval, and the volume is determined by the dose divided by the concentration, or:

number

number

[0253] The initial concentration in the dilution chamber is calculated by multiplying the dose given during the start step (n=0) by the volume of the dilution chamber V d The dose delivered during the initiation step is given by the volume delivered during the initiation step (V0) divided by the volume of the primary drug syringe (C p The volume delivered during the start step is equal to the start step rate (S(0)) multiplied by the duration of the interval (1 / τ min), or

number

[0254] From the above equation 16, if the speed of the section (S1) is given, C d(0) Substituting, we get the following:

number

[0255] If you rearrange it,

number

number

[0256] Since S(0) = S(1), S(0) × S(1) = S(0). 2 :

number

number

number

number

[0257] C p Eliminating the values ​​and multiplying the right hand side by τ / τ gives: S(0) 2 =V mtf (t)1×τ 2 ×V d or

number

[0258] V mtf (t)1 is the integral of the modified tansy (rate) function from 0 to 1 / τ minutes, so

number

number

number

number

[0259] Additional Notes The start step or interval (n=0) is the dose that establishes the concentration in the dilution chamber before the patient receives the drug in the first interval of the Sadleir method (n=1). The initiation step is performed prior to injection:

number

number

number

number

number

number

number

[0260] In particular, for a 30 minute injection from a 50 ml syringe 15 using a 10 ml dilution chamber 32 and 1 / 600 minute steps, the initial injection rate is:

number

number

number

number

[0261] For the same configuration but with τ = 1 / 1200 min, the priming rate (1 / 1200 min duration) is = 2.25526 ml / min).

[0262] FIG. 18 illustrates the volume administered in the first minute using the Sadleir technique using a 30 minute injection from a 50 ml syringe with a 10 ml dilution chamber.

[0263] The estimation accuracy of the volume administered in the first minute of the Sadleir function achieves a significant figure of three when repeated out to a time interval of 1 / 1200 of a minute (see Figure 18 for the first minute volume of a 30 minute injection from a 50 ml syringe with a 10 ml dilution chamber).

[0264] Calculating the speed of the next section

[0265] As noted above, calculating the value of the infusion rate for each subsequent interval occurring after the start interval first requires an estimation of the drug concentration in the dilution chamber 32 at the end of the interval that occurred before the particular subsequent interval for which the infusion rate (the subsequent infusion rate) is calculated. The subsequent infusion rate is calculated by calculating the equivalent dose (D) that would be given by a modified Tansy function (i.e., the dose given by the Tansy function in the corresponding interval reduced by multiplication by a "correction factor", see FIG. 13b and Equation 6a below), assuming the concentration of the drug calculated by Equation 9 below (Equation 14 in FIG. 13b): mtf ) in the dilution chamber 32. Therefore,

[0266] The concentration in the dilution chamber 32 at the end of a particular subsequent interval n is approximated as the amount of drug in the dilution chamber 32 at the end of the subsequent interval n divided by the volume of the dilution chamber 32. The amount of drug in the dilution chamber 32 at the end of the subsequent interval n is approximated by:

[0267] The amount of drug in the dilution chamber 32 at the start of an interval (dilution chamber volume) is multiplied by the dilution chamber drug concentration at the end of the previous interval (C d(n-1) ) multiplied by

[0268] The amount of drug that entered the dilution chamber during this interval (infusion rate (S n ) multiplied by the interval duration (1 / tau) to obtain the concentration of the drug in the pharmaceutical formulation (C p ) multiplied by , and added to

[0269] This section (section injection rate (S n ) multiplied by the interval duration (1 / tau) is the concentration of drug in the dilution chamber at the end of the previous interval (C d(n-1) ) is multiplied by ) and the amount of drug that exited the dilution chamber 32 during

[0270] therefore,

number

[0271] Dilution chamber concentration (C d(n) ) can be simplified to:

number

[0272] Then, the injection rate (S n ) is equal to the volume of pharmaceutical formulation delivered to the dilution chamber 32 divided by the duration of that interval n. This volume is equal to the dose of active ingredient as determined by a modified Tansy function divided by the concentration in the dilution chamber 32 at the end of the previous interval. The rate of the subsequent interval n is equal to or less than this volume divided by the duration of the interval in minutes, or this volume multiplied by the number of intervals per minute.

number

[0273] As noted above, using the Sadleir function instead of the Tansy function results in the administration of a smaller dose than was administered at any point during the Tansy function. The dose according to the Sadleir function is calculated by adding a correction factor to the dose determined by the Tansy function:

number

[0274] By taking into account that at the end of the injection a certain amount of drug remains in the dilution chamber 32, the dose is reduced to ensure that the duration of the injection is equal to that provided by the Tansy function for the same volume of injection.

[0275] The number of subsequent intervals is divided by the duration of the injection (in minutes) to give the number of intervals per minute (τ), which gives a total of (i × τ) intervals over each interval of the injection period (time(n-1) / τ to time(n / τ) minutes, see Figure 13d.

[0276] The volume administered by the Tansy function injection for each interval is calculated by integrating the Tansy function over the duration of each interval, which spans (n-1) / τ ∼ time n / τ minutes.

[0277] The integral of the Tansy function is calculated as follows:

number

number

number

[0278] The administered volume of each interval (calculated above) is converted to a dose by multiplying this volume by the concentration of drug in the syringe 15. The calculated value of the dose is then reduced to take into account that the total dose administered to the patient using the device 10 using the Sadleir method is less than the total dose injected from the syringe 15 due to a portion of the drug remaining in the dilution chamber 32 at the end of the injection. The reduction in the value of the dose is 0.80135 for a 10 ml or 20 ml dilution chamber 32 using a 50 ml or 100 ml syringe 15, respectively, for each dose injected during each interval.

number

[0279] Thus, the dose administered by the modified Tansy function (Sadleir function) for each interval is given by:

number

number

[0280] As noted above, before administering the pharmaceutical formulation to a patient, it is necessary to establish the concentration of the drug in the dilution chamber 32 by filling it with the pharmaceutical formulation. This is done via the start step noted above, which is done before injecting the pharmaceutical formulation into the patient. As noted above, the start interval (n=0, see FIG. 13d) has the same duration as the first subsequent interval (interval n=1, see FIG. 13d), and ideally has the same flow rate and volume as the first subsequent interval n=1, and using equation (4), the start interval (start rate S(0) initiating ) is given by solving

number

number

[0281] This injection, which is carried out during the start-up period, has a volume V d The resulting concentration in the dilution chamber 32 after the start interval is given by:

number

number

[0282] Then, the rate of the first subsequent interval n=1 after the start interval is calculated by dividing C(0) by the initial dilution chamber concentration (C n-1 ) which is calculated as follows:

number

number

number

[0283] The concentration of drug in the dilution chamber 32 at the end of interval n is then calculated using the following formula:

number

[0284] The flow rate for each particular subsequent interval n is calculated from the last two equations (8) and (9) using the appropriate corrected Tansy dose for each particular subsequent interval. In particular, the flow rate for each particular subsequent interval as determined by the Sadleir function is calculated to give a volume that will result in the same dose as the Tansy function multiplied by a correction factor.

number

[0285] The concentration in the dilution chamber 32 is then calculated for the next subsequent interval based on the amount of pharmaceutical formulation that entered the dilution chamber 32 during the particular subsequent interval preceding each next subsequent interval.

[0286] It is important to note that the above process (illustrated in Figures 13b and 13d) provides velocity values ​​that depend on the Sadleir function, which provides the curve shown for the specific example (for 50 mL of pharmaceutical formulation, with a 10 mL dilution chamber) (the Sadleir theoretical curve). Once the Sadleir theoretical curve is calculated, the device 10 according to the second embodiment of the present disclosure is programmed accordingly to administer the drug to the patient using the infusion driver 14.

[0287] The process for administering a drug using the infusion driver 14 according to a Tansy or Sadleir function requires approximating the Tansy or Sadleir function with a series of ramp infusion steps (infusion rate that varies linearly from the start to the end of the step) or constant infusion steps performed sequentially for the duration of the infusion. Each step needs to be adjusted to give the same or an approximate volume of pharmaceutical preparation for the sum of the corresponding interval of the infusion driver 14 controlled by the Sadleir function. This particular approximation process will be described at a later stage.

[0288] In operation, the process of setting up the device 10 according to the second embodiment of the present disclosure to administer a drug requires two "priming" steps and a drug dosing injection sequence to deliver the drug according to the Sadleir function, as follows: a) a first priming step to ensure that the injection driver 14 is not loose and primes the conduit 30a; and b) A second priming step which transfers the diluted pharmaceutical formulation from the outlet of the dilution chamber 38 to the patient's intravenous access point.

[0289] In a first priming step, the conduit 30a is filled with the pharmaceutical formulation by opening the multi-way valve 42 to the atmosphere and operating the infusion driver 14 to purge the drug into the multi-way valve 42. The infusion driver 14 is stopped and the multi-way valve 42 is moved to prevent contact between the conduit 30a and the atmosphere and open the dilution chamber 32 to deliver the pharmaceutical formulation to the container 34 of the dilution chamber 32.

[0290] In a second priming step, the container 34 of the dilution chamber 32 and the catheter 50 plus its distal end 54 are filled with the pharmaceutical formulation, resulting in the pharmaceutical formulation entering the dilution chamber 32. During this second priming step, the infusion driver 14 is programmed to generate alternating fast and slow flow rates to allow mixing of the drug with the diluent contained in the container 34 of the dilution chamber 32. The second priming step continues until the first initial portion of the mixed drug and diluent entering the first outlet 38 advances the length of the conduit 30b to the patient entry point. In this step, the drug is not administered to the patient, and therefore the alternating flow rates must be taken into account when calculating the patient dosage.

[0291] Subsequently, the Sadleir method (eg, using a ramp step or constant step approximation) is then initiated, resulting in the infusion of the pharmaceutical formulation into the patient at a flow rate determined by the Sadleir function.

[0292] The functions used in the Tansy or Sadleir methods (referred to as Tansy and Sadleir functions) define the flow rate of a pharmaceutical formulation for administering the active ingredient (drug) of the pharmaceutical formulation to a patient at an initial slow rate with a varying flow rate as the infusion continues.

[0293] If the infusion driver 14 can deliver only a limited number of infusion steps, an approximation of the Tansy or Sadleir function may be used. The approximation may be done using a constant infusion profile over each infusion step, or a linearly increasing or decreasing infusion rate over each step.

[0294] In fact, typically, programmable infusion devices (such as syringe drivers or peristaltic pumps or similar drug infusion pumps) are not able to provide the pharmaceutical formulation in a continuous manner (with infinitesimally small steps). Instead, the infusion device provides either a series of constant steps, or a series of "ramp" steps. A "ramp step" starts at one rate and linearly increases or decreases to another rate over the duration of the step. The number of steps may be limited due to memory limitations or due to the adverse effect of latency between each step (disruption of the infusion between each step). Note that in the Sadleir method, even a series of constant or ramp rate infusion steps will result in a continuously varying active ingredient (drug) administration rate due to the continuously changing concentration of the pharmaceutical formulation leaving the dilution chamber 32.

[0295] According to this embodiment of the disclosure, several methods of approximating the Tansy or Sadleir function with a series of constant or ramp steps are provided, as well as improved methods for each. Figures 25c and 25d illustrate the dose of active ingredient administered to a patient resulting from the approximation process of the Sadleir function using a constant or ramp injection method over the first 4 minutes of a 30 minute infusion, using 40 steps of 45 second duration.

[0296] As shown in Figures 12 and 13, the Tansy (Figures 23b and 23c) and Sadleir methods each involve defining a volume of injection steps that are to be performed sequentially during the duration of the injection. Each step has a specific duration during which a specific amount of pharmaceutical formulation is provided. In a particular arrangement, the steps will provide a similar volume as the Tansy or Sadleir function over an equivalent time interval of the injection.

[0297] As noted above, during each of these steps, a specific amount of pharmaceutical formulation will be provided. The specific amount of pharmaceutical formulation to be provided during each particular step will depend on the specific amount of Tansy or Sadleir function-defined pharmaceutical formulation that must be provided during the time interval of a particular infusion interval, and in particular, as described below, this specific amount is calculated using the amount determined for each particular interval at a corresponding specific moment of time during the infusion process as determined by the Tansy (see FIG. 12b) or Sadleir (see FIG. 13c) function.

[0298] 12b and 13c illustrate methods for approximating the Tansy and Sadleir functions, respectively, to deliver a pharmaceutical formulation to a patient.

[0299] As shown in Figure 12b in relation to the Tansy method, after calculating the actual amount (volume) of pharmaceutical formulation to be delivered during a particular period of each step, it is determined whether the flow rate should be kept constant or increased linearly over each infusion step depending on the capabilities of the infusion driver 14. The volume delivered at each step may be based on the volume of pharmaceutical formulation calculated to be delivered over the corresponding interval of the Tansy function (see Figure 12b).

[0300] A priming step would then commence by delivering sufficient pharmaceutical formulation to the patient to fill the conduit 30a with the pharmaceutical formulation up to the point of the patient's intravenous access point. At this stage, the infusion process may commence by delivering to the patient during each step an amount of pharmaceutical formulation calculated for each step. Once the infusion period has elapsed, the infusion process is stopped.

[0301] As shown in Fig. 13c for the Sadleir method, after calculating the actual amount of pharmaceutical formulation to be injected at a particular time period of each step, a first priming step will be initiated by delivering enough pharmaceutical formulation to fill the conduit 30a with pharmaceutical formulation, followed by a second priming step to present the dilution chamber 32 and the conduit 30b for the diluted pharmaceutical formulation to reach the patient.

[0302] The infusion process may then begin by (1) calculating the flow rate during the first step, and (2) then delivering the pharmaceutical formulation to the patient at the calculated rate. At this stage, the pharmaceutical formulation may be delivered to the patient during each step until the completion of the infusion process.

[0303] Referring to the Sadleir method shown in Figure 13c, after delivering the pharmaceutical formulation during each step, it is necessary to calculate the flow rate required to deliver the required amount of pharmaceutical formulation during the subsequent step. Finally, once the injection period has elapsed, the injection process is stopped and the remaining pharmaceutical formulation is delivered to the patient, for example, by collapsing the dilution chamber 32 as previously described with respect to the device 10 depicted in Figures 1-11.

[0304] An alternative configuration of the Sadleir method to approximate the active ingredient dosing rate of the Tansy method.

