Drug delivery systems and methods

Abstract

Drug delivery device (90). The drug delivery device (90) comprises a first plunger (92), a second plunger (94), and a container (96) configured to receive at least a portion of the second plunger (94) and the first plunger (92). The container (96) and the second plunger (94) together define a diluent chamber (100) configured to receive a diluent. The diluent chamber (100) includes a diluent chamber opening (110). The diluent chamber opening (110) is defined by the container (96). 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. The activator chamber (98) includes a first activator chamber opening (103) configured to receive at least a portion of the first plunger (92). The second plunger (94) includes a valve (102) configured to control the flow of the pharmaceutical formulation from the activator chamber (98) to the diluent chamber (100) in response to an applied pressure.

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 exclusively, devised with respect to administering a pharmaceutical formulation to a patient at a particular test dose, for example, to detect an adverse reaction during administration of the pharmaceutical formulation, to desensitize the patient to the pharmaceutical formulation, or to immune test 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 solely 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 the administration of those drugs to those patients.

[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 is unpredictable.

[0006] To reduce the risk that any patient will suffer a fatal reaction to the drug, one way of administering certain intravenous drugs 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 can 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] The 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] Among other things, these two reasons make it difficult or even impossible for clinicians to select an appropriate test dose for conducting a trial to determine whether adverse reactions occur during administration of the full therapeutic dose.In particular, administering a relatively small test dose may not induce adverse reactions in patients or result in the detection of such reactions.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.Therefore, administering a 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 the particular drug in one or more incremental steps is called a 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 subthreshold test dose that causes an adverse reaction in a patient who is hypersensitive or allergic to a particular drug, inducing a state of drug tolerance and allowing the administration of a therapeutic dose while avoiding any adverse reactions or inducing only a mild, non-fatal reaction.

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

[0014] Unfortunately, due to the difficulty of determining what specific percentage of the total therapeutic dose administered to a patient is the appropriate test dose for that particular patient, 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 carries risks, as noted above. Administering a total therapeutic dose of a drug without determining whether the patient is hypersensitive or allergic to that particular drug may result in administering a lethal drug dose to a particular patient or cause a serious negative reaction.

[0015] Furthermore, any test doses currently administered to a patient are necessarily administered before and separately from the infusion of the therapeutic dose required by a particular patient. The preparation of separate test doses requires the 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 response 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 particularly true because current methods for administering the full therapeutic dose (fixed 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 sufficient 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 a first aspect of the present disclosure, there is provided a method for delivering an active ingredient to a patient, 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 embodiments, a therapeutic dose is administered to a patient for detection of adverse reactions in the patient.

[0018] In some embodiments, the pharmaceutical formulation is administered to the patient at various flow rates.

[0019] In some embodiments, the method further includes accessing a drug library having a database containing maximum allowable drug administration rates for each particular drug that may be infused into the patient to determine if the drug delivery rate exceeds the maximum allowable drug administration rate, and if so, reducing the infusion rate according to the maximum allowable infusion rate to provide the maximum allowable drug administration rate.

[0020] In some embodiments, the flow rate varies over time according to a curve determined by a particular function that results in a low flow rate during the first stage of the administration process, so that at least a portion of the therapeutic dose is administered during the first stage.

[0021] In some embodiments, the particular function is a Tansy function.

[0022] In some embodiments, the Tansy function is given by the following equation:

number

[0023] In some embodiments, the method further includes providing the following variables to an injection driver having a processor for following the instructions of an algorithm used to calculate the formula of the Tansy function: 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).

[0024] In some embodiments, the volume of the pharmaceutical formulation delivered to the patient in ml (V pThe primary syringe (or injection volume) contains a quantity of drug (active ingredient) mixed in a volume of solvent.

[0025] In some embodiments, the amount of the therapeutic dose delivered to the patient is equal to the concentration of the drug in the solvent multiplied by the total volume of the pharmaceutical formulation delivered to the patient.

[0026] In some configurations, the identity of the particular active ingredient (active ingredient name), the dose of the active ingredient, and / or the maximum active ingredient administration rate (doses / min) for the particular active ingredient may be provided to ensure that the maximum active ingredient administration rate is not exceeded during the infusion process.

[0027] In some embodiments, the method further comprises providing the pharmaceutical formulation to an entry point of the patient.

[0028] In some embodiments, the method further comprises calculating the flow rate (ml / min) of the pharmaceutical formulation at each time point during the duration of the infusion as determined by a Tansy function.

[0029] In some embodiments, the method further comprises calculating the cumulative volume of the pharmaceutical formulation infused at each time point during the infusion as determined by a Tansy function.

[0030] In some embodiments, the method further comprises programming the infusion driver to approximate a flow rate variation of the pharmaceutical formulation exiting the infusion driver to a flow rate variation determined by a Tansy function, the steps comprising: a) dividing the period of administration into a number of infusion steps; b) calculating the volume of each injection step; c) Calculate the flow rate for each injection step; d) providing pharmaceutical preparations to patients; and e) sequentially delivering the pharmaceutical formulation at the calculated flow rate for each infusion step until the administration process is complete.

[0031] In some embodiments, the step of calculating the flow rate for each injection step calculates a constant or linearly increasing (ramp) flow rate for each injection step.

[0032] In an alternative arrangement, the method further comprises diluting the pharmaceutical formulation prior to administration to the patient.

[0033] In some embodiments, dilution occurs as the pharmaceutical formulation is delivered from the infusion driver prior to administration to the patient by the dilution chamber.

[0034] In some embodiments, the dilution chamber contains a specific volume of diluent with which the pharmaceutical formulation will mix during the course of injection.

[0035] In some embodiments, the pharmaceutical formulation after exiting the dilution chamber contains a lower concentration of the active ingredient (relative to the concentration before entering the dilution chamber).

[0036] In some embodiments, a fractional dose of the active ingredient is administered to the patient, which dose is less than the dose administered at any time during the Tansy function.

[0037] In some embodiments, the dose is determined by the Tansy function plus the dose of the active ingredient administered at any time during the Tansy function.

number

[0038] In some embodiments, the flow rate of the lower concentration pharmaceutical formulation is increased for the majority of the infusion while delivering an amount of the pharmaceutical formulation to the patient that is equal to or less than the amount that would be delivered to the patient without reducing the concentration of the pharmaceutical formulation.

[0039] In some embodiments, the minimum flow rate of the less concentrated pharmaceutical formulation exiting the dilution chamber is increased compared to the minimum flow rate delivered by the Tansy method without exceeding the amount of active ingredient delivered at any one time by the Tansy function.

[0040] In some embodiments, the pharmaceutical formulation after exiting the dilution chamber comprises a higher flow rate and a lower concentration of the active ingredient; and

number

[0041] In some embodiments, the method further comprises the step of delivering any remaining pharmaceutical formulation contained in the dilution chamber to the patient upon completion of the administration process.

[0042] Alternatively, the method further comprises the step of discarding any remaining pharmaceutical formulation contained in the chamber.

[0043] In some embodiments, the method further includes providing the following variables to an injection driver having a processor for following the instructions of an algorithm used to calculate the formula of the Sadleir function: a) The volume of 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 (V d ), c) drug concentration in the primary syringe (e.g., percent of therapeutic dose / ml, or units of mass / mL); d) the time (i) over which the pharmaceutical formulation will be administered in minutes (also referred to as the duration of the infusion), and e) The number of intervals per minute over which the Sadleir function is calculated (τ). f) In some configurations, 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.

[0044] In some embodiments, the method comprises: a) calculating 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 a value of the dilution chamber concentration is calculated; b) the starting flow rate S(0) of the pharmaceutical formulation in the starting interval before the start of the administration process during a particular period, as long as there are any of a plurality of subsequent intervals that occur after the starting interval; initiating and calculating c) calculating the concentration of the active ingredient inside the dilution chamber after the start-up interval at the start of the administration process; d) calculating a flow rate determined by the Sadleir function for a first subsequent interval of a plurality of subsequent intervals after the starting interval; e) calculating the concentration of the active ingredient within the dilution chamber after the occurrence of any one of the intervals; f) prior to the occurrence of each of the second and subsequent intervals, calculating a flow rate determined by the Sadleir function for each of the second and subsequent intervals of the plurality of intervals using the concentration of the active ingredient within the dilution chamber.

[0045] In some embodiments, the method further comprises calculating a volume to be administered in each of the plurality of subsequent intervals according to a flow rate determined by the Sadleir function of the plurality of subsequent intervals.

[0046] In some embodiments, any of the sections of the plurality of sections includes a first section and a subsequent section.

[0047] In some embodiments, the method further comprises programming the infusion driver to approximate a flow rate variation of the pharmaceutical formulation exiting the infusion driver to a flow rate variation determined by a Sadleir function, the steps comprising: a) dividing the period of administration into a number of infusion steps; b) calculating the volume of each injection step; c) providing a pharmaceutical formulation to the dilution chamber; d) mixing the pharmaceutical formulation with a diluent contained in a dilution chamber; e) calculating the flow rates of the first injection step and subsequent steps; f) sequentially delivering the pharmaceutical formulation at the calculated flow rate for each infusion step until the administration process is complete.

[0048] In some embodiments, the method further comprises providing the patient with the diluted pharmaceutical formulation remaining in the dilution chamber upon completion of the infusion process.

[0049] In an alternative arrangement, upon completion of the injection, the pharmaceutical formulation remaining in the dilution chamber is discarded.

[0050] In this alternative arrangement, prior to initiation of the infusion process, either: (1) the concentration of the active ingredient in the pharmaceutical formulation in the infusion driver may be increased, or (2) the volume of the pharmaceutical formulation in the infusion driver may be increased.

[0051] In some embodiments, the increased concentration is equal to the original concentration multiplied by the reciprocal of the correction factor, 1 / [(V p -V d (1-e -Vp / Vd )) / V p ].

[0052] In some embodiments, the increased volume of the pharmaceutical formulation is calculated by repeating the Kelly function algorithm to determine the final volume infused after completing the infusion.

[0053] According to a second aspect of the present disclosure, there is provided a system for delivering an active ingredient to a patient, the system comprising an infusion driver having a processor for executing instructions of an algorithm for approximating flow rate fluctuations of the pharmaceutical formulation, such that the active ingredient is part of a pharmaceutical formulation having a specific volume, the pharmaceutical formulation comprising a solvent and a therapeutic dose of the active ingredient, and 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.

[0054] In some embodiments, the algorithm is configured to cause the pharmaceutical formulation to exit the infusion driver at a flow rate variation determined by a Tansy function.

[0055] In some embodiments, the system further comprises a dilution chamber fluidly connected between the infusion driver and the patient, the dilution chamber adapted to reduce the concentration of the pharmaceutical formulation before it enters the patient.

[0056] In some embodiments, the pharmaceutical formulation after exiting the dilution chamber comprises a lower concentration of the active ingredient (relative to the concentration prior to entering the dilution chamber), such that during administration of the pharmaceutical formulation exiting the dilution chamber, a patient is administered a specific dose of the active ingredient equal to the product:

[0057]

number

[0058] In some embodiments, the algorithm is configured to increase the flow rate of a lower concentration pharmaceutical formulation to deliver the same amount of pharmaceutical formulation to the patient.

[0059] In some embodiments, the algorithm is configured to increase the flow rate of the less concentrated pharmaceutical formulation out of the dilution chamber to deliver to the patient a volume of the pharmaceutical formulation equal to the product of:

[0060]

number

[0061] In a further alternative arrangement, the method includes delivering the pharmaceutical formulation through a dilution chamber, but results in the administration of an active ingredient dose equal to the dose administered at any time during the equivalent Tansy function, rather than a dose reduced by a fixed fraction as in the previous arrangement. This includes using a pharmaceutical formulation with an increased concentration of the active ingredient, or alternatively, using a larger volume of pharmaceutical formulation infused over the same period of time. Alternative modifications would be either:

[0062] The concentration of the prepared pharmaceutical formulation was increased ("increased concentration Sadleir method"), whereby the concentration

number

[0063] In some embodiments, the infusion driver comprises memory means for storing a drug library and a database containing maximum allowable drug administration rates for each particular drug that may be infused into a patient.

[0064] In some embodiments, the processor of the infusion driver executes instructions of an algorithm to access a drug library having a database containing the maximum allowable drug administration rate for each particular drug that may be infused into the patient to determine whether the drug delivery rate exceeds the maximum allowable drug administration rate, and if so, to reduce the infusion rate according to the maximum allowable infusion rate to provide the maximum allowable drug administration rate.

[0065] In some embodiments, the dilution chamber comprises a container and a manifold connected to the container, allowing fluid flow (1) from the injection driver into the container via a first conduit and a first inlet of the manifold, and (2) from the container to the patient via the conduit through a first outlet of the manifold.

[0066] In some embodiments, the manifold comprises a second inlet that allows delivery of a flushing fluid for flushing the dilution chamber for the purpose of delivering any drug residue therein to the patient.

[0067] In some embodiments, the manifold comprises a one-way valve for permitting fluid flow from the first inlet to the vessel but preventing fluid flow from the vessel back to the injection driver through the first inlet.