[0305] In an alternative arrangement of the Sadleir method, the device may comprise a container 34 (including the dilution chamber 32) that does not have the ability to be selectively displaced between expanded and deflated states (i.e., has a fixed volume). To compensate for the reduction in the total dose of drug administered compared to an equivalent Tansy function that would result in drug being present in the dilution chamber 32 at the completion of the injection, the concentration or volume of the pharmaceutical formulation may be increased to provide an equivalent Tansy method active ingredient dosing rate. In particular, the following may be increased: a) The concentration of the drug in the syringe 15 of the injection driver 14 before the start of the injection process. The concentration is calculated by multiplying the original concentration (the concentration that would be required to provide the prescribed dose of active ingredient) by the inverse of a "correction factor", i.e.

number

[0306] "Increased concentration Sadleir method" includes the use of the second embodiment of the present disclosure, which increases the concentration of the active ingredient in the pharmaceutical formulation compared to that of the equivalent (same Vp and i) Tansy method. The active ingredient concentration in the pharmaceutical formulation is increased by:

number

number

[0307] A further alternative arrangement of the second embodiment of the present disclosure that provides the same active ingredient dosing profile as the equivalent Tansy method, when increased volume injections are not contraindicated, is the "Increased Volume Sadleir Method". The increased volume Sadleir method uses the same injection duration and pharmaceutical formulation active ingredient concentration when compared to the equivalent Tansy method. However, a larger volume of pharmaceutical injection and a higher rate of injection are used to deliver the same active ingredient dosing as the equivalent Tansy method. The higher injection volume is calculated by an iterative function described below, and the higher injection rate is calculated using a modification of the Sadleir function. At the end of the injection period, any solution in the dilution chamber 32 is discarded.

[0308] The particular infusion driver 14 used in this implementation is capable of a linearly varying speed throughout each infusion step (a ramp step program) or a constant speed throughout each infusion step (a constant step program). If there is a period (pause) between infusion steps during which no fluid is administered, this is defined as a pause period, and the duration of this period is noted and taken into account as discussed above when describing the method for approximating the Tansy curve.

[0309] As mentioned above, the infusion rate of Sadleir and Tansy is relatively low during most of the beginning of the infusion process. This allows for a wide range of test doses to be administered that can recognize negative reactions in patients (who were not known to be allergic to the drug) simultaneously with the actual process of infusion of the pharmaceutical formulation. This can result in the identification that the patient is allergic to the drug being infused into the patient and allows the infusion to be stopped before the patient is administered a dose that would result in a more severe or fatal reaction. This infusion process is also particularly useful in (1) situations where it is suspected that the patient may be allergic to a drug (drug challenge), or (2) to induce hyposensitization in patients who may or may not be previously suspected to be allergic to a drug (drug hyposensitization).

[0310] Alternative Drug Delivery Systems Reference is now made to Figures 30-47, which show particular configurations of a drug delivery system 91 including a drug delivery device 90, according to certain embodiments of the present disclosure.

[0311] As shown in Fig. 30 and Fig. 34a(i), in some embodiments, the drug delivery system 91 comprises a drug delivery apparatus 90 and an injection device 93. The injection device 93 is illustrated in the form of a syringe driver. In some embodiments, the injection device 93 may comprise or be in the form of a vacuum injection device. The injection device 93 may be similar or the same as the injection device 14 already described. The injection device 93 may apply an injection pressure (i.e., vacuum pressure 61) to the dilution chamber opening 53, thereby causing the movement of the first plunger 13 such that the pharmaceutical formulation is output by the drug delivery apparatus 2 at a target flow rate. The injection pressure may be a negative pressure.

[0312] The injection device 93 comprises an injection device processor 250. The injection device 93 comprises an injection device memory 252. The injection device comprises a user interface. The user interface may comprise a display 24, which may be as described herein. The user interface may comprise a keyboard 26, which may be as described herein. The injection device 93 is configured to actuate a first plunger 92 of the medication delivery apparatus 90, as described herein.

[0313] The infusion device processor 250 is configured to execute instructions stored in the infusion device memory 252 that cause the infusion device 93 to function according to the methods described. In some embodiments, the instructions are in the form of instruction program code. The infusion device processor 250 may comprise one or more microprocessors, central processing units (CPUs), application specific instruction set processors (ASIPs), application specific integrated circuits (ASICs), or other processors capable of reading and executing instruction code.

[0314] The infusion device memory 252 may comprise one or more volatile or non-volatile memory types. For example, the infusion device memory 252 may include one or more of a random access memory (RAM), a read-only memory (ROM), an electrically erasable programmable read-only memory (EEPROM), or a flash memory. The infusion device memory 252 is configured to store program code accessible by the infusion device processor 250. The program code includes executable program code modules. In other words, the infusion device memory 252 is configured to store executable code modules configured to be executable by the infusion device processor 250. The executable code modules, when executed by the infusion device processor 250, cause the infusion device 93 to perform certain functions (e.g., actuate the first plunger 92) as described in more detail herein.

[0315] The infusion device 93 includes an infusion device network interface 254. The infusion device network interface 254 enables the infusion device 93 to communicate with one or more other computing devices over a communications network 264. The infusion device network interface 254 may include a combination of network interface hardware and network interface software suitable for establishing, maintaining and facilitating communications over an appropriate communications channel. Examples of suitable communications networks 264 include a cloud server network, a wired or wireless internet connection, Bluetooth™ or other near field radio communications, and / or a physical medium, such as a USB.

[0316] The drug delivery system 91 comprises an infusion computing device 151. The infusion computing device 151 comprises an infusion computing device processor 256. The infusion computing device 151 comprises an infusion computing device memory 258. The infusion computing device 151 comprises an infusion computing device user interface 260. The infusion computing device 151 comprises a network interface 262. The infusion computing device 151 is configured to receive one or more method inputs and to determine an infusion process based at least in part on the one or more method inputs.

[0317] The infusion computer user interface 260 may include a display, which may be as described herein. The infusion computer user interface may include a keyboard, which may be as described herein. The infusion computer 151 is configured to receive one or more method inputs via the infusion computer user interface 260.

[0318] The injection computing device processor 256 is configured to execute instructions stored in the injection computing device memory 258 that cause the injection computing device 151 to function according to the described methods. In some embodiments, the instructions are in the form of instruction program code. The injection computing device processor 256 may comprise one or more microprocessors, central processing units (CPUs), application specific instruction set processors (ASIPs), application specific integrated circuits (ASICs), or other processors capable of reading and executing instruction code.

[0319] The infusion computing device memory 258 may comprise one or more volatile or non-volatile memory types. For example, the infusion computing device memory 258 may include one or more of a random access memory (RAM), a read-only memory (ROM), an electrically erasable programmable read-only memory (EEPROM), or a flash memory. The infusion device memory 252 is configured to store program code accessible by the infusion computing device processor 256. The program code includes executable program code modules. In other words, the infusion computing device memory 258 is configured to store executable code modules configured to be executable by the infusion computing device processor 256. The executable code modules, when executed by the infusion computing device processor 256, cause the infusion computing device 151 to perform certain functions (e.g., determine the infusion process described herein) as described in more detail herein.

[0320] Network interface 262 enables infusion computing apparatus 151 to communicate with one or more other computing apparatuses over communications network 264. For example, network interface 262 enables infusion computing apparatus 151 to communicate with infusion device 93. Network interface 262 may include any combination of network interface hardware and network interface software suitable for establishing, maintaining, and facilitating communications over an appropriate communications channel.

[0321] Although the injection calculation device 151 has been described in connection with the drug delivery system 91, it will be appreciated that in some embodiments the drug delivery system 1 may be equipped with the injection calculation device 151 described herein.

[0322] In some embodiments, the drug delivery device 90 comprises a first plunger 92 (which may also be referred to as a primary plunger) and a second plunger 94 (which may also be referred to as a separate plunger). The drug delivery device 90 also comprises a receptacle 96 for receiving the second plunger 94 and at least a portion of the first plunger 92. This may be a distal portion of the first plunger 92.

[0323] The presence of the separation plunger 94 within the container 96 defines two chambers within the container 96, specifically a first chamber 98 (an active agent chamber) and a second chamber 100 (a mixing chamber). In particular, the container 96 and the second plunger 94 together define a diluent chamber 100 configured to receive a diluent. The diluent chamber 100 may be similar or the same as the diluent chamber 32 already described. The first plunger 92, the container 96, and the second plunger 94 together define an active agent chamber 98. The active agent chamber 98 is configured to receive a pharmaceutical formulation.

[0324] Additionally, as described in conjunction with the method of operation of drug delivery device 90, separation plunger 94 is adapted to allow fluid (e.g., active agent) contained in active agent chamber 98 to flow into diluent chamber 100. Diluent chamber 100 may also be referred to as a mixing chamber. Mixing chamber 100 contains a diluent for mixing with the pharmaceutical formulation (or active agent) flowing from active agent chamber 98 into mixing chamber 100 for preparation of a pharmaceutical composition (diluted pharmaceutical formulation) to be delivered to a patient.

[0325] According to this embodiment of the disclosure, the second plunger 94 comprises a valve means 102 (sometimes referred to as valve 102) adapted to control the flow of the active agent into the mixing chamber 100. In other words, the second plunger 94 comprises a valve 102 configured to control the flow of the pharmaceutical formulation from the active agent chamber 98 to the dilution chamber 100. The valve 102 may be configured to control the flow of the pharmaceutical formulation in response to an applied pressure. The pressure may be applied by the first plunger 92. Alternatively, the pressure may be applied via the first plunger 92. In the particular arrangement shown in Figs. 30-34a, the valve means 102 comprises a duckbill valve 104. The duckbill valve 104 comprises a plurality of flaps 106 that separate from one another to open the duckbill valve 104 when pressure is applied to the first plunger 92. When the pressure applied to the first plunger 92 is removed, the flap 106 returns to its original state, closing the duckbill valve 104 and preventing the backflow of the pharmaceutical formulation into the active agent chamber 98 .

[0326] The valve 102 (or valve means 102) comprises an inlet side 113 and an outlet side 115. The valve 102 (or valve means 102) is configured to move from a closed position to an open position when pressure is applied to the inlet side 113. Pressure may be applied to the inlet side 113 of the valve 102 (or valve means 102) by longitudinally displacing (or actuating) a first plunger in the chamber 96 to displace the pharmaceutical formulation. The valve 102 (or valve means 102) is configured to move from an open position to a closed position when the pressure applied to the inlet side is removed. The valve 102 (or valve means 102) may be configured to move from a closed position to an open position when the pressure applied to the inlet side 113 exceeds a pressure threshold. The valve 102 (or valve means) may be configured to move from an open position to a closed position when the pressure applied to the inlet side 113 falls below a pressure threshold. The valve 102 (or valve means 102) is biased towards a closed position. The valve 102 (or valve means 102) comprises a plurality of flaps 106 configured to separate when pressure is applied to the inlet side 113. The first plunger 92 is configured to contact the second plunger 94 when all or a majority of the pharmaceutical formulation in the active agent chamber 98 is transferred to the dilution chamber 100. Further actuation of the first plunger 92 will also result in the movement of the second plunger 94. Thus, actuation of the first plunger 92 causes the movement of the second plunger 94, causing the pharmaceutical formulation in the dilution chamber 100 to be output by the drug delivery device 90.

[0327] Further, the container 96 comprises at least one first port 108 (inlet port) and a second port 110 (outlet port). The inlet port 108 allows the container 96 to be filled with an active agent, and the second port 110 allows either (1) to submit the mixing chamber with a diluent, or (2) to allow a mixture of the active agent and the diluent (pharmaceutical composition) to exit the container 96 (particularly from the mixing chamber 100) for delivery to a patient. The container 96 comprises a first active agent chamber opening 103 configured to receive at least a portion of the first plunger 92. In particular, the active agent chamber 98 comprises the active agent chamber opening 103. The inlet port 108 may be considered as a second active agent chamber opening configured to receive a pharmaceutical formulation. In other words, the active agent chamber 98 may be said to comprise a second active agent chamber opening configured to receive a pharmaceutical formulation. The second active agent chamber opening (inlet port 108) is defined in the wall of the container 96. The active agent chamber 98 may be filled with a pharmaceutical agent by introducing the pharmaceutical agent into the active agent chamber 98 through a second active agent chamber opening (i.e., first port 108). The first port 108 may therefore be referred to as an active agent chamber inlet. The dilution chamber 100 includes a dilution chamber opening 110 defined by the container 96. The dilution chamber opening 110 may be referred to as an exit port of the container 96.

[0328] In the illustrated arrangement, the inlet and outlet ports 108 and 110 (and inlet and outlet ports 118 and 120) are shown as male luer lock connectors, however, in alternative arrangements, the inlet ports, such as 108 and 118, may include female luer lock connectors.

[0329] The first plunger 92 and the second plunger 94 are each configured to be displaced relative to a longitudinal axis of the container 96. The second plunger 94 is disposed between the first plunger 92 and a dilution chamber opening 110 (i.e., the outlet port 110). The second plunger 94 is disposed between the inlet port 108 (the second activator chamber opening) and the dilution chamber opening 110.

[0330] The container 96 defines an inner container surface 107. The first plunger 92 includes a first plunger sealing surface 109. The first plunger 92 is configured to seal with the inner container surface 107. In particular, the first plunger sealing surface 109 is configured to seal with the inner container surface 107 to prevent fluid flow between the inner container surface 107 and the first plunger sealing surface 109.

[0331] The second plunger 94 includes a second plunger sealing surface 111. The second plunger 94 is configured to seal with the inner container surface 107. In particular, the second plunger sealing surface 111 is configured to seal with the inner container surface 107 to prevent fluid flow between the inner container surface 107 and the second plunger sealing surface 111.

[0332] The drug delivery device 91 comprises a conduit 30a. The conduit 30a is configured to be fluidly connected to the dilution chamber opening 110. The conduit 30a has a predetermined volume. That is, the length and the internal surface area of ​​the conduit 30a are dimensioned such that the conduit 30a defines a predetermined volume. Thus, the conduit 30a can hold or store a volume of the diluted pharmaceutical formulation before it is delivered to the patient. The conduit 30a may be referred to as a minimum volume extension tube. The conduit 30a is configured to maintain a volume of the first injection to be delivered to the patient. The volume of the first injection can be prepared by a priming process at a rate that will result in effective mixing in the dilution chamber 110. This is possible because during this time no pharmaceutical formulation is delivered to the patient. Thus, different flow rates can be used for the first volume during priming while driving the mixed fluid exiting the dilution chamber 100 to the end of the conduit 30a. Although the conduit 30a of the drug delivery device 91 is described as having a predetermined volume, it will be understood that a conduit of a predetermined volume can be used with any of the drug delivery devices disclosed herein to achieve similar functionality and advantages.

[0333] FIG. 31 illustrates a process for submitting the container 96 of the drug delivery device 90 with an active agent and a diluent.

[0334] 31, the process of submitting the container 96 includes delivering diluent into the mixing chamber 100 by opening the outlet 110 and delivering the diluent into the mixing chamber 100. Due to the diluent entering the mixing chamber 100, the separation plunger 94 is displaced away from the outlet 110 to allow the diluent to enter and carry the primary plunger 92 with the diluent.

[0335] Once the mixing chamber 100 has been filled with a corresponding amount of diluent, the outlet 110 is closed to allow the activator chamber 98 to be filled.

[0336] Filling the active agent chamber 98 includes opening an inlet port 108 for delivery of the pharmaceutical formulation to the active agent chamber 98. Filling the active agent chamber 98 displaces the primary plunger 92 farther from the outlet 110 until all of the corresponding amount of the pharmaceutical formulation has been delivered into the active agent chamber 98.

[0337] At this stage, the inlet 108 is closed and the drug delivery device 90 may be prepared to deliver the pharmaceutical composition to the patient.

[0338] Preparing the drug delivery apparatus 90 includes attaching a conduit 30a to the outlet 110, as shown in Figure 32. The conduit 30a comprises a minimal volume tubing adapted to be attached to the outlet 110 and an injection device to deliver the pharmaceutical composition to the patient's bloodstream.