[0068] In some embodiments, the dilution chamber comprises a catheter having a first end fluidly connected to the first inlet for receiving the pharmaceutical formulation from the infusion driver and a second end extending into the container.

[0069] In one arrangement, the second end of the catheter comprises a blind end that prevents fluid flow therethrough and a perforation across the sidewall of the catheter.

[0070] In another arrangement, multiple perforations are positioned in spaced relation along the length of the catheter and around the outer surface of the catheter to allow the drug to flow in different directions through the second end of the catheter.

[0071] In an alternative arrangement, the catheter comprises an end section at the second end of the catheter, the end section comprising a perforation and a sleeve surrounding the end section.

[0072] In some embodiments, the sleeve comprises a plurality of perforations disposed in spaced relation along the length of the end section and around the outer surface of the end section to permit flow of the pharmaceutical formulation through the sleeve in different directions.

[0073] In some embodiments, the sleeve is adapted to expand into a circular or oval shape during its operation.

[0074] In some embodiments, at least one of the perforations made in the sleeve traverses the sleeve diagonally such that fluid flow exiting the sleeve through the perforation is toward the first end of the catheter.

[0075] In one arrangement, the sleeve is perforated with three evenly spaced 30g (0.25mm) perforations oriented 60 degrees above the horizontal.

[0076] In a further alternative arrangement, the catheter comprises a conically truncated end, and the enlarged region of the conically truncated end comprises perforations.

[0077] In another alternative arrangement, the catheter has an open end that allows fluid flow out through the open end of the catheter and into the container.

[0078] In some embodiments, the catheter comprises an air bubble trap.

[0079] In some embodiments, the bubble trap comprises a sleeve that at least partially surrounds the first end of the catheter.

[0080] In some embodiments, the sleeve extends from a particular location within the manifold to a location outside the manifold such that the distal end of the sleeve is located within the dilution chamber.

[0081] In some embodiments, the flow path is defined between an outer wall of the catheter and an inner wall of the sleeve.

[0082] In some embodiments, the flow path is adapted to deliver a diluted pharmaceutical formulation that is delivered to a patient through an outlet of the manifold.

[0083] In some embodiments, the sleeve extends from where the catheter is attached (within the manifold) to an outlet that is fluidly connected to a first inlet of the manifold for delivery of the pharmaceutical formulation that flows through the first inlet of the manifold for delivery into the catheter.

[0084] In some embodiments, the flow path has an open end defined at the distal end of the sleeve to receive the diluted pharmaceutical formulation and a sealed end at a specific location within the manifold where the catheter is attached to the outlet to receive the pharmaceutical formulation from the first inlet, the sealed end ensuring that all diluted pharmaceutical formulation coming from the dilution chamber is delivered to the outlet or to the patient.

[0085] In some embodiments, the flow path is fluidly connected to an outlet of the manifold for delivery of the pharmaceutical formulation to the patient.

[0086] In some embodiments, the flow path comprises a first inlet defined between the distal end of the sleeve and the catheter, the first inlet adapted to receive the pharmaceutical formulation for delivery to the patient.

[0087] In some embodiments, a second inlet is defined between the distal end of the sleeve and the distal end of a manifold onto which the container is connected, the second inlet being adapted to receive air bubbles redirected by the distal end of the sleeve to avoid delivering the air bubbles to the patient.

[0088] In some embodiments, the manifold includes a venting means to relieve excess pressure or remove air bubbles that may be trapped in the manifold.

[0089] In some embodiments, the dilution chamber comprises a container adapted to be selectively displaced between an inflated state and a deflated state.

[0090] In some embodiments, the container comprises a syringe having a plunger adapted to be selectively displaced to displace the container between an inflated state and a deflated state.

[0091] In one arrangement, the Sadleir function-based injection process may be supplemented using pulse width modulated (PWM) digital dilution.

[0092] In some embodiments, the PWM digital dilution includes delivering to the dilution chamber during a specific time interval all or a fraction thereof of a volume of the pharmaceutical formulation determined by a Sadleir function over a specific time interval of the injection process, wherein all or a fraction thereof of the volume of the pharmaceutical formulation is delivered to the dilution chamber over one or more shorter periods within the specific time interval but at a higher flow rate as compared to the flow rate determined by the Sadleir function.

[0093] According to a third aspect of the present disclosure, a dilution chamber is provided comprising a container and a manifold connected to the container, the dilution chamber allowing fluid flow (1) from an injection driver into the container via a first conduit and a first inlet of the manifold, and (2) from the container via a first outlet of the manifold to a patient via the conduit for delivery of a drug.

[0094] In some embodiments, the manifold comprises a second inlet that allows delivery of a flushing fluid for flushing the dilution chamber for the purpose of delivering any drug residue therein to the patient.

[0095] In some embodiments, the manifold comprises a one-way valve for permitting fluid flow from the first inlet to the vessel but preventing fluid flow from the vessel back to the injection driver through the first inlet.

[0096] In some embodiments, the dilution chamber comprises a catheter having a first end fluidly connected to the first inlet for receiving the pharmaceutical formulation from the infusion driver and a second end extending into the container.

[0097] In some embodiments, the dilution chamber comprises a container adapted to be selectively displaced between an inflated state and a deflated state.

[0098] In some embodiments, the container comprises a syringe having a plunger adapted to be selectively displaced to displace the container between an inflated state and a deflated state.

[0099] According to a fourth aspect of the present disclosure, there is provided a catheter for insertion into a dilution chamber according to the third aspect of the present disclosure, the catheter having a first end fluidly connected to a first inlet of the dilution chamber for receiving the pharmaceutical formulation from the injection driver, and a second end extending into a container.

[0100] In one arrangement, the second end of the catheter comprises a blind end that prevents fluid flow therethrough and a perforation across the sidewall of the catheter.

[0101] In another arrangement, multiple perforations are disposed in spaced relation along the length of the catheter and around the outer surface of the catheter to permit outflow of the drug through the second end of the catheter in different directions.

[0102] In an alternative arrangement, the catheter comprises an end section at the second end of the catheter, the end section comprising a perforation and a sleeve surrounding the end section.

[0103] In some embodiments, the sleeve comprises a plurality of perforations disposed in spaced relation along the length of the end section and around the outer surface of the end section to permit flow of the pharmaceutical formulation through the sleeve in different directions.

[0104] In some embodiments, the sleeve is adapted to expand into a circular or oval shape during its operation.

[0105] In some embodiments, at least one of the perforations made in the sleeve traverses the sleeve diagonally such that fluid flow exiting the sleeve through the perforation is toward the first end of the catheter.

[0106] In another alternative arrangement, the catheter comprises a blind end having a plurality of perforations, the catheter being made from a flexible material adapted to expand as the flow rate of the pharmaceutical formulation increases.

[0107] In a further alternative arrangement, the catheter comprises a conically truncated end, and the enlarged region of the conically truncated end comprises perforations.

[0108] In another alternative arrangement, the catheter has an open end that allows fluid flow out through the open end of the catheter and into the container.

[0109] In some embodiments, the catheter comprises an air bubble trap.

[0110] In some embodiments, the bubble trap comprises a sleeve that at least partially surrounds the first end of the catheter.

[0111] In some embodiments, the sleeve extends from a particular location within the manifold to a location outside the manifold such that the distal end of the sleeve is located within the dilution chamber.

[0112] In some embodiments, the flow path is defined between an outer wall of the catheter and an inner wall of the sleeve.

[0113] In some embodiments, the flow path is adapted to deliver a diluted pharmaceutical formulation that is delivered to a patient through an outlet of the manifold.

[0114] In some embodiments, the sleeve extends from where the catheter is attached (within the manifold) to an outlet that is fluidly connected to a first inlet of the manifold for delivery of the pharmaceutical formulation that flows through the first inlet of the manifold for delivery into the catheter.

[0115] In some embodiments, the flow path is fluidly connected to a first outlet of the manifold for delivery of the pharmaceutical formulation to the patient.

[0116] In some embodiments, the flow path comprises a first inlet defined between the distal end of the sleeve and the catheter, the first inlet adapted to receive the pharmaceutical formulation for delivery to the patient.

[0117] In some embodiments, a second inlet is defined between the distal end of the sleeve and the distal end of a manifold onto which the container is connected, the second inlet being adapted to receive air bubbles redirected by the distal end of the sleeve to avoid delivering the air bubbles to the patient.

[0118] In some embodiments, the manifold includes a venting means to relieve excess pressure or remove air bubbles that may be trapped in the manifold.

[0119] According to a fifth aspect of the present disclosure, there is provided a bubble trap for use in a dilution chamber defined in the third aspect of the present disclosure, the bubble trap being adapted to form at a first end of a catheter located within a container of the dilution chamber and to divert any air bubbles floating adjacent to the catheter and prevent any air bubbles from being delivered to a patient.

[0120] In some embodiments, the bubble trap comprises a sleeve that at least partially surrounds the first end of the catheter.

[0121] In some embodiments, the sleeve extends from a particular location within the manifold to a location outside the manifold such that the distal end of the sleeve is located within the dilution chamber.

[0122] In some embodiments, the flow path is defined between an outer wall of the catheter and an inner wall of the sleeve.

[0123] In some embodiments, the flow path is adapted to deliver a diluted pharmaceutical formulation that is delivered to a patient through an outlet of the manifold.

[0124] In some embodiments, the sleeve extends from where the catheter is attached (within the manifold) to an outlet that is fluidly connected to a first inlet of the manifold for delivery of the pharmaceutical formulation that flows through the first inlet of the manifold for delivery into the catheter.

[0125] In some embodiments, the flow path is fluidly connected to a first outlet of the manifold for delivery of the pharmaceutical formulation to the patient.

[0126] In some embodiments, the flow path comprises a first inlet defined between the distal end of the sleeve and the catheter, the first inlet adapted to receive the pharmaceutical formulation for delivery to the patient.

[0127] In some embodiments, a second inlet is defined between the distal end of the sleeve and the distal end of a manifold onto which the container is connected, the second inlet being adapted to receive air bubbles redirected by the distal end of the sleeve to avoid delivering the air bubbles to the patient.

[0128] In some embodiments, the manifold includes a venting means to relieve excess pressure or remove air bubbles that may be trapped in the manifold.

[0129] In a specific configuration of a first embodiment of the present disclosure, a method and system (referred to as the Tansy method) for delivering a pharmaceutical agent to a patient via intravenous infusion from a single pharmaceutical formulation container is provided. Doses are delivered at rates that vary over the duration of the infusion, such that different orders of magnitude of cumulative doses and different orders of magnitude of dose administration rates are separated in time. For example, after 3% of the infusion time, 0.001% of the cumulative dose has been administered. After 14% of the infusion time, 0.01% of the cumulative dose has been administered. After 34%, 56%, 78%, and 100% of the infusion time, 0.1%, 1%, 10%, and 100% of the cumulative dose have been administered. Similarly, as the infusion progresses, the rate of drug administration increases. After 11% of the infusion time, the drug administration rate is at a maximum of 0.01%. After 34%, 56%, 78%, and 100% of the infusion time, 0.1%, 1%, 10%, and 100% of the maximum drug administration rate are achieved.

[0130] A particular arrangement of a second embodiment of the present disclosure (referred to as the Sadleir method) describes a method and system for delivering the same profile of drug administration to a patient from a single pharmaceutical container (although if the same cumulative dose and dosage rate were to be achieved during the infusion, the concentration of the drug in the container would need to be increased by an amount dependent on the characteristics of the delivery system), but a dilution chamber in the delivery device reduces the concentration of the drug in the solution delivered to the patient as it is delivered. This requires increasing the rate of fluid infusion during the initial phase of the infusion to compensate for the difference in the delivered drug concentration. This increase in the rate of fluid infusion reduces the error or inaccuracy associated with a low fluid infusion rate.

[0131] In some embodiments, some of the disclosed embodiments allow for the delivery of cumulative doses or dose administration rates that are separated in time by orders of magnitude of change. This allows negative (or adverse) reactions to be detected during the course of a therapeutic infusion and the infusion to be stopped before a dose that would cause a more severe reaction has been administered. Alternatively, this may induce desensitization, preventing or reducing the severity of a reaction in patients who would otherwise suffer a negative (or adverse) reaction.

[0132] According to a sixth aspect of the present disclosure, there is provided a dilution chamber comprising a container defining an internal volume and having at least one inlet for receiving at least one first fluid and an outlet for discharging a second fluid, a first plunger for applying a pushing force to the at least first fluid, and a second plunger for dividing the internal volume of the container into a first chamber and a second chamber, the second plunger adapted to allow fluid flow between the first chamber and the second chamber.

[0133] In some embodiments, the second comprises valve means for allowing fluid flow between the first and second chambers.

[0134] In some embodiments, the second chamber is fluidly connected to an outlet to allow the fluid contained in the second chamber to be expelled from the container for infusion into a patient.

[0135] In some embodiments, the valve means comprises a check valve that prevents fluid flow from the second chamber to the first chamber.

[0136] In some embodiments, the outlet is adapted to allow a third fluid to enter the second chamber.

[0137] In some embodiments, the inlet is adapted to allow a first fluid to enter the first chamber.