[0339] Subsequently, as shown in Figure 33, drug delivery apparatus 90 is mounted onto injection device 14, thereby forming drug delivery system 91. The injection device of Figure 33 is in the form of a syringe driver 17. Drug delivery apparatus 90 is mounted to syringe driver 17 to: (1) prepare a pharmaceutical composition by mixing a pharmaceutical formulation and a diluent, and (2) deliver the pharmaceutical composition (i.e., the diluted pharmaceutical formulation, or the pharmaceutical formulation when the diluent is consumed) to conduit 30a for injection into a patient.

[0340] As shown in Fig. 34a, preparation of a pharmaceutical composition includes pushing a primary plunger 92 to deliver a pharmaceutical formulation contained in an active agent chamber 98 into a diluent chamber 100 to mix with the diluent contained in the diluent chamber 100. The primary plunger 92 is pushed by a syringe driver 17 in such a manner that the pharmaceutical formulation is delivered into the mixing chamber 100 to provide a specific mixing profile in the mixing chamber 100 in cooperation with a valve means 102 to enable the pharmaceutical formulation to be properly mixed with the diluent.

[0341] When the pharmaceutical formulation contained in the active agent chamber 98 is delivered into the dilution chamber 100, mixing occurs to generate a pharmaceutical composition (in this case, a diluted pharmaceutical formulation), which is then delivered to the conduit 30a for injection into the patient. As the pharmaceutical composition is delivered into the conduit 30a, the concentration of the active agent in the dilution chamber 100 increases as the active agent is delivered into the dilution chamber 100 during injection. To deliver the pharmaceutical composition to the patient, the primary plunger 92 is pushed (with the separation plunger 94 abutting against the primary plunger 92) in such a manner that the pharmaceutical composition is delivered according to a particular profile. In particular, the primary plunger 92 is driven based on a particular algorithm.

[0342] First, the primary plunger 92 is driven based on a particular algorithm and before the conduit 30a is fluidly connected to the patient, the syringe driver 17 is operated to drive the primary plunger 90 in a manner to fill (i.e., prime) the conduit 30a so that it is fluidly connected to the patient for delivery of the pharmaceutical composition.

[0343] One advantage of priming the conduit 30a (as described in the immediately preceding paragraph) is that it ensures that the conduit 30a will be filled with the pharmaceutical composition (i.e., the diluted active agent) prior to delivering the pharmaceutical composition to the patient, thus ensuring that the patient will immediately receive the pharmaceutical composition including the diluted active agent.

[0344] Another advantage of priming the conduit 30a is that while priming the conduit 30a (prior to delivering any pharmaceutical composition to the patient), the active agent may be driven into the dilution chamber 100 at an optionally fast flow rate to allow for good mixing before any of the pharmaceutical compositions are delivered to the patient, thereby ensuring proper mixing of the pharmaceutical formulation and diluent in the dilution chamber 100 prior to delivering any pharmaceutical composition to the patient.

[0345] The injection device actuator (e.g., syringe driver 17) is adapted to drive the primary plunger 92 in a specific manner. For example, the syringe driver 17 may be equipped with processing means for executing an algorithm for driving the primary plunger 92 in a specific manner to obtain a specific mixing profile as well as a delivery profile of the pharmaceutical composition.

[0346] The injection device 93 is configured to control the drug delivery apparatus 90 to deliver the drug according to one or more of the methods described herein. In particular, the injection device 93 is configured to actuate the first plunger 92. The injection device 93 is configured to actuate the first plunger 92 such that the fluid stored in the dilution chamber 100 is expelled from the drug delivery apparatus 90 during the injection process.

[0347] The injection device 93 may actuate the first plunger 92 in one of several ways. The injection device 93 may directly actuate the first plunger 92. That is, the injection device 93 may contact the first plunger 92 as part of the actuation. For example, if the injection device 93 comprises a syringe driver 17 or another physical injection device actuator, the injection device may apply a force to the first plunger 92. The force may be applied in a direction parallel to the longitudinal axis of the container 96. The force may move the first plunger 92 toward the dilution chamber opening 110.

[0348] As described herein, in some embodiments, the injection device 93 comprises or is in the form of a vacuum injection device. In such cases, the injection device 93 is configured to apply a vacuum pressure to the dilution chamber opening 110 (and / or port 110). The vacuum pressure applies a vacuum force to the fluid in the dilution chamber 100. This can draw fluid from the dilution chamber 100 through the dilution chamber opening 110. The fluid can be drawn into the conduit 30A.

[0349] Because the fluid in the dilution chamber 100 is generally incompressible, the vacuum force is also applied to the second plunger 94. The vacuum force can be transferred to the fluid (i.e., pharmaceutical formulation) in the active agent chamber 98 via the valve 102 of the second plunger 94 if the vacuum force exceeds a valve force threshold. The valve 102 is configured to open when a force exceeding the valve force threshold is applied to the inlet side 113 of the valve 102. Similarly, the valve 102 is configured to open when a negative pressure applied to the outlet side 115 of the valve 102 is greater than the valve force threshold. In other words, the valve 102 is configured to open when a pressure difference between the inlet side 113 of the valve 102 and the outlet side 115 of the valve 102 is greater than a pressure difference threshold.

[0350] A vacuum force is applied to the outlet side 115 of the valve 102 so that the valve 102 can open and the vacuum force can draw the pharmaceutical formulation through the valve 102. Thus, the vacuum force can be transferred to the pharmaceutical formulation in the active agent chamber 98. Because the pharmaceutical formulation is a fluid, it is also generally incompressible. For this reason, the vacuum force is also applied to the first plunger 92.

[0351] The first plunger 92 moves due to the vacuum force when the valve threshold force is greater than the release force of the first plunger 92. Thus, the injection device 93 is configured to actuate the first plunger 92 by causing the movement of the first plunger 92 using at least vacuum pressure.

[0352] Sadleir method The drug delivery system 91 as previously described may be controlled to deliver a pharmaceutical formulation to a patient in accordance with the Sadleir method. As previously described, the drug delivery system 91 comprises a drug delivery apparatus 90 and an injection device 93. The injection device 93 comprises at least one injection device processor and an injection device memory as previously described. The injection device memory stores program instructions accessible by the at least one injection device processor. The program instructions are configured to cause the at least one injection device processor to actuate an injection device actuator (e.g., syringe driver 17) to control the drug delivery apparatus 90 to deliver a drug in accordance with the Sadleir method.

[0353] In particular, the program instructions may include programming at least one infusion device processor to receive a concentration input (C p ) The concentration may be the concentration of the active agent in the pharmaceutical formulation. p ) may be received via user-provided input. For example, a concentration input (C p ) may be input using the user interface 22. Alternatively, a concentration input (C p ) may be obtained from the infusion device memory. Throughout this specification, the concentration input (C p ) may be the concentration of drug in or delivered from the active agent chamber.

[0354] The program instructions may include programming the at least one infusion device processor to receive a volume input (V p ), which may be the volume of the pharmaceutical formulation in the active agent chamber. p ) may be received via user-provided input. For example, a volume input (V p ) may be input using the user interface 22. Alternatively, a volume input (V p ) may be obtained from the infusion device memory.

[0355] The program instructions may include programming the at least one injection device processor to receive a dilution chamber volume input (V d ). The dilution chamber volume input (V d ) may be received via a user provided input. For example, a dilution chamber volume input (V d ) may be entered using the user interface 22. Alternatively, a dilution chamber volume input (V d ) may be obtained from the infusion device memory. Throughout this disclosure, the dilution chamber volume input (V d ) may correspond to the volume of the associated dilution chamber.

[0356] The program instructions are further configured to cause the at least one infusion device processor to receive a time input (i) indicating a time window during which the pharmaceutical formulation is to be administered. The time input (i) may be received via an input provided by a user. For example, the time input (i) may be entered using the user interface 22. Alternatively, the time input (V p ) may be obtained from the infusion device memory.

[0357] The program instructions are further configured to cause the at least one infusion device processor to receive an infusion number input (τ) indicating the number of infusion intervals per minute for which the infusion modeling function is to be numerically approximated over a time window. The infusion number input (τ) may be received via an input provided by a user. For example, the infusion number input (τ) may be entered using the user interface 22. Alternatively, the infusion number input (τ) may be retrieved from an infusion device memory. Throughout this disclosure, the infusion number input (τ) may correspond to the number of infusion intervals per minute for which a relevant function (e.g., Sadleir function) is calculated.

[0358] Throughout this disclosure, it will be understood that an infusion interval is an interval where an infusion is approximated through numerical approximation. This may be different from an infusion step. An infusion step is an actual infusion step delivered by an associated infusion device. The number of infusion intervals may exceed the number of pump steps of a given period. For example, a 30s pump step may be numerically approximated by 600 infusion intervals. These infusion intervals are used to improve the accuracy of the numerical approximation when using an infusion modeling function. The volumes, concentrations, and / or flow rates determined for the infusion intervals during the numerical approximation are of interest when performing an infusion step with a lower resolution than is actually performed by the infusion device disclosed herein.

[0359] The program instructions are further configured to cause the at least one infusion device processor to receive a number (h) of infusion steps to be performed during the time window. Receiving a number (h) of infusion steps to be performed during the time the pharmaceutical formulation is to be administered may include receiving an infusion step input indicating a number of infusion steps. Alternatively, receiving the number of infusion steps to be performed during the time the pharmaceutical formulation is to be administered may include retrieving the number of infusion steps from an infusion device memory. Receiving the number of infusion steps to be performed during the time the pharmaceutical formulation is to be administered may include multiplying a time input (i) and a number of infusions input (τ). During the infusion process:

number

[0360] The program instructions are further configured to cause the at least one infusion device processor to receive a pharmaceutical formulation input indicating one or more of an identity of the pharmaceutical formulation, a dose of the pharmaceutical formulation, and a maximum pharmaceutical formulation administration rate.

[0361] The program instructions are further configured to cause the at least one infusion device processor to numerically approximate the infusion modeling function over the time window. The at least one infusion device processor may approximate the infusion modeling function over the time window as described in Figures 13a-13c.

[0362] The program instructions are further configured to cause the at least one infusion device processor to determine an infusion rate for the infusion step by summing a plurality of infusion interval volumes calculated by the numerical approximation over which the infusion step will be performed, and then determining an infusion rate that will deliver this volume over the duration of the infusion step.

[0363] The program instructions are configured to cause the at least one infusion device processor to incorporate user input and create a theoretical program of infusion rate versus time or cumulative infusion volume versus time, where time is the duration over which the pharmaceutical formulation is to be administered. Alternatively, the program instructions may be configured to cause the at least one infusion device processor to reference a theoretical program stored in the device memory. The theoretical program may be a numerical approximation as described herein.

[0364] Numerically approximating the infusion modeling function includes determining a number of infusion intervals within the time window, i.e., the at least one infusion device processor determines the number of infusion intervals within the time window.

[0365] Numerical approximation of the injection modeling function is done by determining the starting target flow parameter (S(0) initiating ) to determine the starting target flow parameter (S(0) initiating ) denotes the target flow rate of the pharmaceutical formulation output by the drug delivery device 90 during the numerically approximated start infusion interval.

[0366] Start target flow rate (S(0) initiating Determining θi ) includes calculating:

number

[0367] The program instructions are further configured to cause the at least one infusion device processor to determine a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the numerically approximated starting infusion interval. The at least one infusion device processor is configured to:

number

number

[0368] The program instructions are further configured to cause the at least one infusion device processor to determine a subsequent target flow rate and a subsequent pharmaceutical agent concentration for each of a plurality of subsequent infusion intervals of the numerical approximation. The subsequent target flow rates each indicate a target flow rate of the pharmaceutical agent output by the drug delivery device 90 during a respective subsequent infusion interval of the numerical approximation. The subsequent pharmaceutical agent concentrations each indicate a subsequent approximate concentration of the pharmaceutical agent in the dilution chamber after a respective subsequent infusion interval.

[0369] Each subsequent target flow rate is determined based at least in part on the subsequent pharmaceutical agent concentration of a previous infusion segment of the respective infusion segment, i.e., each subsequent target flow rate is determined at least in part on the subsequent pharmaceutical agent concentration of the infusion segment that occurred immediately prior to the infusion segment of the subsequent target flow rate, and each subsequent pharmaceutical agent concentration is determined at least in part on the subsequent target flow rate of the respective subsequent infusion segment.

[0370] Determining a subsequent target flow rate for one of the plurality of subsequent injection intervals of the numerical approximation is performed using a flow rate parameter S n where n is the number of associated injection intervals.n Determining the dose parameter D mtf (t) n The dose parameter D mtf (t) n To determine

number

[0371] Flow Parameter S n To determine

number

[0372] In some embodiments, determining the subsequent concentration of the pharmaceutical agent of the numerical approximation comprises:

number

[0373] This calculation may be performed for each subsequent pharmaceutical agent concentration of the iteration.

[0374] In some embodiments, the starting target flow rate (S(0) initiating ) includes calculating:

number

[0375] In some embodiments, determining the dose parameters comprises:

number

[0376] In some embodiments,

number

number

[0377] The subsequent target flow rate indicates a target flow rate of the pharmaceutical formulation output by the drug delivery device 90 during the subsequent infusion step. The subsequent target flow rate is determined based at least in part on the subsequent pharmaceutical formulation concentration. The subsequent target flow rate is limited to a maximum pharmaceutical formulation administration rate. Thus, the subsequent target flow rate does not exceed the maximum pharmaceutical formulation administration rate during the infusion. Determining the subsequent target flow rate includes determining a flow rate parameter S n where n is the number of injection steps involved. n Determining the dose parameter D mtf (t) n The dose parameter D mtf (t) n To determine

number

[0378] Determining the initiating target flow rate (S(0)initiating) may include calculating:

number

[0379] Determining the dose parameter may include determining a Tansy function dose by calculating:

number

[0380] This may be equivalent to the following:

number

[0381] The program instructions are further configured to cause the at least one infusion device processor to determine an injection volume for each of the number of injection steps (h). The at least one processor determines the injection volume for each of the number of injection steps (h) based at least in part on the numerical approximation. Each injection volume indicates a volume of pharmaceutical formulation to be output by the drug delivery device 90 during the respective injection step.

[0382] In some embodiments, determining the injection volume of one of the injection steps comprises:

number

[0383] In some embodiments, the program instructions are further configured to cause the at least one infusion device processor to determine an infusion rate for each of the infusion steps. Determining the infusion rate for one of the infusion steps includes:

number

[0384] In some embodiments, the program instructions are further configured to cause the at least one injection device processor to actuate the injection device actuator to displace the first plunger within the chamber such that the determined injection volume of each injection step is output by the drug delivery device 90 during the respective injection step.

[0385] In some embodiments, the program instructions are further configured to cause the at least one infusion device processor to operate the infusion device actuator such that the determined infusion volume of each infusion step is output by the drug delivery device 90 at the determined infusion rate during each infusion step.

[0386] In some embodiments, the program instructions are further configured to cause the at least one injection device processor to actuate the injection device actuator such that the determined injection volume of each injection step is delivered according to a constant velocity profile or a linearly varying velocity profile. The constant velocity profile can be as described herein. The linearly varying velocity profile can be as described herein.

[0387] In some embodiments, the program instructions are further configured to cause the at least one injection device processor to actuate the injection device actuator such that the determined injection volume of each injection step is output in a burst during each subsequent injection step. The burst may be as described herein with reference to FIG. 48, for example. The volume of injection given during any injection step of the Sadleir method may be given by a constant injection or a linearly varying injection rate ("ramp"). The volume may also be given by a single short injection at a higher injection rate but of lower duration, where the same volume is given but the rate of injection is greater and there is also a period of no advancement of the first plunger. There may be more than one cycle of advancement and no advancement (e.g., a "double burst") during an injection step. The period of no advancement of the first plunger may allow the valve means 102 to close, and resumption of advancement may result in opening and enhanced mixing.

[0388] In some embodiments, the concentration input C p but,

number

[0389] In some embodiments, the injection modeling function is a Sadleir function.

[0390] The program instructions are further configured to cause the at least one injection device processor to actuate the injection device actuator to displace the first plunger 92 within the chamber 96 so that a total of h injection steps are delivered and the pharmaceutical formulation is output by the drug delivery device 90 at a subsequent flow rate for the remaining injection steps until the injection is completed.

[0391] The volume of injection given during any pump step of the Diocles method may be given by a constant injection or a linearly varying injection rate ("ramp"). The volume may also be given by a single short injection at a higher injection rate but of lower duration, where the same volume is given but the injection rate is greater and there is also a period of no advancement of the first plunger. There may be more than one cycle of advancement and no advancement (e.g., a "double burst") during an injection pump step. The period of no advancement of the first plunger 92 may allow the valve means 102 to close, and resumption of advancement may result in opening and enhanced mixing.

[0392] After the injection is complete, the active ingredient remaining in the dilution chamber can be administered to the patient by collapsing the dilution chamber.

[0393] Diocles method Figures 34b, 34c and 34d show a particular arrangement of the manner of operation of the drug delivery system 91 depicted in Figures 30-41. That is, Figures 34b, 34c and 34d show a particular arrangement of the manner of operation of the drug delivery apparatus 90 while mounted on a syringe driver 17 (sometimes referred to as an injection driver or injection device).

[0394] In particular, the rate of drug administration is controlled by a particular function (called the Diocles function) according to this embodiment of the disclosure. The Diocles function may be referred to as an infusion modeling function. The Diocles is an intermittent function with two periods for delivering the same dose of drug to the patient over time as the Tansy function using the drug delivery device 90 depicted in Figures 30-41. The first period (when the volume of the active agent chamber 98 is greater than zero and decreasing) uses the Kelly function (see Figure 34c). The Kelly function is a numerical integration algorithm for determining the volume delivered to the patient over time such that the dose delivered to the patient after mixing in the dilution chamber 100 approximates the dose of the Tansy function. The second period is controlled by a Tansy function corrected for the concentration of the active agent in the dilution chamber 100, which is constant once the active agent chamber 98 is empty.

[0395] The Diocles method is used to actuate an infusion device to deliver a pharmaceutical formulation to a patient by a drug delivery device to give the patient a dose of the pharmaceutical formulation over time defined by a Tansy dose function. The Diocles method provides the pharmaceutical formulation according to a step function with two time windows since there are two physically distinct stages in the use of the drug delivery device (change in drug chamber volume, change in constant dilution chamber volume vs. constant (empty) drug chamber volume, changing dilution chamber volume).

[0396] The dilution chamber 100 is filled with diluent and a cap is placed over the outlet from the dilution chamber 100. The active agent chamber 100 is filled with the pharmaceutical formulation as a solution and a cap is placed over the fill port. The drug delivery device 90 is placed into a syringe driver (i.e., injection driver). The cap is removed from the fill port and the syringe driver advances the first plunger 92 until fluid rises up the fill port (loosely removed from the system). The cap is replaced over the fill port.

[0397] The cap is removed from the outlet of the dilution chamber 100. A minimum volume extension tube is attached to the outlet of the dilution chamber 100. The injection driver advances the first plunger 92, injecting the pharmaceutical formulation into the dilution chamber 100 and injecting fluid from the dilution chamber 100 into the minimum volume extension tube until the mixed fluid reaches the end of the tube, then stops the injection.

[0398] Tubing is attached to the patient's IV access. The program is started and the first of h injection steps begins. When the first injection step is complete, subsequent injection steps begin. When the final injection step is complete, the injection stops.

[0399] 34c and 34d are flow diagrams illustrating a method for delivering a pharmaceutical formulation to a patient. The method is the Diocles method.

[0400] As previously described, the drug delivery system 91 comprises a drug delivery apparatus 90 and an infusion device 93. The infusion device 93 may be as previously described, i.e., comprises at least one infusion device processor and an infusion device memory. The infusion device memory stores program instructions accessible by the at least one infusion device processor.

[0401] In particular, the program instructions may include programming the at least one infusion device processor to receive a concentration input (C p ) The concentration may be the concentration of the active agent in the pharmaceutical formulation. p ) may be received via user-provided input. For example, a concentration input (C p ) may be input using the user interface 22. Alternatively, a concentration input (C p ) may be obtained from the infusion device memory.

[0402] The program instructions may include programming the at least one infusion device processor to receive a volume input (V p ), which may be the volume of the pharmaceutical formulation in the active agent chamber 98. p ) may be received via user-provided input. For example, a volume input (V p ) may be input using the user interface 22. Alternatively, a volume input (V p ) may be obtained from the infusion device memory.

[0403] The program instructions include programming the at least one injection device processor to receive a dilution chamber volume input (V d ). The dilution chamber volume input (V d ) indicates the volume of the dilution chamber 100. The dilution chamber volume input (V d ) may be received via a user provided input. For example, a dilution chamber volume input (V d ) may be entered using the user interface 22. Alternatively, a dilution chamber volume input (V d ) may be obtained from the infusion device memory.

[0404] The program instructions are further configured to cause the at least one infusion device processor to receive a time input (i). The time input (i) indicates a time window during which the pharmaceutical formulation is to be administered. The time input (i) may be received via an input provided by a user. For example, the time input (i) may be entered using the user interface 22. Alternatively, the time input (i) may be obtained from an infusion device memory. The time window includes a first time window and a second time window.

[0405] The program instructions are further configured to cause the at least one infusion device processor to receive an infusion number input (τ). The infusion number input (τ) indicates the number of infusion intervals per minute for which the infusion modeling function is to be numerically approximated over the first time window. The infusion modeling function may be a Kelly function. The infusion number input (τ) may be received via a user-provided input. For example, the infusion number input (τ) may be entered using the user interface 22. Alternatively, the infusion number input (τ) may be retrieved from an infusion device memory.

[0406] The program instructions are further configured to cause the at least one infusion device processor to receive a number (h) of infusion steps to be performed during the time window. During the first time window, a first number of infusion steps (h1) are performed. During the second time window, a second number of infusion steps (h2) are performed. Receiving the number (h) of infusion steps to be performed during the time window may include receiving an infusion step input indicating the number (h) of infusion steps. Alternatively, determining the number (h) of infusion steps to be performed during the time window may include retrieving the number (h) of infusion steps from an infusion device memory. Receiving the number (h) of infusion steps to be performed during the time window may include multiplying a time input (i) and an infusion number input (τ).

[0407] The program instructions may be further configured to cause the at least one infusion device processor to determine a current time (t), which may indicate a time within the time window.

[0408] The at least one infusion device processor numerically approximates the infusion modeling function. In particular, the at least one infusion device processor numerically approximates the infusion modeling function over a first time window. To numerically approximate the infusion modeling function over the first time window, the at least one infusion device processor may perform the functions described below. That is, numerically approximating the infusion modeling function may include the functions described below.

[0409] At least one processor determines the number of infusion intervals for the first time window. Determining the number of infusion intervals in the first time window of the numerical approximation includes multiplying a time input (i) and an infusion number input (τ). As previously described, the infusion device can perform a certain number of infusion "events" (i.e., infusion steps) per minute. The infusion device could be capable of delivering an infusion at a certain rate over an interval of, for example, 20 seconds at a certain constant rate, then 20 seconds at another constant rate, then 20 seconds at another constant rate. Thus, there would be three infusion "events" per minute (i.e., three infusion steps per minute). For example, some infusion devices are limited to 99 programmable "events" during the course of an infusion, so a 30 minute infusion with three events per minute would be near the limit of the programmability of the infusion device. The specific features of the infusion device are variable, and what is important is that these specific features can be programmed and that the infusion device can approximate an "ideal" infusion program by a series of infusion "steps" at a certain rate.

[0410] The at least one processor determines a starting target flow parameter (K(0) initiating The start target flow rate parameter indicates the target flow rate of the pharmaceutical formulation output into the dilution chamber 100 during the start infusion interval of the numerical approximation.

[0411] Starting target flow parameter (K(0) initiating Determining θi ) includes calculating:

number

[0412] The at least one processor determines a starting pharmaceutical agent concentration. The starting pharmaceutical agent concentration indicates an approximate concentration of the pharmaceutical agent in the dilution chamber 100 after the numerically approximated starting injection interval. Determining the starting pharmaceutical agent concentration includes:

number

number

[0413] The at least one processor iteratively determines a subsequent target flow rate and a subsequent pharmaceutical agent concentration for each of a plurality of subsequent infusion intervals of the numerical approximation. The subsequent target flow rates each indicate a target flow rate of the pharmaceutical agent output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation. The subsequent pharmaceutical agent concentrations each indicate a subsequent approximate concentration of the pharmaceutical agent in the dilution chamber 100 after the respective subsequent infusion interval. Each subsequent target flow rate is determined based at least in part on a subsequent pharmaceutical agent concentration of a previous infusion interval of the respective infusion interval. Each subsequent pharmaceutical agent concentration is determined based at least in part on a subsequent target flow rate of the respective subsequent infusion interval.

[0414] Determining the subsequent target flow rates includes determining a flow rate parameter K n The at least one infusion device processor determines:

number

[0415] In particular, the target dose Dose(t) n Determining the dose of the Tansy function T(t) includes determining the dose of the Tansy function T(t). n To determine

number

[0416] In some embodiments,

number

number

[0417] In some embodiments, determining the subsequent pharmaceutical agent concentration of the first numerical approximation comprises:

number

[0418] This calculation may be performed for each subsequent pharmaceutical agent concentration of the iteration.

[0419] The at least one infusion device processor determines a first injection volume for each of the first number of injection steps (h1). In particular, the at least one infusion device processor determines the first injection volume for each of the first number of injection steps (h1) based at least in part on the numerical approximation. The injection volume indicates a volume of the pharmaceutical formulation output by the drug delivery device during the respective injection step.

[0420] The at least one infusion device processor comprises:

number

[0421] The at least one infusion device processor determines a number of infusion intervals for the second time window.

[0422] The at least one infusion device processor calculates a target dose Dose(t) for each of the number of infusion intervals in the second time window. n This can be described in Figures 34a to 34c.

[0423] The at least one infusion device processor determines the target flow rate D for each of the number of infusion intervals of the second time window based at least in part on the target dose for each infusion interval. n Determining the target flow rate for each of the number of injection intervals of the second time window includes:

number

[0424] The at least one infusion device processor determines a second injection volume for each of the second number of injection steps (h2) based at least in part on the target flow rate. Determining the second injection volume for one of the second number of injection steps (h2) includes:

number

[0425] The at least one injection device processor actuates the injection device actuator to displace the first plunger such that the determined injection volume of each injection step (h) is output by the drug delivery device 90 during the respective injection step.

[0426] In some embodiments, the program instructions are further configured to cause the at least one infusion device processor to determine an infusion rate for each of the infusion steps (h), wherein determining the infusion rate for one of the infusion steps comprises:

number

[0427] In some embodiments, the program instructions are further configured to cause the at least one infusion device processor to operate the infusion device actuator such that the determined infusion volume for each infusion step is output by the drug delivery device 90 during the respective infusion step at the determined infusion rate.

[0428] In some embodiments, the program instructions are further configured to cause the at least one injection device processor to operate the injection device actuator such that the determined injection volume of each injection step is delivered according to a constant velocity profile or a linearly varying velocity profile.

[0429] In some embodiments, the program instructions are further configured to cause the at least one infusion device processor to operate the infusion device actuator such that the determined infusion volume of each infusion step is output by the drug delivery device during each subsequent infusion step in a burst.

[0430] In some embodiments, receiving the number of infusion steps to be performed during the time window includes receiving an infusion step input indicating the number of infusion steps, hi some embodiments, receiving the number of infusion steps to be performed during the time window includes retrieving the number of infusion steps from an infusion device memory.

[0431] In some embodiments, the program instructions further configure the at least one infusion device processor to receive a pharmaceutical formulation input. The pharmaceutical formulation input may indicate one or more of an identity of the pharmaceutical formulation, a dose of the pharmaceutical formulation, and a maximum pharmaceutical formulation administration rate. In some embodiments, a subsequent target flow rate is limited to the maximum pharmaceutical formulation administration rate such that the subsequent target flow rate does not exceed the maximum pharmaceutical formulation administration rate.

[0432] Figures 49a to 49g show the V p , V d, and theoretical results provided by an implementation of the Diocles method for particular values ​​of i. FIG. 49a is a chart illustrating the fluid injection rate (y-axis) of the Diocles method versus injection time in minutes (x-axis). FIGS. 49a and 49b (first 3 minutes of a 30 minute injection) are charts illustrating injection flow rate versus time. FIG. 49c is a chart illustrating the concentration (x-axis) of the pharmaceutical formulation delivered to the patient, with the x-axis units being percentage of the total dose (or therapeutic dose per mL) in the active agent chamber 98 versus injection time in minutes (x-axis). FIG. 49d is a logarithmic chart of the instantaneous percentage dose of the pharmaceutical formulation delivered per second (y-axis) versus injection time in minutes (x-axis). FIG. 49e is a chart illustrating the cumulative percentage dose (y-axis) versus injection time in minutes (x-axis). FIG. 49f is a logarithmic chart illustrating the cumulative percentage dose (y-axis) versus injection time in minutes (x-axis). FIG. 49g is a chart showing the number of minutes until the cumulative dose delivered is 10 times the cumulative dose at the time shown on the x-axis. For example, at 2 minutes into the infusion, it will take another 5 minutes for the cumulative dose to be 10 times the cumulative dose that was at 2 minutes, and at 14 minutes into the infusion, it will take another 6.7 minutes for the cumulative dose administered to be 10 times the cumulative dose that was at 14 minutes. FIG. 49h is a chart showing the ratio of the cumulative dose at each time point during the infusion at that time compared to the cumulative dose at 5 minutes into the infusion. For example, at 2 minutes into the infusion, the cumulative dose at 5 minutes will be approximately 10 times the cumulative dose at 2 minutes, and at 14 minutes into the infusion, the ratio of the cumulative dose at 5 minutes will be approximately 5.7 times the cumulative dose that was at 14 minutes. These graphs show the intervals that are likely available to wait for the onset of adverse reactions before a dose is given that would cause a more severe reaction.