[0138] In some embodiments, the second plunger comprises an agitation means for mixing the first fluid with a third fluid to produce a second fluid when the first fluid enters the second chamber due to the application of a pushing force generated by the first plunger.

[0139] In some embodiments, the agitation means is driven by fluid flow through a valve means of the second plunger.

[0140] In some embodiments, the container comprises a barrel of a syringe and the first plunger is the plunger of the syringe.

[0141] In some embodiments, the syringe is adapted to be received by a syringe driver, and the syringe driver is adapted such that actuation of the first plunger applies a pushing force to a first fluid contained in the first chamber during a first period of time to deliver the first fluid into the second chamber to mix the first fluid with a third fluid contained in the second chamber to generate a second fluid.

[0142] In some embodiments, the syringe driver is adapted to apply a pushing force to the first plunger during a second period of time to move the second plunger to expel the second fluid through the outlet and into a conduit for injection into a patient.

[0143] In some embodiments, the syringe driver is controlled by an algorithm that replicates the Diocles function.

[0144] In some embodiments, doses administered over time according to the Diocles function are administered in the same volume of pharmaceutical formulation (V p ), the concentration of the drug from the primary drug container (C p ), and is equal to the dose administered over time for the equivalent Tansy function using the duration of the injection process (i).

[0145] In a particular arrangement, the dilution chamber comprises a plunger lock for holding the first plunger in a particular position, the particular position being a position where, during insertion of the first fluid into the first chamber, the first fluid enters the second chamber for mixing with the third fluid to produce the second fluid.

[0146] In some embodiments, the dilution chamber with the plunger lock is adapted to be fluidly connected to a syringe driver having a syringe containing a first fluid.

[0147] In some embodiments, the syringe driver is adapted to drive a plunger of the syringe to apply a pushing force during a first period to deliver a first fluid to a dilution chamber containing a third fluid to generate a second fluid.

[0148] In some embodiments, the concentration of the first fluid contained in the dilution chamber increases during the process of infusing the second fluid into the patient.

[0149] In some embodiments, the syringe driver is controlled by an algorithm that replicates the Sadleir injection protocol for delivering a first fluid to a dilution chamber with a plunger lock.

[0150] In some embodiments, the first fluid is a pharmaceutical formulation comprising an active agent, and the third fluid diluent, the second fluid comprises a pharmaceutical composition prepared by mixing the first fluid and the third fluid.

[0151] In some embodiments, the concentration of the active agent contained in the dilution chamber increases during the process of injecting the pharmaceutical composition into a patient.

[0152] In one arrangement, the Diocles function based injection process may be supplemented using pulse width modulated (PWM) digital dilution.

[0153] In some embodiments, PWM digital dilution involves delivering all or a fraction of a volume of active agent determined by a Diocles function over a particular time interval of the injection process to a dilution chamber during a particular time interval, where all or a fraction of the volume of active agent is delivered over one or more shorter periods within the particular time interval but at a higher flow rate compared to the flow rate determined by the Diocles function.

[0154] According to a seventh aspect of the present disclosure, there is provided a dilution chamber comprising a first chamber and a second chamber fluidly connected to each other, a first piston slidably received in the first chamber for applying a pushing force to a first fluid contained in the first chamber to deliver the first fluid to the second chamber, and a second piston slidably received in the second chamber for applying a pushing force to a second fluid contained in the second chamber, wherein the first piston is adapted to apply the pushing force during a first period of time and the second piston is adapted to apply the pushing force during a second period of time, the first period starting before the second period of time.

[0155] In some embodiments, the dilution chamber further comprises an outlet fluidly connected to the second chamber for delivering a third fluid, which is a mixture of the first and second fluids, to the patient.

[0156] In some embodiments, the dilution chamber further comprises a piston assembly having first and second pistons, the first piston being longer than the second piston.

[0157] In some embodiments, the first chamber contains a first fluid and is adapted to receive a syringe adapted to receive a first piston.

[0158] In some embodiments, the dilution chamber is adapted to be received by a syringe driver, and the syringe driver is adapted to drive the piston assembly.

[0159] In some embodiments, the syringe driver is controlled by an algorithm that replicates a Kelly injection protocol during a first period of time, and the syringe driver is controlled by an algorithm that replicates a Wood injection protocol during a second period of time.

[0160] In some embodiments, the doses administered over time according to the Kelly function during a first period and the Wood function during a second period are administered in the same volume of pharmaceutical formulation (V p ), the concentration of the drug from the primary drug container (C p ), and is equal to the dose administered over time for an equivalent Tansy function with the duration of the injection process (i).

[0161] In some embodiments, the first fluid comprises a pharmaceutical formulation including an active agent, the second fluid diluent, and the third fluid comprises a pharmaceutical composition prepared by mixing the first and second fluids.

[0162] In some embodiments, the concentration of the first fluid contained in the dilution chamber increases during the process of infusing the second fluid into the patient.

[0163] In one arrangement, an injection process based on a staggered plunger function may be supplemented using pulse width modulated (PWM) digital dilution.

[0164] In some embodiments, the PWM digital dilution involves delivering to the dilution chamber, during a specific time interval, all or a fraction of a volume of the pharmaceutical formulation determined by a staggered plunger function over a specific time interval of the injection process, wherein all or a fraction of the volume of the pharmaceutical formulation is delivered to the dilution chamber over one or more shorter periods within the specific time interval but at a higher flow rate as compared to the flow rate determined by the staggered plunger function.

[0165] In some embodiments, a drug delivery device is provided, comprising: a first plunger, a second plunger, and a container configured to receive the second plunger and at least a portion of the first plunger, wherein the container and the second plunger together define a diluent chamber configured to receive a diluent, the diluent chamber comprising a diluent chamber opening, the diluent chamber opening being defined by the container, wherein the first plunger, the container, and the second plunger together define an activator chamber configured to receive a pharmaceutical formulation, the activator chamber comprising a first activator chamber opening configured to receive at least a portion of the first plunger, and the second plunger comprising a valve configured to control flow of the pharmaceutical formulation from the activator chamber to the diluent chamber in response to an applied pressure.

[0166] In some embodiments, the first plunger and the second plunger are each configured to be displaced relative to a longitudinal axis of the container.

[0167] In some embodiments, a second plunger is disposed between the first plunger and the dilution chamber opening.

[0168] In some embodiments, the activator chamber comprises a second activator chamber opening in the wall of the container.

[0169] In some embodiments, the active agent chamber is configured to receive a pharmaceutical formulation through the second active agent chamber opening.

[0170] In some embodiments, a second plunger is disposed between the second activator chamber opening and the dilution chamber opening.

[0171] In some embodiments, the container defines an interior container surface.

[0172] In some embodiments, the first plunger comprises a first plunger sealing surface configured to seal with the inner container surface to prevent fluid flow between the inner container surface and the first plunger sealing surface.

[0173] In some embodiments, the second plunger comprises a second plunger sealing surface configured to seal with the inner container surface to prevent fluid flow between the inner container surface and the second plunger sealing surface.

[0174] In some embodiments, the valve comprises an inlet side and an outlet side.

[0175] In some embodiments, the valve is configured to move from a closed position to an open position upon application of pressure to the inlet side.

[0176] In some embodiments, the valve is configured to move from an open position to a closed position upon removal of pressure applied to the inlet side.

[0177] In some embodiments, the valve is biased towards a closed position.

[0178] In some embodiments, the valve comprises a plurality of flaps configured to separate upon application of pressure to the inlet side.

[0179] In some embodiments, the drug delivery device further comprises a conduit. The conduit may be configured to be fluidly connected to the dilution chamber opening.

[0180] In some embodiments, the conduit has a predetermined volume.

[0181] In some embodiments of the present disclosure, a drug delivery system is provided, comprising a drug delivery apparatus and an infusion device, the infusion device comprising at least one infusion device processor and an infusion device memory storing program instructions accessible by the at least one infusion device processor.

[0182] In some embodiments, the program instructions are configured to cause the at least one injection device processor to: receive a volume input (Vp) indicating a volume of the pharmaceutical formulation; receive a time input (i) indicating a time at which the pharmaceutical formulation will be administered; receive a number (h) of injection steps to be performed during the time at which the pharmaceutical formulation will be administered; determine a pharmaceutical formulation output volume for each of the number of injection steps, wherein each pharmaceutical formulation output volume corresponds to a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective injection step; determine a target flow rate for each injection step, wherein each target flow rate indicates a target flow rate of the pharmaceutical formulation to be output by the drug delivery device during the respective injection step, and wherein each target flow rate is determined based at least in part on the pharmaceutical formulation output volume for the respective injection step; and actuate the injection device actuator to displace the first plunger such that the pharmaceutical formulation is output by the drug delivery device at the respective target flow rate during each injection step.

[0183] In some embodiments, 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 indicating one or more of an identity of the pharmaceutical formulation, a dose of the pharmaceutical formulation, and a maximum pharmaceutical formulation administration rate.

[0184] In some embodiments, the target flow rate is limited to a maximum pharmaceutical agent administration rate such that the target flow rate does not exceed the maximum pharmaceutical agent administration rate during the infusion.

[0185] In some embodiments, receiving the number of infusion steps includes receiving an infusion step input indicating the number of infusion steps or retrieving the number of infusion steps from an infusion device memory.

[0186] In some embodiments, determining the pharmaceutical formulation output volume for each of the number of infusion steps includes integrating the Tansy function from a first time corresponding to the start of the associated infusion step to a second time corresponding to the end of the associated infusion step.

[0187] In some embodiments, the Tansy function T(t) is

number

[0188] In some embodiments, determining the pharmaceutical formulation output volume for each of a number of infusion steps comprises:

number

[0189] In some embodiments, determining the target flow rate for each infusion step comprises dividing the pharmaceutical formulation output volume of the respective infusion step by the length of that infusion step.

[0190] In some embodiments, determining the target flow rate for each injection step includes determining an initial target flow rate and a final target flow rate for each injection step, wherein the initial target flow rate for each injection step is equal to the final target flow rate of the preceding injection step, and the final target flow rate for each injection step is equal to the initial target flow rate of the following injection step.

[0191] In some embodiments, the program instructions may cause the at least one infusion device processor to receive a concentration input (C ) indicative of the concentration of the pharmaceutical agent in the active agent chamber. p ) and a volume input (V p ) and a dilution chamber volume input (Vd ), a time input (i) indicating a time window over which the pharmaceutical formulation is to be administered, a number of infusions input (τ) indicating the number of infusion segments per minute over which an infusion modeling function is to be numerically approximated over the time window, and a number of infusion steps (h) to be performed during the time window; numerically approximating the infusion modeling function over the time window, wherein the numerical approximation of the infusion modeling function determines the number of infusion segments within the time window; and a starting target flow rate parameter (S(0) initiating determining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a starting infusion interval of the numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the numerical approximation, the subsequent target flow rates each indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation, the subsequent pharmaceutical formulation concentrations each indicating a subsequent approximate concentration of the pharmaceutical formulation in the dilution chamber after the respective subsequent infusion interval, and each subsequent target flow rate being an approximate value for the respective infusion interval. and iteratively determining subsequent pharmaceutical agent concentrations (h) based at least in part on subsequent pharmaceutical agent concentrations of a previous infusion interval, each subsequent pharmaceutical agent concentration being determined at least in part on a subsequent target flow rate of the respective subsequent infusion interval; determining an injection volume for each of a number of infusion steps (h) based at least in part on the numerical approximation, wherein the injection volume indicates a volume of the pharmaceutical agent to be output by the drug delivery device during the respective injection step; and actuating the injection device actuator to displace the first plunger such that the first injection volume or the second injection volume of each injection step is output by the drug delivery device during the respective injection step.

[0192] In some embodiments, receiving a number of infusion steps to be performed during the time the pharmaceutical formulation is to be administered includes receiving an infusion step input indicating the number of infusion steps or retrieving the number of infusion steps from an infusion device memory.

[0193] In some embodiments, 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 indicating one or more of an identity of the pharmaceutical formulation, a dose of the pharmaceutical formulation, and a maximum pharmaceutical formulation administration rate.

[0194] In some embodiments, the 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.

[0195] In some embodiments, determining the number of injection intervals within the time window of the numerical approximation comprises multiplying a time input (i) by a number of injections input (τ).

[0196] In some embodiments, the starting target flow parameter (S(0) initiating ) is determined by

number

[0197] In some embodiments, determining the starting pharmaceutical formulation concentration comprises:

number

number

[0198] In some embodiments, determining a subsequent target flow rate of one of the plurality of subsequent injection intervals of the numerical approximation comprises determining a flow rate parameter Sn where n is the number of relevant injection intervals, and the flow parameter S n Determining the dose parameter D mtf (t) n This includes determining:

[0199] In some embodiments, the dose parameter D mtf (t) n To determine

number

[0200] In some embodiments, the flow parameter S n To determine

number

[0201] In some embodiments, determining the subsequent concentration of the pharmaceutical agent of a numerical approximation comprises:

number

[0202] In some embodiments, the starting target flow rate (S(0) initiating ) is determined by

number

[0203] In some embodiments, determining the dose parameters comprises:

number

[0204] In some embodiments,

number

number

[0205] In some embodiments, determining the injection volume of one of the injection steps comprises:

number

[0206] 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, wherein determining the infusion rate for one of the infusion steps comprises:

number

[0207] 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 medication delivery device during the respective infusion step at the determined infusion rate.