[0433] The volume of injection given during any pump step of the Diocles method may be given by a constant injection or a linearly varying injection rate ("ramp"). The volume may also be given by a single short injection at a higher injection rate but of lower duration, where the same volume is given but the injection rate is greater and there is also a period of no advancement of the first plunger 92. There may be more than one cycle of advancement and no advancement (e.g., a "double burst") during an injection step. The period of no advancement of the first plunger 92 may allow the valve means 102 to close, and resumption of advancement may result in opening and enhanced mixing.

[0434] Delivery methods that exceed the maximum delivery rate or the maximum tolerated dose As a result of user settings, it is possible to exceed the maximum rate of delivery of the drug during the injection process. To prevent this from happening, the drug delivery system can check that each injection step does not exceed the maximum allowed dosage rate by estimating the dilution chamber drug concentration and the fluid injection rate. The dilution chamber drug concentration as a function of the cumulative drug volume injected (V) is given by the following equation:

number

[0435] Cisplatin medication

[0436] For example, the man's current dosing is 40 mg / m2 over 1 hour in 1000 mL of diluent. The protocol (i.e., drug delivery system) delivers 72 mg of cisplatin in 1000 mL over 60 minutes, which is a fluid infusion rate of 16.7 ml / min, and a dose rate of 1.2 mg / min.

[0437] If this is delivered using the drug delivery device 90 previously disclosed, 72 mg of cisplatin in 1000 mL of diluent can be prepared in a flask connected to the drug delivery device 90 by a peristaltic fluid pump. The dilution chamber 100 can be set to a volume of 50 mL. In both described cases, the Diocles algorithm can be used so that the injection duration is limited by the maximum dosing rate (rather than using the Sadleir algorithm, which is chosen if the dilution chamber 100 is not automatically collapsed and if an automatic program prior to manually collapsing the dilution chamber is desired to have a set duration).

[0438] The duration of the infusion can be set to 60 minutes using 120 constant infusion steps of 30 seconds. Using this arrangement, the dose rate increases exponentially over the duration of the infusion. The minimum infusion flow rate is 0.306 ml / min (18.4 ml / hr). The maximum allowable dose rate (1.2 mg / min) is reached at 46 minutes 29 seconds, when the cumulative volume administered is 143 mL, the dilution chamber concentration is 0.0.0679 mg / mL, and the infusion rate is 17.7 ml / min. For the subsequent infusion step, the infusion rate is limited to 17.7 mL / min, and the cumulative volume at the end of the step is 161 mL. The dilution chamber concentration is then estimated to be 0.0691 mg / mL. The following step will reduce the infusion rate to 17.4 mL / min to ensure the maximum allowable dose rate (not to exceed 1.2 mg / min). This adjustment of the injection rate for each step will continue until the injection is complete. The duration of the injection will be extended to a total injection duration of approximately 98 minutes. The injection rate for the final step is approximately 16.7 mL / min with a dilution chamber concentration of 0.072 mg / ml. After the injection is complete, the dilution chamber can either be collapsed to deliver the final 50 mL of solution or an additional 50 mL of drug injection can be delivered from the drug flask through the dilution chamber.

[0439] The duration of the infusion can be set to 180 minutes using 360 constant infusion steps of 30 seconds. Using this arrangement, the dose rate increases exponentially over the duration of the infusion. The minimum infusion flow rate is 0.1 mL / min (6 ml / hr). Because the maximum allowable infusion dose rate (1.2 mg / min) is exceeded at 158 ​​minutes 29 seconds, the infusion will be limited to the infusion rate of the subsequent interval (starting at 158 ​​minutes 30 seconds). The cumulative volume delivered is 338.5 mL and the infusion rate is 16.7 ml / min. The dilution chamber concentration is estimated to be 0.0719 mg / mL, so the allowable infusion rate for all subsequent intervals is 16.7 mL / min. Infusion of the remaining 661.5 mL is completed in another 40 minutes (approximately 198 minutes total infusion time). After the 1000 mL drug infusion has been injected, the dilution chamber can be collapsed to deliver the final 50 mL of solution, or an additional 50 mL drug infusion can be delivered from the drug flask through the dilution chamber.

[0440] Rocuronium Dosing Rocuronium is a non-depolarizing neuromuscular blocking agent and is chosen as an example of a drug where only a portion of its therapeutic dose can be administered slowly (the remainder must be administered either quickly or slowly when anesthetized). Rocuronium is administered intravenously at a dose of 0.6 mg / kg (50 mg for an 80 kg patient). It is usually administered as a push after anesthesia is induced.

[0441] Rocuronium may be administered to awake patients at doses up to approximately 0.03 mg / kg (2.4 mg for an 80 kg patient), which produces minor and tolerable side effects (blurred vision).

[0442] A test dose or desensitization may be administered by diluting 50 mg of rocuronium in a 50 mL injection volume Vp infused over 30 minutes using a 10 mL dilution chamber, but interrupting the infusion for induction of anesthesia once 0.03 mg / kg has been administered. The remaining infusion can then be given as a push (if immediate relaxation is required upon induction) or by continuing the remaining infusion.

[0443] Using drug delivery system 91 with this protocol, 2.4 mg is administered after 21 minutes and 14 seconds. The infusion rate at this point is 1.43 ml / min and 7.83 ml of solution has been infused.

[0444] Method for calculating infusion rate and cumulative volume delivered using drug delivery system 91 As stated, the dilution chamber drug concentration as a function of the cumulative drug volume injected (V) is given by the following equation:

number

[0445] This relationship can be maintained until the volume of the dilution chamber is reduced by the advancing plunger, beyond which point the dilution chamber concentration remains constant.

[0446] Exemplary Injection with Diocles Method and Drug Delivery System 91 30-34d and 42 show a drug delivery device 90 operating as a syringe for attachment to a syringe driver 17 for delivering a pharmaceutical composition (i.e., a mixture of an active agent and a diluent). This particular arrangement of the drug delivery device 90 is particularly useful (when compared with the diluent chamber 32 depicted with reference to FIG. 2) because it allows for the omission of the diluent chamber 32 (located remotely from the syringe driver 17) that is used to mix the active agent and the diluent prior to delivery of the pharmaceutical composition (containing the active agent and the diluent) to a patient.

[0447] However, in an alternative arrangement (see FIG. 43), the dilution chamber 100 may function as the dilution chamber 32 located remotely from the syringe driver 17, as depicted in FIG.

[0448] As shown in FIG. 43, the drug delivery device 90 includes a plunger lock 134 to secure the primary plunger 92 in a specific location that allows delivery of the active agent (coming from the syringe driver 17) into the active agent chamber 98 for delivery of the drug via a separate plunger and into a mixing chamber 100 for delivery to the patient via conduit 30b.

[0449] 43 comprises a body having a lower surface 137 for resting on a support surface and an upper surface 139 having spaced grooves 141a and 141b for receiving flanges 145 and 147 of the primary plunger 92 and activator chamber 98. In this manner, the primary plunger 92 is fixed in a particular position where it cannot move within the activator chamber 98.

[0450] 43, the primary plunger 92 is located at a particular location such that the activator chamber 98 has a relatively small volume. The primary plunger 92 being locked in place due to the plunger lock 134 prevents the primary plunger 92 from moving, thus maintaining the relatively small volume of the activator chamber 98 constant as the activator is delivered from the syringe driver 17 through the conduit 30a into the activator chamber 98.

[0451] In operation, as the active agent is delivered to the volumetric active agent chamber 98, the pharmaceutical formulation flows through the separation plunger 94 into a mixing chamber 100 for mixing the pharmaceutical formulation with a diluent to prepare a pharmaceutical composition for delivery to the patient's bloodstream via conduit 30a. Figures 43b and 43c illustrate the method of operation of drug delivery device 90 when operated remotely from a syringe driver 17 with a syringe 15 filled with the active agent alone.

[0452] In particular, the rate of active agent administration is governed by the Sadleir function, which is a numerical integration function for determining the volume delivered to the patient over time such that the dose delivered to the patient after mixing in the drug delivery device 90 approximates a fixed fraction of the Tansy function dose at that time using the Sadleir embodiment. This is because at the end of the injection, some pharmaceutical composition still remains in the mixing chamber 100 that will be delivered to the patient by moving the primary plunger 92 towards the outlet 110.

[0453] In an alternative arrangement, as described above, the concentration of active agent in the dilution chamber 100 can be increased over time to deliver the same dose as the Tansy function, and then the remaining pharmaceutical composition in the dilution chamber 100 can be discarded without being delivered to the patient.

[0454] Control of an injection device using analytical solutions for cumulative volume and rate functions.

[0455] Several methods for delivering pharmaceutical formulations to a patient described herein involve using a numerical approximation of an injection modeling function to control the actuation of an injection device actuator and the flow rate of a fluid exiting the drug delivery device 1, 90. Such use of a numerical approximation may increase the computational demands of the hardware on which the method is implemented. For example, the injection computing unit 151 and / or the injection device 93 may require a more powerful processor and / or more memory to calculate the numerical approximation of the injection modeling function. It may therefore be beneficial to be able to deterministically calculate a solution to the injection modeling function that may be used to control the drug delivery system 1, 91. That is, controlling the drug delivery system 1, 91 using an analytical solution to the injection modeling function may reduce the demands, and thereby the cost, of the injection computing unit 151 and / or the injection device 93. In some embodiments, controlling the drug delivery system 1, 91 using an analytical solution to the injection modeling function may reduce the pre-injection delay time associated with the injection computing unit 151 and / or the injection device 93 preparing for injection (i.e., the required calculations may be performed faster on existing hardware than alternative methods).

[0456] Disclosed herein are multiple methods of delivering a pharmaceutical formulation to a patient. One or more of these methods include determining an infusion process to be performed by an infusion device. The infusion process is determined by the infusion computing unit 151. The infusion process is stored as an infusion process file. For example, the infusion process may be stored in the infusion computing unit memory 258 as an infusion process file. The infusion process file may be transmitted to the infusion device 93 for execution.

[0457] Method for delivering a pharmaceutical formulation to a patient 5500 Figure 55 is a process flow diagram of a method 5500 for delivering a pharmaceutical formulation to a patient, according to some embodiments. The method 5500 may be performed by a drug delivery system 1 and / or a drug delivery device 10 described with reference to Figures 1-2. The method 5500 may be performed by a drug delivery system 91 and / or a drug delivery device 90 described with reference to Figures 30-34a or Figures 42-43. The drug delivery system 91 comprises the drug delivery device 90 and an injection device 93, as described herein. The pharmaceutical formulation is delivered to the patient according to an injection process.

[0458] The injection process is initiated at an initial time. Although the method 5500 is described with reference to the drug delivery system 91 of Figures 30-34A and 42-43, it will be understood that the description also applies to the drug delivery system and / or drug delivery device 10 and drug delivery system described with reference to Figures 1-2.

[0459] Part or all of the method 5500 may be performed by the infusion device processor 250 (i.e., the processor of the infusion device 93). Part or all of the method may be performed by the infusion computing device 151. Part or all of the method may be performed by another computing device. Thus, the method 5500 may be considered a computer-implemented method.

[0460] As described herein, the drug delivery device 90 is configured to store at least one fluid. Specifically, the drug delivery device 90 includes an active agent chamber 98 configured to store a fluid including an active agent. The fluid including the active agent may be referred to as a first fluid. The fluid including the active agent may be referred to as a pharmaceutical formulation, as described herein. The drug delivery device 90 includes a diluent chamber 100 configured to store a diluent. The diluent may be referred to as a second fluid.

[0461] The drug delivery device 90 is configured to output a fluid. When the active agent chamber 98 stores a fluid, actuation of the first plunger 92 (i.e., movement of the first plunger towards the dilution chamber outlet 27) applies a pushing force to the fluid. This pushing force forces the fluid stored in the active agent chamber 98 through the valve 39 of the second plunger 94 and into the dilution chamber 100. The fluid in the dilution chamber 100 (i.e., the diluent or diluted pharmaceutical formulation) is thereby pushed out of the dilution chamber outlet 110 (via the conduit 30a) towards the patient. That is, the fluid in the dilution chamber 100 is discharged from the dilution chamber 100.

[0462] Once the active agent chamber 98 is emptied, actuation of the first plunger 92 (i.e., movement of the first plunger 92 towards the dilution chamber outlet 110) applies a biasing force to the second plunger 94 causing the second plunger 94 to move. This forces the fluid stored in the dilution chamber 100 out the dilution chamber outlet 110 towards the patient. That is, the fluid in the dilution chamber 100 is expelled from the dilution chamber 100. For purposes of at least one of the methods disclosed herein, the fluid expelled from the drug delivery device is the fluid stored in the dilution chamber 100 (i.e., the diluted pharmaceutical formulation).

[0463] In some embodiments, the fluid forced out of the dilution chamber outlet 110 may be referred to as a pharmaceutical formulation. In some embodiments, the fluid forced out of the dilution chamber outlet 110 may be referred to as a diluted pharmaceutical formulation. In some embodiments, the fluid forced out of the dilution chamber outlet 110 may be referred to as a pharmaceutical composition.

[0464] In some embodiments, the method 5500 may be referred to as the analytical Diocles method, or the Diocles method.

[0465] At 5502, the infusion computing device 151 receives one or more method inputs. In particular, the infusion computing device processor 256 receives the one or more method inputs. In some embodiments, the one or more method inputs include a plurality of method inputs. The one or more method inputs may be received via the infusion computing device user interface 260 (e.g., via a display and / or keyboard). In some embodiments, at least one of the one or more method inputs is an input of a cumulative delivery volume function. In some embodiments, at least one of the one or more method inputs is an input of a dose function. A clinician may input the one or more method inputs.

[0466] In some embodiments, one or more method inputs include a concentration input (C p ) is included. Concentration input (C p ) may be as described herein. p ) indicates the concentration of the pharmaceutical agent in the active agent chamber 98. p ) may indicate the concentration of a drug dissolved in a solvent, where the solvent containing the dissolved drug is a pharmaceutical formulation.

[0467] In some embodiments, the one or more method inputs include a volume input (V p ) is included. Volume input (V p ) may be as described herein. p ) indicates the volume of the pharmaceutical formulation in the active agent chamber 98. p ) may correspond to the volume of the activator chamber 98.

[0468] In some embodiments, one or more method inputs include a dilution chamber volume input (V d ) Dilution chamber volume input (V d ) may be as described herein. Dilution chamber volume input (V d ) indicates the volume of the dilution chamber 100. The dilution chamber volume input (V d ) may correspond to the volume of diluent.

[0469] In some embodiments, the one or more method inputs include a time input (i). The time input (i) may be as described herein. The time input (i) indicates at least a portion of a time window for delivering the pharmaceutical formulation. In some embodiments, the time input (i) indicates a total length of the time window. The time window includes a first time window and a second time window.

[0470] In some embodiments, the first time window extends over a period of time during which the first plunger 92 is displaced towards the second plunger 94 without contacting the second plunger 94. This may be the case, for example, when the method 550 is performed by the drug delivery system 91 described with reference to Figures 30-34A or 42-43. During the first time window, actuation of the first plunger 92 displaces the pharmaceutical formulation from the active agent chamber 98 to the diluent chamber 100.

[0471] The second time window extends over a period of time during which the first plunger 92 and the second plunger 94 move simultaneously. In some embodiments, this is when the first plunger 92 and the second plunger 94 are in contact. This may be the case, for example, when the method 550 is performed by the drug delivery system 93 described with reference to Figures 30-34A or 42-43. During the first time window, actuation of the first plunger 92 displaces the pharmaceutical formulation from the active agent chamber 98 to the diluent chamber 100.

[0472] During the second time window, displacement of the first plunger 92 causes a corresponding displacement of the second plunger 94. During the second time window, the concentration of the pharmaceutical agent in the dilution chamber 100 remains constant because the active agent chamber 98 has emptied its contents into the dilution chamber 100.

[0473] The method 5500 includes performing a number (h) of injection steps within a time window. A first number of injection steps (h1) are performed within the first time window. A second number of injection steps (h2) are performed within the second time window.

[0474] In 5504, the infusion computing device 151 determines the number of infusion steps (h) to be performed within the time window. In particular, the infusion computing device processor 256 determines the number of infusion steps (h) to be performed within the time window. The infusion computing device processor 256 determines a first number of infusion steps (h1) to be performed within a first time window. The infusion computing device processor 256 determines a second number of infusion steps (h2) to be performed within a second time window. The time window, the first time window, the second time window, the number of infusion steps (h), the first number of infusion steps (h1), and / or the second number of infusion steps (h2) may be as described herein.

[0475] In some embodiments, determining the number of infusion steps (h) includes receiving the number of infusion steps (h), which is received (e.g., by the infusion computing device processor 256) as an infusion steps input. Alternatively, one or more method inputs may include the number of infusion steps (h).

[0476] In some embodiments, determining the number of injection steps (h) includes calculating the product of the number of injection steps (per minute) performed within the time window (g) and the time input (i). That is, to determine the number of injection steps (h), the injection computing device processor 256 calculates: h = g × i where h is the number of injection steps performed within the time window, g is the number of injection steps performed per minute during the injection process, and (i) is the time input. Thus, the time input (i) indicates the length of the injection process in minutes. In these embodiments, the injection computing device processor 256 may store the number of injection steps (h) in the injection computing device memory 258. The injection computing device processor 256 may then issue a read transaction to the injection computing device memory 258 for the number of injection steps (h) and receive the number of injection steps (h) in response. Thus, receiving the number of injection steps (h) may include determining the number of injection steps (h).

[0477] In some embodiments, the infusion computing device processor 256 determines the first number of infusion steps (h1) based at least in part on the determined transition time. For example, the infusion computing device processor 256 may divide the difference between the transition time and the initial time of the infusion process by the infusion step duration. The infusion computing device processor 256 may determine the second number of infusion steps (h2) based at least in part on the transition time. For example, the infusion computing device processor 256 may divide the difference between the infusion end time (i.e., the time of the end of the infusion process) and the initial time by the infusion step duration. The infusion computing device processor 256 may subtract this from the first number of infusion steps (h1) to determine the second number of infusion steps (h2). The transition time may be as described herein.

[0478] In 5506, the injection calculation device 151 determines a first cumulative delivery volume (KV1) of an injection step of the first number of injection steps (h1). In particular, the injection calculation device processor 256 determines a first cumulative delivery volume (KV1) of an injection step of the first number of injection steps (h1). The first cumulative delivery volume (KV1) indicates a cumulative volume of fluid discharged from the drug delivery device 90 between an initial time and an initial injection step time. The fluid discharged from the drug delivery device 90 is a fluid stored in the dilution chamber 100 at the time of the injection step of the first number of injection steps (h1). That is, the fluid is a diluted pharmaceutical formulation. As described herein, the initial time corresponds to the start of the injection process. For example, the initial time may be 0. The initial injection step time corresponds to the start of an injection step of the first number of injection steps (h1). The initial injection step time may be indexed with respect to the initial time. For example, the initial injection step time may be the number of milliseconds or seconds after the initial time that an injection step of the first number of injection steps (h1) begins.

[0479] The injection computation unit processor 256 determines a first cumulative delivery volume (KV1) using a cumulative delivery volume function, sometimes referred to as a Kelly cumulative volume function. The cumulative delivery volume function has one or more inputs. The one or more inputs of the cumulative delivery volume function include an initial injection step time of an injection step of the first number of injection steps (h1), a time input (i), a dilution chamber volume input (V d ) and volume input (V p ) for the first number of injection steps (h1). Thus, the injection computation unit processor 256 may include one or more of the following inputs: an initial injection step time, a time input (i), a dilution chamber volume input (V d ) and volume input (V p ) determining a first cumulative delivered volume (KV1) based at least in part on one or more of:

[0480] The cumulative delivered volume function is

number

[0481] This is sometimes called the Kelly cumulative volume function.

[0482] Solving for KV in the cumulative delivered volume function provides a measure of the cumulative volume of fluid expelled from the drug delivery device 90 between an initial time and a given time (t).

[0483] Thus, the injection calculation unit processor 256:

number

[0484] The first cumulative delivery volume KV1 is calculated by dividing the initial time by the initial injection step time (t i ) provides an indication of the cumulative volume of fluid expelled from the drug delivery device 90 between the

[0485] In 5508, the injection calculation device 151 determines a second cumulative delivery volume (KV2) of the injection step of the first number of injection steps (h1). In particular, the injection calculation device processor 256 determines a second cumulative delivery volume (KV2) of the injection step of the second number of injection steps (h2). The second cumulative delivery volume (KV2) indicates a cumulative volume of fluid discharged from the drug delivery device 90 between an initial time and a subsequent injection step time. The cumulative volume of fluid discharged from the drug delivery device 90 between an initial time and a subsequent injection step time may be referred to as a second cumulative volume. The fluid discharged from the drug delivery device 90 is the fluid stored in the dilution chamber 100 at the time of the injection step of the first number of injection steps (h1). That is, the fluid is a diluted pharmaceutical formulation. As described herein, the initial time corresponds to the start of the injection process. The subsequent injection step time corresponds to the end of the injection step of the first number of injection steps (h1). The subsequent injection step time may be indexed relative to the initial time, for example, the subsequent injection step time may be the number of milliseconds or seconds after the initial time that an injection step of the first number of injection steps (h1) ends.

[0486] The infusion calculator processor 256 determines a second cumulative delivery volume (KV2) using a cumulative delivery volume function.

[0487] In particular, the injection computing device processor 256 includes:

number

[0488] The second cumulative delivery volume KV2 is calculated by dividing the initial time by the time of the subsequent injection step (t s ) provides an indication of the cumulative volume of fluid expelled from the drug delivery device 90 between the

[0489] In 5510, the injection calculation device 151 determines a first injection volume of an injection step of the first number of injection steps (h1). In particular, the injection calculation device processor 256 determines the first injection volume. The first injection volume indicates a volume of fluid discharged from the drug delivery device 90 during an injection step of the first number of injection steps (h1). The injection calculation device processor 256 determines the first injection volume based at least in part on the first cumulative delivery volume (KV1) and the second cumulative delivery volume (KV2).

[0490] In some embodiments, the injection calculation device processor 256 determines the first injection volume by determining the difference between the second cumulative delivery volume (KV2) and the first cumulative delivery volume (KV1). That is, the injection calculation device processor 256 subtracts the first cumulative delivery volume (KV1) from the second cumulative delivery volume (KV2). The result of this subtraction is the first injection volume.

[0491] In 5512, the injection calculation device 151 determines a first target flow rate for an injection step among the first number of injection steps (h1). In particular, the injection calculation device processor 256 determines the first target flow rate. The first target flow rate is a target flow rate for an injection step among the first number of injection steps (h1). The injection calculation device processor 256 determines the first target flow rate based at least in part on a first injection volume for an injection step among the first number of injection steps (h1).

[0492] The drug delivery system 91 is configured to deliver an injection step of a first number of injection steps (h1) over a first injection step duration. The first injection step duration is a period of time (e.g., 20 seconds). In some embodiments, determining the first target flow rate includes dividing the first injection volume by the first injection step duration.

[0493] In some embodiments, the first target flow rate is determined using a target flow rate function, which may be a derivative of the cumulative volume function.

number

[0494] It should be noted that in some embodiments, each injection step of the first number of injection steps (h1) may have the same injection step duration. Alternatively, at least some of the injection steps of the first number of injection steps (h1) may have different injection step durations. For example, a first injection step duration may be different from the injection step duration of another injection step of the first number of injection steps (h1).

[0495] In some embodiments, the first injection step duration is shorter than the injection step duration of another injection step of the first number of injection steps (h1). In such a case, an injection step of the first number of injection steps (h1) may be delivered closer to the initial time than another injection step of the first number of injection steps (h1). Alternatively, an injection step of the first number of injection steps (h1) may be delivered further away from the initial time than another injection step of the first number of injection steps (h1).

[0496] In 5514, the infusion computing device 151 calculates the first pharmaceutical dose (Dose) of the infusion step of the second number of infusion steps (h2).c1 In particular, the infusion computing device processor 256 determines a first pharmaceutical dose. c1 Determine the first pharmaceutical dose. c1 ) indicates the cumulative pharmaceutical formulation dose output by the drug delivery device between the initial time and the initial injection dose time. This may be the cumulative dose of the active agent of the pharmaceutical formulation. The initial injection dose time corresponds to the start of the injection step of the second number of injection steps (h2). The fluid discharged from the drug delivery device 90 is the fluid stored in the dilution chamber 100 at the time of the injection step of the second number of injection steps (h2). That is, the fluid is the diluted pharmaceutical formulation. The cumulative pharmaceutical formulation dose is the dose (i.e., amount) of the active agent in this fluid output by the drug delivery device 90. As described herein, the initial time corresponds to the start of the injection process. For example, the initial time may be 0. The initial injection dose time corresponds to the start of the injection step of the second number of injection steps (h2). The initial injection dose time may be indexed with respect to the initial time. For example, the initial injection dose time may be the number of milliseconds or seconds after the initial time that the injection step of the second number of injection steps (h2) begins.

[0497] The infusion calculator processor 256 calculates the first pharmaceutical dose using the dose function. c1 The dose function has one or more inputs. The one or more inputs of the dose function include an initial infusion dose time of an infusion step of the second number of infusion steps (h2), a concentration input (C p ), time input (i), dilution chamber volume input (V d ) and volume input (V p ) The dose function involves a flow rate function. More specifically, the dose function involves a flow rate function at the initial infusion dose time. The flow rate function may be a Tansy function as described herein. Thus, the infusion calculator processor 256 may include one or more of the concentration inputs (C p ), and a first pharmaceutical dose based at least in part on the value of the flow rate function at the initial infusion dose time. c1 ) to determine

[0498] The dose function is

number

number

[0499] Dose in the dose function c Solving for x gives an indication of the cumulative dose of active agent (ie, pharmaceutical agent) output by the drug delivery device 90 between an initial time and a relevant time (t).

[0500] Thus, the injection calculation unit processor 256:

number

number

[0501] First Pharmaceutical Dose c1 ) is the time between the initial time and the initial injection dose (t i2 ) provides a cumulative dose of active agent (i.e., pharmaceutical formulation) output by drug delivery device 90.

[0502] In 5516, the infusion computing device 151 calculates a second pharmaceutical dose (Dose) of an infusion step of the second number of infusion steps (h2). c2 In particular, the infusion computing device processor 256 determines the second pharmaceutical dose. c2 Determine the second pharmaceutical dose. c2 ) indicates the cumulative pharmaceutical formulation dose output by the drug delivery device between the initial time and the subsequent injection dose time. This may be a cumulative dose of the active agent of the pharmaceutical formulation. The cumulative pharmaceutical formulation dose output by the drug delivery device between the initial time and the subsequent injection dose time may be referred to as the second cumulative pharmaceutical formulation dose. The fluid discharged from the drug delivery device 90 is the fluid stored in the dilution chamber 100 at the time of the injection step of the second number of injection steps (h2). That is, the fluid is a diluted pharmaceutical formulation. The cumulative pharmaceutical formulation dose is the dose (i.e., amount) of the active agent in the fluid output by the drug delivery device 90. As described herein, the initial time corresponds to the start of the injection process. The subsequent injection dose time corresponds to the end of the injection step of the second number of injection steps (h2). The subsequent injection dose time may be indexed with respect to the initial time. For example, the subsequent injection dose time may be the number of milliseconds or seconds that the injection step of the second number of injection steps (h2) ends after the initial time.

[0503] The infusion calculator processor 256 calculates the second pharmaceutical dose using the dose function. c2 ) to determine

[0504] In particular, the injection computing device processor 256 includes:

number

number

[0505] Second Pharmaceutical Dose c2 ) is the time between the initial dose and the time of the subsequent dose (t s2 ) provides an indication of the cumulative dose of active agent (i.e., pharmaceutical formulation) output by the drug delivery device 90.

[0506] In 5518, the infusion computing device 151 determines a dose target for an infusion step of the second number of infusion steps (h2). In particular, the infusion computing device processor 256 determines the dose target. The dose target indicates a pharmaceutical formulation dose to be output by the drug delivery device during an infusion step of the second number of infusion steps (h2). The pharmaceutical formulation dose may be a dose of an active agent to be output by the drug delivery device during an infusion step of the second number of infusion steps (h2). The infusion computing device processor 256 determines a first pharmaceutical dose (Dose c1 ) and the second pharmaceutical dose (Dose c2 ) to determine dose targets based at least in part on:

[0507] In some embodiments, the infusion computing device processor 256 determines the second pharmaceutical dose. c2 ) and the first pharmaceutical dose (Dose c1 That is, the infusion computing device processor 256 determines the dose target by determining the difference between the first pharmaceutical dose (Dose c1 ) as the second pharmaceutical dose c2 ) The result of this subtraction is the dose target.

[0508] In 5520, the injection calculation device 151 determines a concentration estimate. In particular, the injection calculation device processor 256 determines a concentration estimate. The concentration estimate is for an injection step of the second number of injection steps (h2). The concentration estimate indicates the pharmaceutical agent concentration of the fluid discharged from the drug delivery device 90 during an injection step of the second number of injection steps (h2). This may be the concentration of the active agent in the fluid stored in the dilution chamber 100. The concentration estimate indicates the pharmaceutical agent concentration of the fluid discharged from the drug delivery device 90 during each injection step of the second number of injection steps (h2). This is because the concentration of the pharmaceutical agent in the fluid of the dilution chamber 100 is constant during the second time window.

[0509] The infusion calculation unit processor 256 calculates the concentration estimate using a concentration estimate function. The concentration estimate function may be as described herein. The concentration estimate function has one or more inputs. The one or more inputs of the concentration estimate function may be a concentration input (C p ), dilution chamber volume input (V d ) and volume input (V p ) The infusion calculation device processor 256 therefore includes one or more of the concentration inputs (C p ), dilution chamber volume input (V d ) and volume input (V p ) to determine a concentration estimate based at least in part on one or more of:

[0510] The concentration function is

number

[0511] In 5522, the injection calculation device 151 determines a second injection volume of an injection step of the second number of injection steps (h2). In particular, the injection calculation device processor 256 determines the second injection volume. The second injection volume indicates a volume of fluid discharged from the drug delivery device 90 during an injection step of the second number of injection steps (h2). The injection calculation device processor 256 determines the second injection volume based at least in part on the dose target and the concentration estimate.