[0208] 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.

[0209] 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 medication delivery device during each subsequent infusion step in bursts.

[0210] In some embodiments, the concentration input C p but,

number

[0211] In some embodiments, the injection modeling function is a Sadleir function.

[0212] In some embodiments, the program instructions may cause the at least one infusion device processor to receive a concentration input (C ) indicative of the concentration of the pharmaceutical agent in the active agent chamber. p ) and a volume input (V p ) and a dilution chamber volume input (V dreceiving a time input (i) indicating a time window over which the pharmaceutical formulation is to be administered, the time window including a first time window and a second time window; a number of infusions input (τ) indicating a number of infusion segments per minute over which an infusion modeling function is to be numerically approximated over the first time window; a number (h) of infusion steps to be performed during the time window, wherein a first number of infusion steps (h1) are to be performed during the first time window and a second number of infusion steps (h2) are to be performed during the second time window; numerically approximating the infusion modeling function over the first time window, wherein the numerical approximation of the infusion modeling function determines the number of infusion segments for the first time window; and a starting target flow rate parameter (K(0) initiating determining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output into the dilution chamber during a starting infusion interval of the numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the numerical approximation, the subsequent target flow rates each indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation, and the subsequent pharmaceutical formulation concentrations each indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the respective subsequent infusion interval. determining a target dose Dose(t) for each of the first number of infusion steps (h) based at least in part on the numerical approximation, the target dose Dose(t) for each of the first number of infusion steps (h) being indicative of a similar concentration of the pharmaceutical formulation in the previous infusion interval, each subsequent target flow rate being determined based at least in part on the subsequent pharmaceutical formulation concentration of the previous infusion interval of the respective infusion interval, the subsequent target flow rate being determined at least in part on the subsequent target flow rate of the respective subsequent infusion interval; determining a first infusion volume for each of the first number of infusion steps (h) based at least in part on the numerical approximation, the infusion volume being indicative of a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective infusion step; determining a number of infusion intervals for a second time window; and determining a target dose Dose(t) for each of the number of infusion intervals for the second time window. nand determining a target flow rate D for each of the number of infusion intervals in the second time window based at least in part on the target dose for each infusion interval. n determining a second injection volume for each of a second number of injection steps (h2) based at least in part on a target flow rate; and actuating an injection device actuator to displace the first plunger such that the first injection volume or the second injection volume of each injection step (h) is output by the medication delivery device during the respective injection step.

[0213] In some embodiments, receiving a certain number of infusion steps to be performed during the time window includes receiving an infusion step input indicating the certain number of infusion steps or retrieving the certain number of infusion steps from an infusion device memory.

[0214] In some embodiments, 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 indicating one or more of an identity of the pharmaceutical formulation, a dose of the pharmaceutical formulation, and a maximum pharmaceutical formulation administration rate.

[0215] In some embodiments, the 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.

[0216] In some embodiments, determining the number of injection intervals within the time window of the numerical approximation comprises multiplying a time input (i) by a number of injections input (τ).

[0217] In some embodiments, the starting target flow parameter (S(0) initiating ) is determined by

number

[0218] In some embodiments, determining the starting pharmaceutical formulation concentration comprises:

number

number

[0219] In some embodiments, determining the subsequent target flow rate comprises:

number

[0220] In some embodiments, the target dose Dose(t) n To determine

number

[0221] In some embodiments,

number

number

[0222] In some embodiments, determining the subsequent pharmaceutical agent concentration comprises:

number

[0223] In some embodiments, determining the first injection volume of one of the first number of injection steps (h1) comprises:

number

[0224] In some embodiments, the target flow rate D for each of the number of infusion intervals in the second time window is n To determine

number

[0225] In some embodiments, determining the second injection volume of one of the second number of injection steps (h2) comprises:

number

[0226] 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

[0227] 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 medication delivery device during the respective infusion step at the determined infusion rate.

[0228] 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.

[0229] 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 medication delivery device during each subsequent infusion step in bursts.

[0230] In some embodiments, the injection modeling function is a Kelly function.

[0231] In some embodiments, a drug delivery device is provided that may include a plunger, a container configured to receive at least a portion of the plunger, and a dilution chamber fluidly connectable to the container, the dilution chamber configured to receive a diluent, the plunger and the container together defining an activator chamber configured to receive a pharmaceutical formulation, the activator chamber comprising an activator chamber opening configured to receive at least a portion of the plunger and an activator chamber outlet, the dilution chamber configured to receive the pharmaceutical formulation from the activator chamber outlet, the dilution chamber comprising a dilution chamber outlet, and the plunger configured to be displaced to displace the pharmaceutical formulation in the activator chamber through the activator chamber outlet into the dilution chamber, thereby producing a diluted pharmaceutical formulation, and to displace the diluted pharmaceutical formulation in the dilution chamber through the dilution chamber outlet.

[0232] In some embodiments, the drug delivery device further comprises a second inlet configured to receive flushing fluid, a one-way valve configured to allow fluid from the activator chamber to enter the dilution chamber and to prevent fluid in the displacement chamber from entering the activator chamber, and a multi-way valve configured to be actuated between a first position and a second position, wherein the multi-way valve, when in the first position, allows flushing of fluid from the second inlet into the dilution chamber while preventing displacement of the pharmaceutical formulation into the dilution chamber, and is configured, when in the second position, to allow displacement of the pharmaceutical formulation into the dilution chamber and to prevent flushing fluid from entering the dilution chamber.

[0233] In some embodiments, the drug delivery device further comprises a first conduit configured to fluidly connect the active agent chamber outlet and the dilution chamber inlet.

[0234] In some embodiments, the drug delivery device further comprises a catheter configured to be at least partially disposed within the dilution chamber.

[0235] In some embodiments, a catheter comprises: a catheter body comprising a hollow core defining a catheter body fluid flow path; and a plurality of catheter body perforations disposed in an end portion of the catheter, each of the plurality of catheter body perforations extending between the hollow core and an exterior of the catheter body; a blind end; and a flexible sleeve connected to the end portion, the flexible sleeve comprising a plurality of sleeve perforations extending between an inner surface of the sleeve and an outer surface of the sleeve such that a pharmaceutical formulation catheter flow path is defined between the hollow core and each of the plurality of sleeve perforations through the plurality of catheter body perforations.

[0236] In some embodiments, a catheter is configured to fluidly connect to the second end of the first conduit.

[0237] In some embodiments, the end portion is configured to be disposed within the dilution chamber.

[0238] In some embodiments, the catheter comprises an air bubble trap.

[0239] In some embodiments, the drug delivery device further comprises a manifold, the manifold configured to connect to the dilution chamber.

[0240] In some embodiments, the manifold comprises a manifold inlet and a manifold outlet, the manifold inlet configured to receive the pharmaceutical formulation from the dilution chamber and the manifold outlet configured to connect to a second conduit that enables the pharmaceutical formulation to be delivered to the patient.

[0241] In some embodiments, a drug delivery system is provided, comprising a drug delivery apparatus and an infusion device, the infusion device comprising at least one infusion device processor and an infusion device memory storing program instructions accessible by the at least one infusion device processor.

[0242] In some embodiments, the program instructions cause the at least one infusion device processor to receive a volume input (V) indicating the volume of the pharmaceutical formulation. p receiving a time input (i) indicating a time at which the pharmaceutical formulation is to be administered; determining a number of injection steps to be performed during the time at which the pharmaceutical formulation is to be administered; determining a pharmaceutical formulation output volume for each of the injection steps among the number of injection steps, wherein each pharmaceutical formulation output volume corresponds to a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective injection step; determining a target flow rate for each injection step, wherein each target flow rate indicates a target flow rate of the pharmaceutical formulation output by the drug delivery device during the respective injection step, and wherein each target flow rate is determined based at least in part on the pharmaceutical formulation output volume for the respective injection step; and actuating the injection device actuator to displace the plunger such that the pharmaceutical formulation is output by the drug delivery device at the respective target flow rate during each injection step.

[0243] In some embodiments, the program instructions may cause the at least one infusion device processor to receive a concentration input (C ) indicative of the concentration of the pharmaceutical agent in the active agent chamber. p ) and a volume input (V p ) and a dilution chamber volume input (V d), a time input (i) indicating a time window over which the pharmaceutical formulation is to be administered, a number of infusions input (τ) indicating the number of infusion segments per minute over which an infusion modeling function is to be numerically approximated over the time window, and a number (h) of infusion steps to be performed during the time window; numerically approximating the infusion modeling function over the time window, wherein the numerical approximation of the infusion modeling function determines the number of infusion segments within the time window; and a starting target flow rate parameter (S(0) initiating determining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a starting infusion interval of the numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the numerical approximation, the subsequent target flow rates each indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation, the subsequent pharmaceutical formulation concentrations each indicating a subsequent approximate concentration of the pharmaceutical formulation in the dilution chamber after the respective subsequent infusion interval, and each of the subsequent target flow rates being respectively determining an injection volume for each of a number (h) of injection steps based at least in part on the numerical approximation, wherein the injection volume indicates a volume of the pharmaceutical formulation to be output by the drug delivery device during each injection step; and actuating an injection device actuator to displace a plunger such that the determined injection volume for each injection step is output by the drug delivery device during each injection step.

[0244] In some embodiments, the program instructions may cause the at least one infusion device processor to receive a concentration input (C ) indicative of the concentration of the pharmaceutical agent in the active agent chamber.p ) and a volume input (V p ) and a dilution chamber volume input (V d receiving a time input (i) indicating a time window over which the pharmaceutical formulation is to be administered, the time window including a first time window and a second time window; a number of infusions input (τ) indicating a number of infusion segments per minute over which an infusion modeling function is to be numerically approximated over the first time window; a number (h) of infusion steps to be performed during the time window, wherein a first number of infusion steps (h1) are to be performed during the first time window and a second number of infusion steps (h2) are to be performed during the second time window; numerically approximating the infusion modeling function over the first time window, wherein the numerical approximation of the infusion modeling function determines the number of infusion segments for the first time window; and a starting target flow rate parameter (K(0) initiatingdetermining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output into the dilution chamber during a starting infusion interval of the numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the numerical approximation, the subsequent target flow rates each indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation, and the subsequent pharmaceutical formulation concentrations each indicating a subsequent approximate concentration of the pharmaceutical formulation in the dilution chamber after the respective subsequent infusion interval. determining a target dose Dose(t) for each of the first number of infusion steps (h1) based at least in part on the numerical approximation, the target dose Dose(t) being indicative of a concentration of the pharmaceutical formulation in a previous infusion interval of the respective infusion interval, and each subsequent target flow rate being determined based at least in part on the subsequent target flow rate of the respective subsequent infusion interval; determining a first infusion volume for each of the first number of infusion steps (h1) based at least in part on the numerical approximation, the infusion volume being indicative of a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective infusion step; determining a number of infusion intervals for a second time window; and determining a target dose Dose(t) for each of the number of infusion intervals for the second time window. n and determining a target flow rate D for each of the number of infusion intervals in the second time window based at least in part on the target dose for each infusion interval. n determining a second injection volume for each of the second number of injection steps (h2) based at least in part on the target flow rate; and actuating the injection device actuator to displace the plunger such that the first injection volume or the second injection volume of each injection step (h) is output by the medication delivery device during the respective injection step.

[0245] In some embodiments, a method for delivering a pharmaceutical formulation to a patient is provided, the method comprising: a volume input (V) indicating a volume of the pharmaceutical formulation; preceiving a time input (i) indicating a time at which the pharmaceutical formulation is to be administered; determining a number of infusion steps to be performed during the time at which the pharmaceutical formulation is to be administered; determining a pharmaceutical formulation output volume for each of the infusion steps among the number of infusion steps, wherein 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 a target flow rate for each infusion step, wherein each target flow rate indicates a target flow rate of the pharmaceutical formulation output by the drug delivery device during the respective infusion step, and wherein each target flow rate is determined based at least in part on the pharmaceutical formulation output volume for the respective infusion step; and actuating the infusion device actuator such that the pharmaceutical formulation is output by the drug delivery device at the respective target flow rate during each infusion step.