[0512] In some embodiments, the infusion computation unit processor 256 determines the second infusion volume by dividing the dose target by the concentration estimate.

[0513] In 5524, the injection calculation device 151 determines a second target flow rate for an injection step of the second number of injection steps (h2). In particular, the injection calculation device processor 256 determines the second target flow rate. The second target flow rate is a target flow rate for an injection step of the second number of injection steps (h1). The injection calculation device processor 256 determines the second target flow rate based at least in part on a second injection volume for an injection step of the second number of injection steps (h2).

[0514] In some embodiments, the second target flow rate is determined using a target flow rate function described herein.

[0515] The drug delivery system 91 is configured to deliver the injection steps of the second number of injection steps (h2) over a second injection step duration. The second injection step duration is a period of time (e.g., 20 seconds). In some embodiments, determining the second target flow rate includes dividing the second injection volume by the second injection step duration.

[0516] It should be noted that in some embodiments, each injection step of the second number of injection steps (h2) may have the same injection step duration. Alternatively, at least some of the injection steps of the second number of injection steps (h2) may have different injection step durations. For example, a second injection step duration may be different from the injection step duration of another injection step of the second number of injection steps (h2).

[0517] In some embodiments, the second injection step duration is shorter than the injection step duration of another of the second number of injection steps (h2). In such cases, an injection step of the second number of injection steps (h2) may be delivered closer to the initial time than another of the second number of injection steps (h2). Alternatively, an injection step of the second number of injection steps (h2) may be delivered further away from the initial time than another of the second number of injection steps (h2).

[0518] The injection computing device processor 256 generates an injection process based at least in part on the first injection volume. The injection computing device processor 256 generates an injection process based at least in part on the second injection volume. The injection process may be referred to as an injection program. The injection process defines the speed at which the first plunger is actuated during injection to deliver the active agent as intended. That is, the injection process defines the volume of fluid to be expelled by the drug delivery device 90 over a given unit of time. The injection computing device processor 256 stores the injection process in the injection computing device memory 258. In particular, the injection computing device processor 256 stores the injection process in the injection computing device memory 258 in the form of an injection process file.

[0519] In some embodiments, the clinician saves the infusion process file on a removable storage medium, such as a USB memory module. The clinician may transfer the infusion process file to the infusion device 93. The infusion device 93 may then use the infusion process file to perform the infusion process. In some embodiments, the infusion computing device processor 256 transmits the infusion process file to the infusion device 93. For example, the communications network 264 may be in the form of a network (e.g., the Internet or a local area network). In these cases, the infusion computing device processor 256 may transmit the infusion process file to the infusion device 93 over the communications network 264.

[0520] At 5526, the injection device 93 performs the injection process. Specifically, at 5526, the injection device 93 actuates a plunger of the medication delivery device. Specifically, the injection device 93 actuates the first plunger 92. The injection device processor sends a control signal to the injection device actuator to actuate the first plunger 92. Thus, in some embodiments, it can be said that the injection device 93 actuates the injection device actuator to actuate the first plunger 92.

[0521] If the injection device actuator is in the form of a syringe driver (or another contact type actuator), the injection device 93 may actuate the syringe driver (or other actuator) to actuate the first plunger 92. The injection device 93 may move the injection device actuator so that it contacts the first plunger 92. The injection device 93 may continue to move the injection device actuator to cause movement of the first plunger 92 within the container 96. In particular, the injection device actuator may be actuated to move the first plunger 92 towards the dilution chamber outlet 110. This movement of the first plunger 92 may be considered an actuation of the first plunger 92.

[0522] As described herein, in some embodiments, the injection device 93 may be in the form of a vacuum injection device. The vacuum injection device may apply a vacuum pressure to the dilution chamber outlet 110, which may cause the first plunger 92 to move. This movement of the first plunger 92 is considered an actuation of the first plunger 92. Thus, in some embodiments, the injection device 93 actuates the first plunger 92, at least in part, by applying a vacuum pressure to the dilution chamber outlet 110.

[0523] The injection device 93 actuates the first plunger 92 such that a first injection volume of fluid is discharged from the drug delivery device 90 during an injection step of the first number of injection steps (h1). In other words, the injection device 93 actuates the first plunger 92 to discharge a first injection volume of fluid from the drug delivery device 90 during an injection step of the first number of injection steps (h1). The injection device 93 actuates the first plunger 92 such that a first injection volume of fluid is discharged from the drug delivery device 90 at a first target flow rate during an injection step of the first number of injection steps (h1).

[0524] The injection device 93 actuates the first plunger 92 such that a second injection volume of fluid is expelled from the drug delivery device 90 during an injection step of the second number of injection steps (h2). In other words, the injection device 93 actuates the first plunger 92 to expel a second injection volume of fluid from the drug delivery device 90 during an injection step of the second number of injection steps (h2). The injection device 93 actuates the first plunger 92 such that a second injection volume of fluid is expelled from the drug delivery device 90 at a second target flow rate during an injection step of the second number of injection steps (h2).

[0525] In some embodiments, the concentration of the active agent in the fluid discharged from the drug delivery device 90 during the injection step of the first number of injection steps (h1) is a first concentration. The concentration of the active agent in the fluid discharged from the drug delivery device 90 during the injection step of the second number of injection steps (h2) is a second concentration. In some embodiments, the first concentration is at least one order of magnitude lower than the second concentration. That is, in some embodiments, the concentration of the active agent in the injection volume of the fluid discharged from the drug delivery device 90 during the injection step of the first number of injection steps (h1) is at least one order of magnitude lower than the concentration of the active agent in the second injection volume of the fluid discharged from the drug delivery device 90 during the injection step of the second number of injection steps (h2). In some embodiments, the first concentration is at least one order of magnitude higher than the second concentration. In some embodiments, the first concentration is at least one order of magnitude lower than the second concentration. In some embodiments, the first concentration is equal to the second concentration.

[0526] Transition injection step In some embodiments, during the injection step of the injection process, the first plunger 92 contacts the second plunger 94. That is, the first time window transitions to the second time window during the injection step of the injection process. This injection step of the injection process is referred to as a transition injection step (h t The transition time indicates the time point that separates the first and second time windows.

[0527] In some embodiments, the method 5500 includes determining a transition time. The infusion computing device 151 determines the transition time. In particular, the infusion computing device processor 256 determines the transition time. The infusion computing device processor 256 determines the transition time by calculating a transition cumulative delivered volume (KV T ) to enter the volume (V p ) to determine the transition time. The injection computing device processor 256 may determine the transition time using a cumulative volume function. For example, the injection computing device processor 256 may determine the transition time by equating the transition time (t t ) can be solved.

number

[0528] In some embodiments, the infusion computing device processor 256 determines the transition time using a transition time function, which is as follows:

number

[0529] In some embodiments, the method 5500 includes a transition injection step (h t The injection calculation unit processor 256 determines the transition injection step volume (h t ) to determine the transition injection step volume. The first transition injection volume is the transition injection step (h t The second transition injection volume indicates the volume of fluid expelled from the drug delivery device 90 during the first portion (i.e., during the first time window) of the transition injection step (h t 2 illustrates a volume of fluid expelled from the drug delivery device 90 during a second portion of the infusion time (i.e., during a second time window). The infusion calculation device processor 256 determines the transition infusion step volume by determining the sum of the first transition infusion volume and the second transition infusion volume.

[0530] In some embodiments, the infusion calculation device processor 256 uses the cumulative delivered volume function described with respect to 5506 to determine the transition infusion step (h t The injection calculation device processor 256 calculates the volume of fluid delivered from the initial time to the initial transition injection step time. The initial transition injection step time is determined by the first transition injection step (h t ) corresponds to the start of the injection calculation device processor 256. tThe injection calculation device processor 256 calculates the volume of fluid delivered from the initial time to the initial transition injection step time by dividing the volume of fluid delivered from the initial time to the transition time (t t ) from the volume of fluid delivered between

[0531] In some embodiments, the infusion computing device processor 256 performs the transition infusion steps (h) as described with respect to 5514, 5516, 5518, 5520 and 5522. t ) to determine the second transition injection volume.

[0532] In some embodiments, the infusion computing device processor 256 determines a transition target flow rate. The transition target flow rate is determined by the transition infusion step (h t ) indicates the flow rate at which fluid is expelled from the drug delivery device 90 during the transition infusion step (h). The infusion computing device processor 256 determines the transition target flow rate based at least in part on the transition step volume. In particular, the infusion computing device processor 256 determines the transition target flow rate by dividing the transition step volume by the transition step duration. The transition step duration is determined by the transition infusion step (h t ) corresponds to the duration during which the

[0533] Transition injection step (h t ) is performed for a transition infusion step duration, which includes the transition time.

[0534] The injection device 93 performs a transition injection step (h t ) to expel a transition step injection volume of fluid from the drug delivery device 90. In other words, the injection device 93 actuates the first plunger 92 to perform a transition injection step (h t The injection device 93 ejects a transition injection volume of fluid from the drug delivery device 90 during the transition injection step (h t ), the first plunger 92 is actuated such that a transition injection volume of fluid is expelled from the drug delivery device 90 at a transition target flow rate.

[0535] Transition injection step (h t ) is between an injection step of the first number of injection steps (h1) and an injection step of the second number of injection steps (h2).

[0536] As described herein, in some cases, the infusion process, if left unattended, may deliver the active agent at a rate that exceeds the maximum infusion rate. The maximum infusion rate may vary depending on the active agent. In some embodiments, when determining the infusion process, the infusion computing device processor 256 determines a maximum dose time. The maximum dose time indicates the dose time point at which the maximum infusion rate threshold is reached. The maximum infusion rate threshold corresponds to the maximum rate at which the active agent can be safely provided to the patient. The infusion computing device processor 256 uses a dose rate function to determine the time at which the infusion process would be delivering the active agent at the maximum infusion rate. The dose rate function is as described herein and is shown below. D r =C p ×T(t) In the formula, D r is the dose rate at a particular time (t) in the infusion process, and T(t) is the Tansy function.

[0537] The clinician may look up the maximum infusion rate for a particular active agent, or the infusion device may consult a database to obtain the maximum infusion rate. The maximum infusion rate is determined by the dose rate function D r ) The time at which this maximum infusion rate is delivered can then be determined. This is the maximum dose time.

[0538] The infusion computing device 151 determines whether this time is within the first or second time window. If it is within the first time window, the infusion computing device 151 determines the cumulative volume of fluid delivered up to this point. This may be done using a cumulative volume function as described herein. The infusion computing device 151 then uses a constant volume function to ensure that the infusion proceeds while providing active agent at or below the maximum infusion rate.

[0539] If the maximum dose time falls within the second time window, the infusion computing device 151 uses a constant infusion rate function to ensure that the infusion proceeds while providing active agent at or below the maximum infusion rate, which may occur for the remainder of the second time window and until the infusion process is terminated.

[0540] Derivation of cumulative volume function (Kelly cumulative volume function) The derivation of the cumulative volume function is detailed herein. The cumulative volume function is a Kelly cumulative volume function. The cumulative volume function is used to control the drug delivery system 91 when the dilution chamber 100 empties during the injection process. However, the cumulative volume function is only used during the time when the volume of the dilution chamber 100 remains constant. That is, the cumulative volume function is only used during the first time window. The cumulative volume function determines the rate at which the active agent chamber 98 is emptied by actuation of the first plunger 92. This actuation of the first plunger 92 can be done either by directly contacting and moving the first plunger 92 with an applied force or by sucking the fluid stored in the dilution chamber 100 out of the dilution chamber opening 110.

[0541] The rate of change of the amount of pharmaceutical formulation in the dilution chamber 100 is A d '(v)' may be expressed in terms of the cumulative volume of fluid delivered into or out of the dilution chamber 100. The cumulative volume of fluid delivered into or out of the dilution chamber 100 (v) may be expressed in terms of the concentration of the active agent in the active agent chamber 98 (C p ) to obtain the concentration C of the active agent in the dilution chamber 100 at the time (v) mL is injected. d (v) is the sum of the two. A' d (v)=C p -C d (v)

[0542] The concentration C of the active agent in the dilution chamber 100 d (v) is the amount of activator in the dilution chamber A d(v) is the volume of the dilution chamber (V d ) divided by . Therefore,

number

number

number

[0543] This first-order linear equation describes the amount of drug in the dilution chamber with respect to the cumulative volume (v) of fluid entering or leaving the dilution chamber, and is expressed by an integral coefficient I:

number

number

number

number

number

number

number

number

number

number

[0544] At V=0, A(V d )=0, therefore, C1=-V d C p And then, Therefore,

number

number

[0545] The concentration of active agent in the dilution chamber 100 (C(V d ))teeth,

number

[0546] C(V d ) is the cumulative dose leaving the dilution chamber 100 with respect to the cumulative volume (V) that left the dilution chamber at that point.

number

number

[0547] At dose=0, V=0;

number

number

number

[0548] The inventors also determined that the dose at any time during the infusion process was p It is also known that the dose function is given by the Tansy dose function (described herein), which is a × Tansy volume function, C p × the integrated Tansy velocity function.

number

[0549] Therefore, for any cumulative dose we can calculate both the cumulative volume and the cumulative elapsed time. Thus, we can express the cumulative volume delivered with respect to time:

number

number

[0550] Solving this for cumulative volume (v) with respect to time (t) gives the exact form of the cumulative volume function (the exact form of the Kelly cumulative volume function):

number

[0551] In this case, v is equivalent to the cumulative delivery volume KV described herein. W0 is the principal branch (branch 0) of the Lambert W function. The Lambert W function is expressed as we w It is defined as the inverse function of

[0552] The derivative of the cumulative volume is the rate (volume per unit time), and the exact form of the rate function is (the exact form of the Kelly rate function):

number

[0553] Constant dose injection cumulative volume function In some embodiments, the infusion device processor is configured to perform an infusion according to method 5500 over a first infusion portion, and to perform the method according to a fixed dose process over a second infusion portion. The infusion computing device processor 256 is configured to determine a maximum dose time. The maximum dose time is the time within the time window at which the dose rate of the infusion process reaches a maximum dose threshold. If the maximum dose time is within the first time window, the infusion device processor is governed (via the infusion process file) by a fixed dose accumulation volume function rather than using the accumulation volume function described above. In method 5500, the fixed dose accumulation volume function may be referred to as the Kelly fixed dose accumulation volume function. The Kelly fixed dose accumulation volume function is:

number

[0554] Method for delivering a pharmaceutical formulation to a patient 5600 FIG. 56 is a process flow diagram of a method 5600 for delivering a pharmaceutical formulation to a patient, according to some embodiments. The method 5600 may be performed by the drug delivery system 1 and / or drug delivery device 10 described with reference to FIGS. 1-11e. The method 5600 may be performed by the drug delivery system 91 and / or drug delivery device 90 described with reference to FIGS. 30-34a or 35-43. The method 5600 may be performed by the drug delivery system and / or drug delivery device 136 described with reference to FIGS. 44-47A. The pharmaceutical formulation is delivered to the patient by an injection process that is initiated at an initial time. Although the method 5600 is described with reference to the drug delivery system 1 of FIGS. 1-11e, it will be understood that the description also applies to the drug delivery system 91 and / or drug delivery device 90 described with reference to FIGS. 30-34a or 35-43, as well as the drug delivery system and / or drug delivery device 136 described with reference to FIGS. 44-47A.