[0246] In some embodiments, a method for delivering a pharmaceutical formulation to a patient is provided, the method comprising receiving a concentration input (C ) indicative of the 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 ), a time input (i) indicating a time window over which the pharmaceutical formulation is to be administered, a number of infusions input (τ) indicating the number of infusion segments per minute over which an infusion modeling function is to be numerically approximated over the time window, and a number (h) of infusion steps to be performed during the time window; numerically approximating the infusion modeling function over the time window, wherein the numerical approximation of the infusion modeling function determines the number of infusion segments within the time window; and a starting target flow rate parameter (S(0) initiatingdetermining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a starting infusion interval of the numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the numerical approximation, the subsequent target flow rates each indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation, the subsequent pharmaceutical formulation concentrations each indicating a subsequent approximate concentration of the pharmaceutical formulation in the dilution chamber after the respective subsequent infusion interval, and each of the subsequent target flow rates being respectively the injection volume for each of a number (h) of injection steps is determined at least in part based on a subsequent pharmaceutical agent concentration of a previous infusion interval, with each subsequent pharmaceutical agent concentration being determined at least in part based on a subsequent target flow rate for a respective subsequent infusion interval; determining an injection volume for each of a number (h) of injection steps based at least in part on the numerical approximation, the injection volume indicating a volume of the pharmaceutical agent to be output by the drug delivery device during the respective injection step; and actuating an injection device actuator to displace a plunger within a chamber of the drug delivery device such that the determined injection volume for each injection step is output by the drug delivery device during the respective injection step.

[0247] In some embodiments, a method for delivering a pharmaceutical formulation to a patient is provided, the method comprising receiving a concentration input (C ) indicative of the 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 dreceiving a time input (i) indicating a time window over which the pharmaceutical formulation is to be administered, the time window including a first time window and a second time window; a number of infusions input (τ) indicating a number of infusion segments per minute over which an infusion modeling function is to be numerically approximated over the first time window; a number (h) of infusion steps to be performed during the time window, wherein a first number of infusion steps (h1) are to be performed during the first time window and a second number of infusion steps (h2) are to be performed during the second time window; numerically approximating the infusion modeling function over the first time window, wherein the numerical approximation of the infusion modeling function determines the number of infusion segments for the first time window; and a starting target flow rate parameter (K(0) initiating determining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output into the dilution chamber during a starting infusion interval of the numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the numerical approximation, the subsequent target flow rates each indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the numerical approximation, and the subsequent pharmaceutical formulation concentrations each indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the respective subsequent infusion interval. determining a target dose Dose(t) for each of the first number of infusion steps (h1) based at least in part on the concentration of the pharmaceutical formulation in a previous infusion interval of the respective infusion interval, each subsequent target flow rate being determined based at least in part on the concentration of the pharmaceutical formulation in a subsequent infusion interval of the respective infusion interval, and each subsequent target flow rate being determined based at least in part on the subsequent target flow rate for the respective subsequent infusion interval; determining a first infusion volume for each of the first number of infusion steps (h1) based at least in part on the numerical approximation, the infusion volume being indicative of a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective infusion step; determining a number of infusion intervals for a second time window; and determining a target dose Dose(t) for each of the number of infusion intervals for the second time window. nand determining a target flow rate D for each of the infusion intervals of the second time window based at least in part on the target dose for each infusion interval. n determining a second injection volume for each of the second number of injection steps (h2) based at least in part on the target flow rate; and actuating the injection device actuator to displace a plunger within a chamber of the drug delivery device such that the first injection volume or the second injection volume of each injection step (h) is output by the drug delivery device during the respective injection step.

[0248] In some embodiments, a drug delivery device is provided, comprising: a drug delivery device body, a first plunger configured to be slidably received within the drug delivery device body, a first chamber configured to receive a pharmaceutical formulation, and a second chamber configured to receive a diluent, wherein the first plunger is configured to force a portion of the pharmaceutical formulation into the second chamber to mix with the diluent to form a diluted pharmaceutical formulation, and to force the diluted pharmaceutical formulation out of an outlet of the second chamber.

[0249] In some embodiments, 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.

[0250] In some embodiments, a system for delivering an active ingredient to a patient is provided, the system comprising an infusion driver having a processor for executing instructions of an algorithm for approximating flow rate fluctuations of the pharmaceutical formulation, such that the active ingredient is part of a pharmaceutical formulation having a specific volume, the pharmaceutical formulation comprising a solvent and a therapeutic dose of the active ingredient, and 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.

[0251] In some embodiments, a dilution chamber is provided that includes a container and a manifold connected to the container, allowing fluid flow from the infusion driver into the container via a first conduit and a first inlet of the manifold, and from the container via a first outlet of the manifold, for delivery of a drug to a patient via the conduit.

[0252] In some embodiments, a catheter for insertion into the dilution chamber is provided, the catheter having a first end fluidly connected to a first inlet of the dilution chamber for receiving the pharmaceutical formulation from the injection driver, and a second end extending into the container.

[0253] In some embodiments, a bubble trap for use with a catheter is provided, the bubble trap being adapted to form at a first end of the catheter located within a reservoir of a dilution chamber and to divert any air bubbles floating adjacent to the catheter and prevent any air bubbles from being delivered to a patient.

[0254] In some embodiments, a dilution chamber is provided comprising a container defining an internal volume and having at least one inlet for receiving at least one first fluid and an outlet for discharging a second fluid, a first plunger for applying a pushing force to the at least first fluid, and a second plunger for dividing the internal volume of the container into a first chamber and a second chamber, the second plunger adapted to allow fluid flow between the first chamber and the second chamber.

[0255] In some embodiments, a dilution chamber is provided comprising a first chamber and a second chamber fluidly connected to one another, a first piston slidably received within the first chamber for applying a pushing force to a first fluid contained in the first chamber to deliver the first fluid to the second chamber, and a second piston slidably received within the second chamber for applying a pushing force to a second fluid contained in the second chamber, wherein the first piston is adapted to apply the pushing force during a first period of time and the second piston is adapted to apply the pushing force during a second period of time, the first period starting before the second period of time.

[0256] In some embodiments, a drug delivery device is provided that can include a first plunger, a second plunger, a first container configured to receive at least a portion of the first plunger, and a second container configured to receive at least a portion of the second plunger, wherein the first container and the first plunger together define an activator chamber configured to receive a pharmaceutical formulation, the activator chamber having an activator chamber opening, the second container and the second plunger together define a diluent chamber configured to receive a diluent, the diluent chamber having a diluent chamber opening, the first plunger configured to be actuated to apply a pushing force to the pharmaceutical formulation in the first container to deliver the pharmaceutical formulation to the second container, and the second plunger configured to be actuated to apply a pushing force to the pharmaceutical formulation in the second container to push the pharmaceutical formulation through a drug delivery device outlet.

[0257] In some embodiments, the drug delivery device further comprises a valve configured to allow fluid from the active agent chamber to enter the dilution chamber and to prevent fluid in the dilution chamber from entering the active agent chamber.

[0258] In some embodiments, the first container and the second container are connected by a conduit.

[0259] In some embodiments, a drug delivery system is provided, comprising a drug delivery apparatus and an infusion device, the infusion device comprising at least one infusion device processor and an infusion device memory storing program instructions accessible by the at least one infusion device processor.

[0260] In some embodiments, the program instructions may cause the at least one infusion device processor to receive a concentration input (C ) indicative of the concentration of the pharmaceutical agent in the active agent chamber. p ) and a volume input (V p) and a dilution chamber volume input (V d receiving a time input (i) indicating a time window over which the pharmaceutical formulation will be administered, the time window including a first time window and a second time window; an infusion number input (τ) indicating a number of infusion intervals per minute over which the first infusion modeling function and the second infusion modeling function will be numerically approximated; a number (h) of infusion steps to be performed during the time window, wherein a first number of infusion steps (h1) will be performed during the first time window and a second number of infusion steps (h2) will be performed during the second time window; numerically approximating the first infusion modeling function over the first time window, wherein the numerical approximation of the first infusion modeling function over the first time window is a first numerical approximation, and wherein the numerical approximation of the first infusion modeling function determines a first number of infusion intervals within the first time window; and initiatingdetermining a starting target flow rate parameter indicating a target flow rate of the pharmaceutical formulation output into the dilution chamber during a starting infusion interval of the first numerical approximation; determining a starting pharmaceutical formulation concentration, the starting pharmaceutical formulation concentration indicating an approximate concentration of the pharmaceutical formulation in the dilution chamber after the starting infusion interval of the first numerical approximation; and iteratively determining subsequent target flow rates and subsequent pharmaceutical formulation concentrations for each of a plurality of subsequent infusion intervals of the first numerical approximation, the subsequent target flow rates of the first numerical approximation each indicating an approximate target flow rate of the pharmaceutical formulation output into the dilution chamber during a starting infusion interval of the first numerical approximation; and iteratively determining a first numerically approximated subsequent pharmaceutical agent concentration indicating a target flow rate of the pharmaceutical agent output by the drug delivery device during an infusion interval, each subsequent pharmaceutical agent concentration indicating a subsequent approximate concentration of the pharmaceutical agent in the dilution chamber after a respective subsequent infusion interval, each subsequent target flow rate of the first numerically approximated subsequent pharmaceutical agent concentration being determined at least in part based on a subsequent pharmaceutical agent concentration of a previous infusion interval of the respective infusion interval, and each subsequent target flow rate of the first numerically approximated subsequent pharmaceutical agent concentration being determined at least in part based on a subsequent target flow rate of a respective subsequent infusion interval. and numerically approximating a second infusion modeling function over a second time window, wherein the numerical approximation of the second infusion modeling function over the second time window is a second numerical approximation, and wherein numerically approximating the second infusion modeling function includes iteratively determining a subsequent target flow rate, a subsequent dilution chamber volume, and a subsequent pharmaceutical formulation concentration for each of a plurality of subsequent infusion intervals of the second numerical approximation, wherein the subsequent target flow rates of the second numerical approximation each indicate a target flow rate of the pharmaceutical formulation output by the drug delivery device during a respective subsequent infusion interval of the second numerical approximation, and the chamber volumes each indicate a volume of the dilution chamber after a preceding infusion interval of the respective infusion interval, the second numerically approximated subsequent pharmaceutical agent concentrations each indicate a subsequent approximate concentration of the pharmaceutical agent in the dilution chamber after a respective subsequent infusion interval, each of the second numerically approximated subsequent target flow rates is determined based at least in part on the subsequent pharmaceutical agent concentration of the previous infusion interval of the respective infusion interval, and the second numerically approximated subsequent pharmaceutical agent concentration is determined based at least in part on the subsequent target flow rate of the respective subsequent infusion interval and the corresponding subsequent dilution chamber volume.and determining a first injection volume for each of a first number of injection steps (h1) based at least in part on the first numerical approximation and a second injection volume for each of a second number of injection steps (h2) based at least in part on the second numerical approximation, the first and second injection volumes indicating a volume of the pharmaceutical formulation to be output by the drug delivery device during the respective injection step; and actuating the injection device actuator to displace the first plunger and / or the second plunger such that the first injection volume or the second injection volume of each injection step (h) is output by the drug delivery device during the respective injection step.

[0261] In some embodiments, the first infusion modeling function is a Kelly function.

[0262] In some embodiments, numerically approximating the first infusion modeling function over the first time window includes numerically approximating a Kelly function.

[0263] In some embodiments, determining the subsequent target flow rate of the second numerical approximation comprises:

number

[0264] In some embodiments, the target dose Dose(t) n To determine

number

[0265] In some embodiments,

number

number

[0266] In some embodiments, determining the subsequent dilution chamber volume of the second numerical approximation comprises:

number

[0267] In some embodiments, determining the subsequent pharmaceutical agent concentration of the second numerical approximation comprises:

number

[0268] In some embodiments, determining the second injection volume of one of the second number of injection steps (h2) comprises:

number

[0269] 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

[0270] 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 first infusion volume or second infusion volume of each infusion step is output by the medication delivery device during the respective infusion step at the determined infusion rate.

[0271] 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 first injection volume or second injection volume of each injection step is delivered according to a constant velocity profile or a linearly varying velocity profile.

[0272] 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 first infusion volume or second infusion volume of each infusion step is output by the medication delivery device during each subsequent infusion step in a burst.

[0273] In some embodiments, the first infusion modeling function is a Kelly function and the second infusion modeling function is a Wood function.

[0274] Further features of the present disclosure will be more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for purposes of illustrating the present disclosure and, as stated above, 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 accompanying drawings. [Brief explanation of the drawings]

[0275] [Figure 1a] 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; FIG. [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. [Figure 2] 1A-1D are perspective views of particular configurations of devices for delivery of pharmaceutical formulations (drug delivery devices), according to some embodiments. [Figure 3] 1 is a perspective view of a particular arrangement of a drug delivery device including a dilution chamber, the drug delivery device being connected to an injection device, according to some embodiments. [Figure 4] 4 is a top view of the dilution chamber of the drug delivery device shown in FIG. 3 according to some embodiments. [Figure 5] 5 is an enlarged view of a portion of the dilution chamber shown in FIG. 4, illustrating a particular placement of a catheter inserted into the dilution chamber, according to some embodiments. [Figure 6] 6 is a top view of the dilution chamber shown in FIG. 3 showing the catheter shown in FIG. 5 withdrawn from the dilution chamber, according to some embodiments. [Figure 7a] FIG. 6 is a top view of the catheter shown in FIG. 5 being withdrawn from the dilution chamber, according to some embodiments. [Figure 7b] FIG. 10 is a top view of a lower portion of a manifold according to some embodiments. [Figure 8a] FIG. 1 is a top view of a catheter, according to some embodiments. [Figure 8b] FIG. 1 is a top view of a distal end of a catheter, according to some embodiments. [Figure 8c] FIG. 1B is a top view of the distal end of the catheter when the catheter is attached to the manifold, according to some embodiments. [Figure 8d] FIG. 1B is a top view of the distal end of the catheter when the catheter is attached to the manifold, according to some embodiments. [Figure 9a] 1A-1C are schematic diagrams of alternative catheter placements, according to some embodiments. [Figure 9b] FIG. 9b is a perspective view of the catheter shown in FIG. 9a, according to some embodiments. [Figure 10] 1A-1C are perspective views of the distal end of alternative catheter configurations, according to some embodiments. [Figure 11a] FIG. 10 is a top view of an alternative arrangement of a catheter, where the catheter is attached to a lower portion of a manifold, according to some embodiments. [Figure 11b] FIG. 11b is a top view of the catheter shown in FIG. 11a, according to some embodiments. [Figure 11c] FIG. 11b is a top view of the catheter shown in FIG. 11a with a manifold attached to a connection body, according to some embodiments. [Fig. 11d-11e] FIG. 11B is a top view of the catheter shown in FIGS. 11a and 11b attached to a dilution chamber, according to some embodiments. [Figure 12a] 1 depicts a flowchart 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 flowchart 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 method, including a Sadleir function configured to allow calculation of the infusion rate and delivered volume at various points during the Sadleir method, according to some embodiments. [Figure 13c] 13b 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 flowchart in Figure 13b illustrates the use of the Sadleir method when used for intervals 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 to be 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-14b] Figures 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. [Figures 15a-15d] Figures 15a (logarithmic y-axis scale) and 15b (linear y-axis scale) illustrate the difference in cumulative dose administered at each stage of a 30-minute infusion using an infusion method according to a first embodiment of the present disclosure (referred to as the Tansy method) compared to 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). [Figures 17a-17c]Figures 17a (calculating the Sadleir function using an integral interval of 60 per minute, i.e., τ = 60) and 17C (calculating the Sadleir function using an integral interval of 1200 per minute, i.e., τ = 1200) illustrate the variation in flow rate for different cases of the second embodiment of the present disclosure, each of which differs as a result of selecting different start interval rates (30 minute infusion duration, 10 ml dilution chamber, 50 ml pharmaceutical formulation volume). [Figures 17b-17d] 17a and 17c illustrate the difference in minimum flow rate for the Sadleir function as a result of different starting interval velocities in FIGS. 17a and 17c, respectively. [Figure 17e] A graph plotting the minimum flow rate values ​​for each of the Sadleir method cases (shown in Figure 17d) that differ from each other in start-up section speed is shown. [Figure 18] 1 illustrates the volume of drug administered during the first minute of the Sadleir method with different precision calculations (number of integration intervals per minute, or tau), with or without the volume of the start interval. [Figures 19a-19b] Figures 19a (linear y-axis scale) and 19b (logarithmic y-axis scale) illustrate the rate of infusion of pharmaceutical formulation liquid from the dilution chamber into the patient when using the Tansy method for a 50 ml infusion over various exemplary infusion durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes). [Figure 20a] The rates of infusion of pharmaceutical formulation from the dilution chamber are illustrated and compared when using the Sadleir (10 mL dilution chamber, Vd) or Tansy method for a 50 mL infusion over the first 4 minutes of various exemplary infusion durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes). [Figure 20b] Illustrates the infusion rate of a pharmaceutical formulation from a dilution chamber when using the Sadleir method (Vd of 10 mL in this example) for a 50 mL infusion over various exemplary infusion durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes). [Figure 20c]Illustrates the rate of infusion of pharmaceutical formulation liquid from a drug container using the Sadleir technique for a 50 mL infusion and a 10 mL dilution chamber over the first 10 minutes of various exemplary infusion durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes). [Figure 21a-21b] Figure 21a (linear y-axis scale) and Figure 21b (logarithmic y-axis scale) illustrate the rate of pharmaceutical formulation dose (in percentage of total dose given during each 1 / 1500 minute period of infusion when using the Sadleir method for a 50 ml infusion volume, 10 ml dilution chamber, and τ = 1200) administered to a patient over various total infusion durations (20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, 180 minutes). [Figure 21c] Illustrated is the cumulative dose (as a percentage of the total dose using the Sadleir method for a 50 ml infusion volume, a 10 ml dilution chamber, and τ=1200) administered to a patient over the course of an infusion for various total infusion durations (20 min, 25 min, 30 min, 45 min, 60 min, 120 min, 180 min). [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, 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-22c] 22a and 22b 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, with FIG. 22b illustrating the first 15 minutes of the 30 minute infusion. [Figure 22d-22e]22a-22c illustrate the difference in cumulative volume injected from a pharmaceutical formulation liquid syringe or container over the course of a 30 minute infusion when using a first (Tansy) or second (Sadleir with 10 ml dilution chamber) embodiment of the present disclosure for a 50 ml infusion, with FIG. 22d illustrating the first 15 minutes of the 30 minute infusion. [Figure 23a] 1 is a table of the instantaneous rate of the Tansy function at various times during a 60-minute infusion of 1000 mL of a pharmaceutical formulation, and the values ​​at which the infusion device approximates this function using either the 40 constant rate steps or the 40 ramp rate steps method. [Figures 23b-23c] Figures 23b (linear y-axis scale) and 23c (logarithmic y-axis scale) illustrate the flow rates of two approximations of the Tansy function using 40 injection steps over a 30 minute injection of 1000 ml. [Figure 24a] 1 is a table of two example values ​​of an approximation of the Sadleir function for a 50 mL infusion of a pharmaceutical formulation over 30 minutes using a 10 mL dilution chamber and a τ of 1200 / min. [Figure 24b-24c] Figures 24a and 24c illustrate the infusion rate over the duration of the infusion period resulting from the Sadleir approximation using either a ramp rate step or constant rate step program (40 infusion steps of 45 seconds each for Figure 24a) over a 30 minute infusion; Figure 24c illustrates (the first 15 minutes of a 30 minute infusion). [Figure 24d-24e] 24b and 24c illustrate the dose of drug administered when using the approximations in FIGS. 24b and 24c with the second embodiment of the present disclosure (Sadleir method) (first 5 minutes of a 30 minute infusion), and FIG. 24e illustrates the first 15 minutes of a 30 minute infusion. [Figure 25a-25b] Figure 25 illustrates the flow rate of the Sadleir function compared to three different approximations of the constant infusion rate step of the Sadleir method using infusion steps of 45 second duration, a rate of ml / min, over a 30 minute infusion (40 steps, τ=1200), Figure 25b illustrates the first 4 minutes of the 30 minute infusion. [Fig. 25c-25d]Figures 25c (linear y-axis scale) and 25d (logarithmic y-axis scale) illustrate the cumulative dose administered to a patient as a percentage of the total drug dose over the first 3 minutes of a 30-minute infusion, comparing the Sadleir function with five examples of Sadleir infusion rate approximations using 45-second infusion step durations (40 infusion steps total). [Figures 26a-26d] As shown in Figure 8c, experimental results of two specific implementations of the second embodiment of the present disclosure using a 10 mL dilution chamber with a balloon-tip catheter, three 3 og (0.25 mm) perforations deliver 50 ml of pharmaceutical formulation over 30 minutes using 40 ramp rate infusion steps. [Figure 26a] 1 illustrates experimental results for two specific realizations of a second embodiment of the present invention (dashed and dotted lines), comparing dilution chamber concentrations over time with those of theoretical results assuming perfect mixing (dashed line). [Figure 26b] Illustrated is the percentage dose delivered per 1 / 1200 minute period over a 30 minute infusion duration using a logarithmic y-scale. [Figure 26c] Figure 8c illustrates the cumulative percentage dose (percentage of pharmaceutical formulation concentration) delivered over time over a 30 minute infusion (solid line) compared to that predicted by the Sadleir function (dashed line) using a 10 ml dilution chamber with a balloon-tip catheter shown in Figure 8c with three 30 g (0.25 mm) perforations. [Figure 26d] 26c illustrates the cumulative percentage dose delivered over a 30 minute infusion for a particular implementation of the second embodiment of the present disclosure with reference to FIG. 26c, except that the cumulative percentage dose (percentage of pharmaceutical agent concentration) is plotted on a logarithmic y-scale, and the decimal separators for the magnitude of the cumulative percentage dose are provided. [Figure 27] 1 is a software code written in Python3 for calculating values ​​that can be sent to an infusion device to implement the Tansy method (first embodiment of the present disclosure). [Figure 28]10 is a software code written in Python3 for calculating values ​​that can be sent to an injection device to implement the Sadleir method (second embodiment of the present disclosure). [Figure 29a] 10 depicts a flowchart illustrating a modified Sadleir function applied to calculate the infusion rate of the "Increasing Volume Sadleir Method." [Figures 29b-29c] 29a and 29b illustrate the cumulative volume injected using an alternative embodiment of the second embodiment of the present disclosure (the "increasing volume Sadleir method") with various dilution chamber volumes (10 mL, 20 mL, and 30 mL), with FIG. 29c illustrating the first 15 minutes of a 30-minute injection. [Figure 29d-29e] 29A-29E illustrate injection rates using alternative embodiments of the second embodiment of the present disclosure ("Increasing Volume Sadleir Method") with various dilution chamber volumes (10 mL, 20 mL, and 30 mL), with FIG. 29E illustrating the first 10 minutes of a 30 minute injection. [Figure 29f] 1 illustrates similar active ingredient dosing over the infusion period using the "increasing volume Sadleir method" with varying dilution chamber volumes compared to the equivalent Tansy method. [Figure 30] 1 shows a side view of a medication delivery device, according to some embodiments. [Figure 31] 1 illustrates a process for filling a drug delivery device, according to some embodiments. [Figure 32] FIG. 31 shows a side perspective view of the drug delivery device shown in FIG. 30 filled with an active agent and a diluent, according to some embodiments. [Figure 33] 33 is a perspective view of the medication delivery device shown in FIG. 32 during attachment to an injection driver in the form of a syringe driver, according to some embodiments. [Figure 34a] 1 illustrates a process for mixing an active agent and a diluent in a dilution chamber according to some embodiments. [Figure 34b] 1 illustrates a method of operating a medication delivery device, according to some embodiments. [Figure 34c]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 the operation of the drug delivery device depicted in FIGS. 30-41 while attached to the infusion device in the form of a syringe driver. [Figure 34d] A flowchart illustrating a method of approximating the infusion rate and volume calculated in FIG. 34c using an infusion pump, according to some embodiments. [Figure 35] A front perspective view of a drug delivery device, according to some embodiments. [Figure 36] A perspective view of a longitudinal section of the drug delivery device shown in FIG. 35, according to some embodiments. [Figure 37] A view of the drug delivery device shown in FIG. 36 depicting the proximal side of a separable plunger having valve means in a first arrangement, according to some embodiments. [Figure 38] A perspective view of a separable plunger having agitation means, withdrawn from the drug delivery device, according to some embodiments. [Figure 39] A view of the drug delivery device of FIG. 36 depicting the proximal side of a separable plunger having valve means in a second arrangement, according to some embodiments. [Figure 40] A front perspective view of a drug delivery device having a separable plunger with valve means in a third arrangement, according to some embodiments. [Figure 41] A view of the dilution chamber shown in FIG. 40, according to some embodiments, depicting the proximal side of a separable plunger having valve means in a fourth arrangement. [Figure 42] A side view of the drug delivery device shown in FIG. 35 filled with an active agent and a diluent, according to some embodiments. [Figure 43a] A side view of the drug delivery device shown in FIG. 35 filled with an active agent and a diluent, with the active agent being 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] It is a block diagram that illustrates a method of delivering a therapeutic dose of a drug according to some embodiments. This method can be for calculating the Sadleir infusion protocol used during the operation of the dilution chamber depicted in FIG. 43a. [Figure 43d] It is a flowchart that illustrates a method of approximating the infusion rate and volume calculated in FIG. 43c using an infusion pump according to some embodiments. [Figure 44] Shows a perspective view of the arrangement of the drug delivery device during attachment to an infusion device in the form of a syringe driver according to some embodiments. [Figure 45] They are respectively a distal perspective view and a side view of the drug delivery device shown in FIG. 44 during its assembly according to some embodiments. [Figure 46] They are respectively a distal perspective view and a side view of the drug delivery device shown in FIG. 44 during its assembly according to some embodiments. [Figure 47a-47b] Illustrates the operation process of the drug delivery device shown in FIG. 44 according to some embodiments. [Figure 47c] It is a block diagram for calculating an infusion protocol used during the operation of the dilution chamber depicted in FIGS. 44 to 47a according to some embodiments. [Figure 48] Illustrates a specific arrangement of pulse width modulation (PWM) digital dilution for controlling the infusion process. [Figures 49a-49h] Illustrates the results of an exemplary infusion performed according to the Diocles method. [Figure 50] Illustrates a dilution chamber drug concentration profile of an exemplary infusion performed according to the Diocles method over a sub-section of the infusion. [Figure 51] Illustrates a comparison between an infusion performed according to the Diocles method and an infusion performed according to the Tansy method. [Fig. 52a-52f]Figure 52a shows a test comparison of a 30-minute infusion using 60 30-second steps of the Diocles method, each step being a constant infusion (darker gray) ("Constant") and a 30-minute infusion using 60 bursts at a higher infusion rate (lighter gray) ("Burst"). Figure 52a shows the flow rate of fluid leaving the drug delivery device versus time using two programs, where the volume of each step is either given at a constant rate over the step ("Constant", darker gray) or at a rate of 15 mL / min for the portion of the step that results in the same volume for each step ("Burst", lighter gray). Figure 52b shows the concentration of drug entering the patient (percentage of the total dose in the initial drug chamber per mL) versus time using the "Constant" program (darker gray) and the "Burst" program (lighter gray). Figure 52c shows the rate of drug delivery (percentage of total dose per minute) administered to a patient over time using the "constant" (dark gray) and "burst" (light gray) programs. Figure 52d shows the cumulative percentage dose (percentage of total dose) administered to a patient over time using a logarithmic y-scale for the "constant" (dark gray) and "burst" (light gray) programs. Figure 52e illustrates the ratio of the cumulative dose administered to a patient at 5 minutes after the time indicated on the x-axis to the cumulative dose administered to a patient at the time indicated on the x-axis using the "constant" (dark gray) and "burst" (light gray) programs. Figure 52f shows the delay in minutes between the time indicated on the x-axis and the time at which the cumulative dose is 10 times the cumulative dose at the time indicated on the x-axis for the "constant" (dark gray) and "burst" (light gray) programs. [Figure 52g-52l] A test comparison of a 25 minute infusion using fifty 30 second steps with double bursts at 15 mL / min separated by 1 second (darker outline) is illustrated compared to a single burst at 15 mL / min with the second burst volume spread throughout the interval (i.e., no valve closure and no disruption (lighter outline)). [Figures 53a-53d]Illustrated are constant step, burst, burst-constant, and burst-burst infusion delivery programs for the Diocles method, and the resulting pharmaceutical formulation delivery results. Figure 53a shows the fluid infusion rates for four alternative modifications of the Diocles method. The "constant" program delivers the amount delivered in each step of the Diocles method at a constant rate for the entire duration of the step (531). The "burst" program delivers the volume delivered in each step of the Diocles method at a rate of 15 mL / min for a period shorter than the step (533). The "burst-burst" program delivers the volume delivered in each step of the Diocles method in two infusion periods of 15 mL / min, each period separated by 1 second relative to the step (535). The "burst-constant" program delivers half of the volume delivered during each step at 15 mL / min, and the other half of the volume is delivered at a constant rate for the remaining duration of the step (535). Figure 53b shows the concentration of drug delivered to the patient (percentage of the total dose in the initial drug chamber per mL) over time for each of the four programs. Figure 53c shows the cumulative percentage dose administered to the patient over time on a logarithmic y-scale for each of the four programs. Figure 53d shows the ratio of the cumulative dose administered to the patient 5 minutes after the time shown on the x-axis to the cumulative dose administered at the time shown on the x-axis. [Figure 53e] 1 illustrates constant step, single burst, burst constant, and double burst infusion step programs according to some embodiments. [Fig. 54a-54c] 1 shows software code written in Python3 for calculating values ​​that can be sent to an infusion device to implement the Diocles method, according to some embodiments.