[0555] Part or all of the method 5600 may be performed by an infusion device processor (i.e., a processor of the infusion device). Part or all of the method may be performed by the infusion computing device 151. Part or all of the method may be performed by another computing device. Thus, the method 5600 may be considered a computer-implemented method.

[0556] At 5602, the infusion computing device receives one or more method inputs. In particular, the infusion computing device processor receives the one or more method inputs. In some embodiments, the one or more method inputs include a plurality of method inputs. The method inputs may be received via the infusion computing device user interface 260 (e.g., via a display and / or keyboard). In some embodiments, at least one of the method inputs is an input of a cumulative delivery volume function. In some embodiments, at least one of the method inputs is an input of a dose function. A clinician may input the one or more method inputs.

[0557] In some embodiments, one or more method inputs include a concentration input (Cp ) is included. Concentration input (C p ) may be as described herein. In some embodiments, one or more method inputs include a volume input (V p ) is included. Volume input (V p ) may be as described herein. In some embodiments, one or more method inputs include a dilution chamber volume input (V d ) Dilution chamber volume input (V d ) may be as described herein. In some embodiments, the one or more method inputs include a time input (i). The time input (i) may be as described herein. The time input (i) indicates a time window during which the pharmaceutical formulation is delivered.

[0558] At 5604, the infusion computing device determines the number of infusion steps (h) to be performed within the time window. In particular, the infusion computing device processor determines the number of infusion steps (h) to be performed within the time window. The time window and the number of infusion steps (h) may be as described herein.

[0559] In some embodiments, determining the number (h) of injection steps includes receiving the number (h) of injection steps. The number (h) of injection steps may be received (e.g., by an injection computing device processor) as an injection step input. Alternatively, one or more method inputs may include the number (h) of injection steps.

[0560] In some embodiments, determining the number of injection steps (h) comprises calculating the product of the number of injection steps (per minute) performed within the time window (g) and the time input (i). That is, to determine the number of injection steps (h), the injection computing device processor: h = g × i where h is the number of injection steps performed within the time window, g is the number of injection steps performed per minute during the injection process, and (i) is the time input. Thus, the time input (i) indicates the length of the injection process in minutes. In these embodiments, the injection computing device processor may store the number of injection steps (h) in the injection computing device memory. The injection computing device processor may then issue a read transaction to the injection computing device memory for the number of injection steps (h) and receive the number of injection steps (h) in response. Thus, receiving the number of injection steps (h) may include determining the number of injection steps (h).

[0561] In 5606, the infusion calculation device determines a first cumulative delivery volume (KV1) of the target infusion step. The target infusion step is an infusion step of the number (h) of infusion steps. In particular, the infusion calculation device processor determines a first cumulative delivery volume (KV1) of the target infusion step. The first cumulative delivery volume (KV1) indicates a cumulative volume of fluid discharged from the drug delivery device 10 between an initial time and an initial infusion step time. The fluid discharged from the drug delivery device 10 is the fluid stored in the dilution chamber 32 at the time of the target infusion step. That is, the fluid is a diluted pharmaceutical formulation. As described herein, the initial time corresponds to the start of the infusion process. For example, the initial time can be 0. The initial infusion step time corresponds to the start of the target infusion step. The initial infusion step time can be indexed with respect to the initial time. For example, the initial infusion step time can be the number of milliseconds or seconds after the initial time that the target infusion step is started.

[0562] The infusion computing device processor determines a first cumulative delivery volume (KV1) using a cumulative delivery volume function.

[0563] Determining injection volume using a constant cumulative volume function The cumulative delivery volume function may be referred to as a second cumulative delivery volume function. The cumulative delivery volume function may be referred to as a constant cumulative volume function. The cumulative delivery volume function may have one or more inputs. The one or more inputs of the cumulative delivery volume function include an initial injection step time, a time input (i), a dilution chamber volume input (V d ) and volume input (V p ) The injection calculation device processor thus includes one or more of the initial injection step time, the time input (i), the dilution chamber volume input (V d ) and volume input (V p ) determining a first cumulative delivered volume (KV1) based at least in part on one or more of:

[0564] The cumulative delivered volume function is

number

[0565] Solving for KV in the cumulative delivered volume function provides a measure of the cumulative volume of fluid expelled from the drug delivery device 10 between an initial time and a given time (t).

[0566] Thus, the injection computing device processor:

number

[0567] The first cumulative delivery volume KV1 is calculated by dividing the initial time by the initial injection step time (t i ) provides an indication of the cumulative volume of fluid expelled from the medication delivery device 10 between the

[0568] In 5608, the injection calculation device determines a second cumulative delivery volume (KV2) of the target injection step. In particular, the injection calculation device processor determines a second cumulative delivery volume (KV2) of the target injection step. The second cumulative delivery volume (KV2) indicates a cumulative volume of fluid discharged from the drug delivery device 10 between the initial time and the subsequent injection step time. The cumulative volume of fluid discharged from the drug delivery device 10 between the initial time and the subsequent injection step time may be referred to as the second cumulative volume. The fluid discharged from the drug delivery device 10 is the fluid stored in the dilution chamber 32 at the time of the injection step of the first number of injection steps (h1). That is, the fluid is a diluted pharmaceutical formulation. As described herein, the initial time corresponds to the start of the injection process. The subsequent injection step time corresponds to the end of the target injection step. The subsequent injection step time may be indexed with respect to the initial time. For example, the subsequent injection step time may be the number of milliseconds or seconds that the target injection step ends after the initial time.

[0569] The infusion computing device processor determines a second cumulative delivery volume (KV2) using a cumulative delivery volume function.

[0570] In detail, the injection computing device processor includes:

number

[0571] The second cumulative delivery volume KV2 is calculated by dividing the initial time by the time of the subsequent injection step (t s ) provides an indication of the cumulative volume of fluid expelled from the medication delivery device 10 between the

[0572] At 5610, the injection calculation device determines an injection volume for the target injection step. In particular, the injection calculation device processor determines the injection volume. The injection volume indicates a volume of fluid to be discharged from the drug delivery device 10 during the target injection step. The injection calculation device processor determines the injection volume based at least in part on the first cumulative delivery volume (KV1) and the second cumulative delivery volume (KV2).

[0573] In some embodiments, the injection calculation device processor determines the first injection volume by determining the difference between the second cumulative delivery volume (KV2) and the first cumulative delivery volume (KV1). That is, the injection calculation device processor subtracts the first cumulative delivery volume (KV1) from the second cumulative delivery volume (KV2). The result of this subtraction is the first injection volume.

[0574] Determining injection volume using a changing cumulative volume function. In some embodiments, the cumulative delivery volume function is in the form of a varying cumulative volume function, i.e., the volume of fluid ejected by the drug delivery device 10 when controlled according to the varying cumulative volume function varies over time (e.g., increases over successive injection steps).

[0575] As described herein, the cumulative delivery volume function has one or more inputs. The one or more inputs of the cumulative delivery volume function include an initial injection step time, a time input (i), a dilution chamber volume input (V d ), volume input (V p ) and the principal branch of Lambert's W function (W0). Thus, the injection calculation device processor includes one or more of an initial injection step time, a time input (i), a dilution chamber volume input (V d ) and volume input (V p) determining a first cumulative delivered volume (KV1) based at least in part on one or more of:

[0576] The cumulative delivered volume function (i.e., the cumulative volume change function) is

number

[0577] During the ceremony, KV indicates the corresponding cumulative delivered volume; V d is the dilution chamber volume input, i is the time input, t is the time at which the cumulative delivered volume function is solved; β is a volume parameter, V p is the volume input.

[0578] In some embodiments, the volume parameter (β) is

number

[0579] In these embodiments, the cumulative delivery volume function may be referred to as the Sadleir cumulative volume function.

[0580] In some embodiments, the volume input V p Increase the volume input V p2 teeth,

number

[0581] In these embodiments, the cumulative delivery volume function may be referred to as the Sadleir incremental volume cumulative function. p2 is determined because a portion of the pharmaceutical formulation remains in the dilution chamber when using this delivery method.

[0582] Solving for KV in the cumulative delivered volume function provides a measure of the cumulative volume of fluid expelled from the drug delivery device 10 between an initial time and a given time (t).

[0583] Thus, in some embodiments, in 5606, the injection computing device processor:

number

[0584] The first cumulative delivery volume KV1 is calculated by dividing the initial time by the initial injection step time (t i ) provides an indication of the cumulative volume of fluid expelled from the medication delivery device 10 between the

[0585] In some embodiments, in 5608, the infusion computing device determines a second cumulative delivery volume (KV2) of the target infusion step. In particular, the infusion computing device processor determines a second cumulative delivery volume (KV2) of the target infusion step. The second cumulative delivery volume (KV2) indicates a cumulative volume of fluid discharged from the drug delivery device 10 between an initial time and a subsequent infusion step time of the target infusion step. The cumulative volume of fluid discharged from the drug delivery device 10 between the initial time and the subsequent infusion step time may be referred to as the second cumulative volume. The fluid discharged from the drug delivery device 10 is the fluid stored in the dilution chamber 32 at the time of the target infusion step. That is, the fluid is a diluted pharmaceutical formulation. As described herein, the initial time corresponds to the start of the infusion process. The subsequent infusion step time corresponds to the end of the target infusion step. The subsequent infusion step time may be indexed with respect to the initial time. For example, the subsequent infusion step time may be the number of milliseconds or seconds that the target infusion step ends after the initial time.

[0586] The infusion computing device processor determines a second cumulative delivered volume (KV2) using a variable cumulative delivered volume function.

[0587] In detail, the injection computing device processor includes:

number

[0588] When determining the second cumulative delivery volume KV2, the injection calculation device processor uses the same volume parameter (β) as that used to determine the first cumulative delivery volume KV1, i.e., when determining the first cumulative delivery volume KV1 and the second cumulative delivery volume KV2, the volume parameter (β) is determined in the same way.

[0589] ...

Claims

1. 1. An infusion device for use with a drug delivery apparatus comprising an active agent chamber for receiving a pharmaceutical formulation, a diluent chamber for receiving a diluent, and a diluent chamber opening through which the diluted pharmaceutical formulation can be discharged for intravenous delivery to a patient, comprising: A processor; a memory storing instructions executable by the processor for causing the drug delivery device to deliver the pharmaceutical formulation to the patient according to a dose profile, the dose profile delivering a therapeutic dose of the pharmaceutical formulation to the patient over an infusion time, the dose profile including a first phase and a second phase; Including, during said first stage, the concentration of said pharmaceutical formulation in said dilution chamber increases and the dose rate at which said pharmaceutical formulation is delivered to said patient increases until a maximum dose rate for said pharmaceutical formulation is reached; during said second stage, the concentration of said pharmaceutical formulation in said dilution chamber is increased and the flow rate of said diluted pharmaceutical formulation exiting said dilution chamber is decreased such that said flow rate does not exceed said maximum dose rate. The injection device.

2. 2. The injection device of claim 1, wherein the dose rate in the second stage is constant.

3. 2. The injection device of claim 1, wherein the dose rate in the second stage is the maximum dose rate of the pharmaceutical formulation.

4. An injection device according to any of claims 1 to 3, wherein the dose profile further comprises a third stage in which the concentration of the pharmaceutical formulation in the dilution chamber is constant.

5. 5. The injection device of claim 4, wherein the dose rate in the third stage is constant, e.g., may be the maximum dose rate of the pharmaceutical formulation.

6. 4. The injection device of claim 1, wherein the dose profile is such that the cumulative dose of the pharmaceutical formulation delivered to the patient increases exponentially over time over at least a portion of the first stage of the dose profile.

7. The first stage of the dose profile comprises: a first period during which the cumulative dose reaches 0.01% to 0.1% of said therapeutic dose; a second period during which the cumulative dose reaches 0.1% to 1% of said therapeutic dose; Including, The first period and the second period are At least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least selected from the group comprising: An injection device according to any one of claims 1 to 3.

8. the medication delivery device comprising a container, a first plunger and a second plunger within the container; the first plunger and the second plunger are arranged such that a space between the first plunger and the second plunger defines the activator chamber, and a space between the second plunger and a distal end of the container defines the dilution chamber; 4. The injection device of claim 1, wherein the first and second stages of the dose profile correspond to a first time window, during which the first plunger moves towards the second plunger to expel the pharmaceutical formulation from the active agent chamber to the dilution chamber for mixing with the diluent and for output of the diluted pharmaceutical formulation from the dilution chamber opening.

9. 5. The injection device of claim 4, wherein the third stage of the dose profile corresponds to a second time window, during which a first plunger contacts a second plunger and the second plunger moves toward a distal end of the container to reduce the volume of the dilution chamber and to expel the pharmaceutical formulation from the dilution chamber through the dilution chamber opening.

10. 1. An injection device for use with a drug delivery apparatus comprising a syringe with an active agent chamber for receiving a pharmaceutical formulation, a diluent chamber for receiving a diluent, and a diluent chamber opening through which the diluted pharmaceutical formulation can be discharged for intravenous delivery to a patient, comprising: A processor; a memory storing dose delivery instructions executable by said processor; Including, the dose delivery instructions are for causing the medication delivery device to deliver the pharmaceutical formulation to the patient according to a dose profile; the dose profile delivers a therapeutic dose of the pharmaceutical formulation to the patient over an infusion period in a manner that facilitates safe detection of an adverse reaction of the patient to the pharmaceutical formulation or desensitization of the patient to the pharmaceutical formulation; the dose delivery instructions include instructions to cause the injection device to move a plunger of the syringe towards the dilution chamber opening in a plurality of injection steps implementing the dose profile; A maximum dose rate is reached after 50% of the infusion time has elapsed; over the infusion steps occurring after the first 3% of the infusion time and before the maximum dose rate is reached, each infusion step has a higher dose rate than the preceding infusion step; The injection device.

11. Dividing the injection time into a plurality of injection steps, A target injection rate or target injection amount is set for each injection step. The infusion device according to any one of claims 1 to 3 and 10, wherein the infusion steps and the target infusion rates or amounts are stored in an infusion file in a memory.

12. The dose profile is stored as a plurality of infusion steps in an infusion file in memory; The injection device according to any of claims 1 to 3 and 10, wherein each injection step has a corresponding value for each of the dose rates.

13. The dose profile is stored as a plurality of infusion steps in an infusion file in memory; The injection device according to any one of claims 1 to 3 and 10, wherein each injection step has a corresponding output volume.

14. The injection device of claim 1, wherein the injection device controls the delivery of the pharmaceutical formulation based on an analytical solution of an injection modeling function.

15. A drug delivery system comprising an injection device as described in any one of claims 1 to 3 and 10, comprising a syringe having an activator chamber for receiving a pharmaceutical formulation, a diluent chamber for receiving a diluent, and a diluent chamber opening through which the diluted pharmaceutical formulation can be discharged for delivery to a patient by intravenous infusion, wherein the injection device is a pump, a peristaltic pump, a vacuum pump or a syringe driver.

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