[0276] It should be noted that Figures 1-11e and Figures 30-34a, 35-43, and 44-47a are schematic only, and the location and arrangement of components may vary according to the particular configuration of the embodiment of the present disclosure and a particular application of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0277] Methods and systems according to embodiments of the present disclosure allow for the administration of a therapeutic dose of a particular drug along with a test dose in a single infusion process. These methods and systems are particularly useful because they do not require multiple test doses for a given patient prior to the infusion of the therapeutic dose. Instead, the test dose is given during the infusion of the full therapeutic dose, since the test dose is a portion of the therapeutic dose. Providing a test dose without using embodiments of the present disclosure requires (1) preparing multiple pharmaceutical formulations (including the test dose) with various concentrations and (2) injecting the multiple pharmaceutical formulations into the patient, with each test dose for each pharmaceutical formulation. This process of injecting multiple pharmaceutical formulations containing test doses (pre-infusion of the therapeutic dose) can be cumbersome and time-consuming and may not be suitable, for example, in situations where the therapeutic dose must be injected immediately to sustain the patient's life.

[0278] 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 receives 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 unknown.

[0279] This embodiment of the present 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.

[0280] It will be understood that the term "active agent" used in the description may correspond to or may also be referred to as an "active ingredient" or a "drug." That is, throughout this disclosure, the terms "active ingredient," "active agent," and "drug" are used to describe an active agent that will be administered to a patient. In some embodiments, a pharmaceutical formulation may be delivered to a 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 specific 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 in some embodiments, the term "drug" used in the description may correspond to the active agent of the "pharmaceutical formulation."

[0281] The method and system according to the first embodiment of the present disclosure uses a specific function (Tansy function) to sequentially deliver (infuse) a range of test doses of a pharmaceutical formulation to a patient, with the dose increasing over the duration of the infusion. This aims to overcome the problem of patient sensitivity to a particular drug 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 for 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, after confirming that the patient will not have a negative reaction to the drug, the pharmaceutical formulation can be continued to be infused into the patient. Therefore, according to the first embodiment of the present disclosure, only a single pharmaceutical formulation is needed to provide the full therapeutic dose, including any test doses.

[0282] The method and system according to the second embodiment of the present disclosure also allows for the administration of a single pharmaceutical formulation to a 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 delivered to the patient. This is done by allowing for an increased initial flow rate of the pharmaceutical formulation driven by the infusion driver 14 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 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.

[0283] Since it is known that the infusion driver 14 does not deliver the pharmaceutical formulation accurately at relatively low rates, such as those that occur when using the 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.

[0284] However, the method and system according to the second embodiment of the present disclosure uses a different function (the Sadleir function) to control the rate at which the pharmaceutical formulation is delivered (infused) to the patient. Infusing a 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 initially performed by repeatedly varying the flow rate between low and high values ​​during a second priming step (occurring when the initially mixed pharmaceutical formulation is infused from the dilution chamber 32 through conduit 30b into the patient's intravenous access point). Subsequent mixing and dilution occur 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 within the dilution chamber 32 that includes a flexible sleeve to allow for dynamic adjustment of resistance depending on flow rate.

[0285] 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 compared to the Tansy method. Therefore, 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 delivered by 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. It is important to note, however, that the use of either the Tansy or Sadleir method results in orders of magnitude of cumulative dose of the active ingredient of the pharmaceutical formulation.

[0286] 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 (Saddleir 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, with the infusion rate (in ml / min) of pharmaceutical formulation being greater for the Sadleir method early in the infusion, and the Tansy method having a higher flow rate at the end of the infusion.

[0287] 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 infusion when using either the first (Tansy) or second (Sadleir with 10 ml dilution chamber) embodiment of the present disclosure for a 50 ml infusion. Figure 22d illustrates the first 15 minutes of a 30-minute infusion. The cumulative volume injected at a given time point is intended to mean the total volume of pharmaceutical formulation injected into the patient from the start of the infusion up to that point.

[0288] According to a first embodiment of the present disclosure, there is provided a method and system for providing a pharmaceutical formulation to a patient, the flow rate of which follows a Tansy function curve (see FIGS. 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.

[0289] Drug Delivery Systems The drug delivery system 1 comprises a drug delivery device 10 for providing a pharmaceutical formulation, which may be referred to herein as device 10. The drug delivery device 10 is configured to provide the pharmaceutical formulation at or approximating a flow rate determined by a Tansy function.

[0290] The drug delivery system 1 includes an infusion device, which may be in the form of an infusion driver 14. In some embodiments, the apparatus 10 may include an infusion driver 14 (such as a syringe driver, or a peristaltic pump, or similar drug infusion pump).

[0291] The infusion driver 14 includes 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 includes hardware and software for controlling the infusion driver 14 to deliver the drug at a rate established by a Tansy function. The software includes instructions for executing an algorithm designed to calculate the rate determined by the Tansy function.

[0292] FIG. 1b shows a block diagram of an apparatus 10 in which an infusion driver 14 controls the flow rate at which medication is delivered from a syringe or bag through a standard length of tubing to a patient.

[0293] The apparatus 10 includes a computer system 12. The medication delivery apparatus 10 includes an injection driver 14. The injection driver 14 may be referred to as an injection device. The injection driver 14 includes a syringe 15 and a syringe driver 17. The syringe 15 defines an injection container 19. The syringe 15 includes 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.

[0294] 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.

[0295] Plunger 21 is configured to be displaced relative to the longitudinal axis of the infusion container. Displacement of plunger 21 along the longitudinal axis of the infusion container displaces the pharmaceutical formulation in the activator chamber through activator chamber outlet 25. The pharmaceutical formulation is displaced into conduit 30a.

[0296] 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, for example, according to either a Tansy function or a Sadleir function.

[0297] The computer system 12 includes computer components such as a processor 16, 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.

[0298] In some embodiments, the infusion device includes at least one infusion device processor in communication with an infusion device memory. The at least one infusion device processor may include, or be in the form of, processor 16. The infusion device memory may include 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.

[0299] In some embodiments, the infusion device program instructions are in the form of program code. The 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.

[0300] 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 random access memory (RAM), read-only memory (ROM), electrically erasable programmable read-only memory (EEPROM), or 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 specific functions, as described herein.

[0301] The computer system 12 may optionally include a drug library and database containing the 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 a Tansy or Sadleir procedure) exceeds the maximum allowable drug administration rate, the infusion rate is increased by 100% by the dilution chamber (C d ) will be reduced in accordance with the maximum allowable infusion rate so that the concentration of drug leaving the infusion chamber 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.

[0302] During the method of infusing a pharmaceutical formulation according to the method of the present disclosure, the drug library may be accessed by 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.

[0303] The processor 16 may execute instructions to control the drive mechanism of the syringe driver 17 to deliver a 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 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 determined by Tansy, Sadleir, or another function specifying the rate at which the pharmaceutical formulation will 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 before 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 (e.g., FIG. 27) executed by the processor 16 includes instructions for executing an algorithm for calculating an injection rate determined by a Tansy function to control the flow rate using the syringe driver 17.

[0304] 2-8, which illustrate a drug delivery device 10 according to a second embodiment of the present disclosure. The drug delivery device 10 may also be referred to as the device 10. The device 10 according to the second embodiment is similar to the device 10 according to the first embodiment, and like reference numerals are used to identify like parts.

[0305] As described with reference to FIG. 1 , the drug delivery device 10 includes an infusion reservoir and a plunger 21. The infusion reservoir and plunger 21 may form at least a portion of a syringe. The infusion reservoir is configured to receive at least a portion of the plunger 21. The plunger 21 and the infusion reservoir together define an activator chamber 98. The activator chamber 98 is configured to receive a pharmaceutical formulation. The pharmaceutical formulation includes an active agent, as described above. The activator chamber 98 includes an activator chamber opening 23. The activator chamber opening 23 is configured to receive at least a portion of the plunger 21. The activator chamber 98 includes an activator chamber outlet 25.

[0306] One of the differences in the device 10 of the second embodiment of the present disclosure is that the infusion driver 14 delivers the pharmaceutical formulation to a dilution chamber 32 before the pharmaceutical formulation is delivered to the patient (see, e.g., FIGS. 2 and 4). Accordingly, the drug delivery device 10 includes a dilution chamber 32. The dilution chamber 32 is fluidly connected to an 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 includes a dilution chamber outlet 27.

[0307] 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.

[0308] The software code executed by the processor 16 includes instructions for executing an algorithm for calculating 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 the first conduit. Conduit 30b may be referred to as the second conduit. Conduit 30a is configured to fluidly connect the activator chamber outlet 25 and the dilution chamber inlet 29.

[0309] As noted above, the apparatus 10 according to the second embodiment of the present disclosure includes a dilution chamber 32. Figures 6-8 depict a first configuration of the dilution chamber 32. This particular configuration of the dilution chamber 32 is shown in operation in Figures 2 and 3.

[0310] 4 and 6, this particular arrangement of the drug delivery device 10 includes a container 34. The container 34 may be referred to as a dilution chamber container. The drug delivery device 10 includes a manifold 36. In particular, the dilution chamber 32 includes the manifold 36. The manifold 36 is connected to the container 34 to allow fluid flow (1) from the injection driver 14 (i.e., the activator container 98) into the container 34 via the conduit 30a and a first inlet 37 of the manifold 36. In other words, the manifold 36 is configured to connect to the dilution chamber 32.

[0311] Manifold 36 also allows fluid flow (2) from container 34 through flow path 51 (see FIG. 5) and first outlet 38 of manifold 36 for delivery of drug to the patient via conduit 30b, as shown in FIG. 3. In certain arrangements, manifold 36 may include a lower portion 39 for connecting to container 32. Manifold 36 may also include an upper portion 43 for connecting with conduit 30a—see, e.g., FIG. 7a. In some arrangements, upper and lower portions 43 and 39 of manifold 36 may be releasably attached to one another.

[0312] Additionally, manifold 36 includes a second inlet 40 (see FIG. 4 ) that allows delivery of a flushing fluid to flush dilution chamber 32 for the purposes of delivering any drug residue inside dilution chamber 32 to the patient or priming device 10 with diluent. Second inlet 40 may be referred to as a flushing inlet. The flushing inlet is configured to receive a flushing fluid.

[0313] Additionally, the manifold 36 includes a multi-way valve 42 (best seen in FIG. 7 ) for controlling fluid flow from the infusion driver 14 (via the conduit 30 a) and the second inlet 40. In particular, rotation of a valve plug (with at least one plug port traversing the valve plug) of the multi-way valve 42 allows selective displacement of the valve plug between a first state (for opening the first inlet 37 and closing the second inlet 40), a second state (for closing the first inlet 37 and opening the second inlet 40), and a third state (for opening the first inlet 37 and opening the second inlet 40 but preventing flow of the pharmaceutical formulation into the container 34). In the first state, fluid flow is permitted from the infusion driver 14 to the container 34. In the second state, fluid flow is permitted through the second inlet 40 but is prevented through the first inlet 37. This is particularly useful as it allows for setup of the device 10 (priming with diluent) before delivering the pharmaceutical formulation to the container 34. In the third state, the pharmaceutical formulation flows from the injection driver 14 and is allowed contact between the conduit 30a and the atmosphere through the second inlet 40, allowing the pharmaceutical formulation to reach the manifold 36 for the first time prior to the injection process.

[0314] In other words, the multi-way valve 42 is configured to be actuated between a first position and a second position. When in the first position, the multi-way valve 42 is configured to allow flushing of fluid from the second inlet 40 into the dilution chamber 32 while preventing displacement of the pharmaceutical formulation into the dilution chamber 32. When in the second position, the multi-way valve 42 is configured to allow displacement of the pharmaceutical formulation into the dilution chamber 32 and prevent flushing fluid from entering the dilution chamber 32. The multi-way valve 42 is also configured to be actuated to a third position. In the third position, the pharmaceutical formulation can flow to the atmosphere through the first inlet 37 and the second inlet 40.

[0315] The drug delivery device 10 includes a one-way valve 44. Specifically, the manifold 36 includes the one-way valve 44 (see FIG. 5 ). The one-way valve 44 is configured to allow fluid from the first inlet 37 into the container 34 but to prevent fluid flow from the container 34 back to the injection driver 14 through the first inlet 37. In other words, the one-way valve 44 is configured to allow fluid from the activator chamber 98 to enter the dilution chamber 32 and to prevent fluid in the displacement chamber 32 from entering the activator chamber 98. In this way, any flow exiting the container 34 must flow through the flow path 51 to the outlet 38 for delivery to the patient via the conduit 30 b.

[0316] 6-8, the manifold 36 can be removed from the container 34. To this end, a releasable joint is provided between an end 39 of the manifold 36 and an end 48 of the container 34. Separation of the manifold 36 allows for replacement of a catheter 50 extending into and out of the manifold 36 for positioning within the container 34. The drug delivery device 10 includes a catheter 10. The catheter 10 is configured to be at least partially disposed within the dilution chamber 32.

[0317] As shown in FIG. 8 , the catheter 50 includes a catheter body 71. The catheter body 71 defines a hollow core 73 that defines a catheter body fluid flow path. The catheter 50 includes a plurality of catheter body perforations 58. The catheter body perforations 58 may also be referred to as perforations 58. The catheter body perforations 58 are disposed in end portions of the catheter 50. The catheter 50 includes a proximal end 52 and a distal end 54. The distal end 54 may include an end portion. That is, the distal end 54 may include a catheter body perforation 58. Each catheter body perforation 58 extends between the hollow core 73 and the exterior of the catheter body 71.

[0318] The proximal end 52 is fluidly connected to the one-way valve 44 and is adapted to allow fluid from the infusion driver 14 through the catheter 50 and into the container 34. The distal end 54 of the catheter 50 (in certain configurations) includes a blind end 56 (best seen in FIGS. 9a and 9b). The blind end 56 obstructs fluid flow therethrough. This forces fluid to flow through perforations 58 traversing the sidewall of the distal end 54 of the catheter 50—see FIG. 8b.

[0319] The manifold 36 includes a manifold inlet 53. In particular, a lower portion 39 of the manifold 36 includes the inlet 53. The manifold 36 includes a manifold outlet 38. The manifold outlet 38 is configured to connect to the second conduit 30b, thereby enabling delivery of the pharmaceutical formulation to the patient. The manifold inlet 36 allows the dilution chamber 32 to be fluidly connected to the outlet 38, thereby enabling delivery of the pharmaceutical formulation contained in the dilution chamber 32. As best shown in FIG. 5 , a flow path 51 is formed within the lower portion 39 of the manifold 36 around the proximal end 52 of the catheter 50.

[0320] As described below with reference to Figures 8b-11e, different types of placement of catheter 50 are provided according to this embodiment of the disclosure.

[0321] According to an embodiment of the present disclosure, the distal end 54 of the catheter 50 is adapted to deliver a drug received from the infusion driver 14 to the container 34. In the particular arrangement shown in FIGS. 8b-10, the distal end 54 of the catheter 50 includes a plurality of perforations 58 (see FIG. 8b). The perforations 58 are disposed in spaced relation along the length of the catheter 50 and around the outer surface of the catheter 50. The perforations 58 allow the drug (i.e., pharmaceutical formulation) to exit the distal end 54 of the catheter 50 in various directions (illustrated by the arrows, or fluid jets 70, shown in FIG. 9a). In particular, the perforations 58 allow the drug to exit the catheter 50 for the purpose of dispensing the drug into the container 34 and ensuring proper dilution of the drug in the diluent contained in the container 34, as shown in FIG. 8d.

[0322] As shown in FIG. 8b, the catheter 50 may include an end section 66. The end section 66 may be on or part of the distal end 54 of the catheter 50. The end section 66 includes the previously mentioned perforations 58. The catheter 50 may also include a sleeve 68. The sleeve 68 may be flexible. The sleeve 68 surrounds the end section 66. The sleeve 68 is connected to the end portion of the catheter 50. The sleeve 68 includes a plurality of sleeve perforations 69. The sleeve perforations 69 may also be referred to as perforations 69. The sleeve perforations 69 are disposed in spaced relation along the length of the end section 66 and around the outer surface of the end section 66. The sleeve perforations 69 allow the pharmaceutical formulation to exit the sleeve 68 in various directions, as illustrated in FIG. 8d. In certain instances, during operation, the sleeve 68 expands into a circular or elliptical shape, as seen in FIG. 8c.

[0323] The sleeve 68 includes an inner surface 68a and an outer surface 68b. The sleeve perforations 69 extend between the inward surface 68a of the sleeve 68 and the outer surface 68b of the sleeve 68. Thus, an active agent catheter flow path is defined between the hollow core 73 and each of the plurality of sleeve perforations 69 via the plurality of catheter body perforations 58.

[0324] The catheter 50 is configured to connect to the second end of the first conduit 30a. The end portion of the catheter 50 is configured to be disposed within the dilution chamber 32.

[0325] As shown in Figure 8d, perforations 69 made in sleeve 68 traverse catheter body 71. In particular, sleeve perforations 69 are angled obliquely to encourage fluid (depicted as jets of fluid 70) exiting sleeve 68 through perforations 69 to be directed toward lower portion 39 of manifold 36. In a specific arrangement, flexible sleeve 68 (see Figure 8c) of catheter 50 is perforated with three equally spaced 30g (0.25mm) perforations oriented 60 degrees above horizontal.

[0326] In an alternative arrangement, the catheter 50 includes a blind end having a plurality of perforations 69. The catheter 50 may be made of or constructed from a flexible material adapted to expand as the flow rate of the active agent increases. Expansion of the catheter 50 causes the perforations 69 to enlarge, providing a reduced resistance to flow at high flow rates.

[0327] 9a and 9b show a second configuration of the catheter 50 having perforations 58 that traverse the catheter 50 diagonally so that fluid flow exiting the distal end 54 of the catheter 50 through the perforations 58 is directed toward the proximal end 52 of the catheter 50.

[0328] Additionally, Figure 10 illustrates a third configuration of the catheter 50. In this particular configuration, the distal end 54 of the catheter 50 includes a plurality of perforations 58 spaced apart about the sidewall of the end 60. In the particular configuration illustrated in Figure 10, the end 60 includes a conically truncated end, with an enlarged region of the conically truncated end including the perforations 58. The distal end 54 may include a flexible material.

[0329] 11a-11e further illustrate a fourth configuration of the catheter 50. In the particular configuration shown in FIGS. 11a-11e, the catheter 50 includes a proximal end 52 and a distal end 54. In this particular configuration, the catheter 50 does not have a blind end at its end 56. Instead, the end 56 of the catheter 50 is open, allowing fluid flow out through the open end 56 of the catheter 50 and allowing the pharmaceutical formulation to enter the container 34 of the dilution chamber 32.

[0330] As shown in Figure 11a, the proximal end of catheter 50 is attached to lower end 72 of connecting body 74. Connecting body 74 has an upper end 76. Connecting body 74 allows upper and lower portions 43 and 39 of manifold 36 to join together. As shown in Figure 11b, lower portion 72 of connecting body 74 is connected to lower portion 39 of manifold 36.

[0331] 11a-11e, connecting body 74 comprises a body having two end sections 78 and 80 that define lower and upper portions 72 and 76 of connecting body 74. Each end section 78 and 80 comprises internal threads to permit attachment of (1) the lower portion 39 of manifold 36 to the lower end 72 of connecting body 74, as shown in FIG. 11c, and (2) the upper end 76 of connecting body 74 to a valve 82 (see FIG. 11e) attached to conduit 30a. Conduit 30a is fluidly attached to infusion driver 14 for delivering the pharmaceutical formulation through catheter 50 to dilution chamber 32.

[0332] 11d, which shows the lower portion 39 of the manifold 36 with the catheter 50 inserted into the connector 74 and attached to the container 34. As noted above, in this arrangement, the pharmaceutical formulation is delivered through the catheter 50 and into the container 34. This is done through a one-way valve 84 having a proximal end for attachment to a one-way valve 82 (see FIG. 11e) that is connected to the conduit 30a. Additionally, the valve 84 at least partially traverses the connector 74. The valve 84 has a distal end for attachment to the proximal end 52 of the catheter 50.

[0333] During delivery of the pharmaceutical formulation into the container 34, air bubbles may form due to mixing of the pharmaceutical formulation (coming from the infusion driver 14) with the diluent contained in the container 34. The air bubbles may reach the conduit 30b that delivers the pharmaceutical formulation (exiting the container 34) to the patient. This should be avoided. Figures 8c, 8d, and 9b depict a catheter 50 that includes an air bubble trap. The bubble trap is configured to prevent or minimize the extent to which air bubbles reach the conduit 30b.

[0334] 8c, a particular bubble trap arrangement includes a sleeve 86 that at least partially surrounds the proximal end 52 (first end) of the catheter 50. In particular, the sleeve 86 extends from a particular location within the manifold 36 to a location outside the manifold 36 such that a distal end 87 of the sleeve 86 is located within the container 34 of the dilution chamber 32. A flow path 51 is defined between the outer wall of the catheter 50 and the inner wall of the sleeve 86. As described below, the flow path 51 allows the diluted pharmaceutical formulation (located within the container 34) to be delivered to the patient through the outlet 38 of the manifold 36.

[0335] In one arrangement, the particular location within the manifold 36 to which the sleeve 68 extends is where the catheter 50 is attached (within the manifold 36) to an outlet that is fluidly connected to the first inlet 37 of the manifold 36 and allows delivery of the pharmaceutical formulation that flows through the conduit 30a and into the first inlet 37 of the manifold 36 for delivery into the catheter 50.

[0336] The flow path 51 has an open end defined at the distal end 87 of the sleeve 86. The open end is for receiving the diluted pharmaceutical formulation. The flow path 51 has a sealed end at a specific location within the manifold 36 where the catheter 50 is attached to the outlet. The sealed end is for receiving the pharmaceutical formulation from the first inlet 37. Having a sealed end for the flow path 51 ensures that all of the diluted pharmaceutical formulation coming from the dilution chamber 32 is delivered to the outlet 38 for delivery to the patient.

[0337] Furthermore, the purpose of having distal end 87 of sleeve 86 within container 34 is to allow the diluted pharmaceutical formulation to enter flow path 51 for delivery to outlet 38. To this end, flow path 51 is fluidly connected to outlet 38. As shown in FIG. 8c, sleeve 86 includes an opening 89 that is fluidly connected to flow path 51 defined by outlet 38.

[0338] As shown in FIG. 8c, a first inlet 53a is defined at the distal end 87 of the sleeve 86. This inlet 53a allows the diluted pharmaceutical formulation to enter the flow path 51 for delivery to the patient via the outlet 38. A second inlet 53b is formed where the sleeve 86 exits the manifold 36. This inlet 53b is defined between (1) the particular end (distal end) of the manifold 36 onto which the container 34 is connected and (2) an outer wall section of the sleeve 86 opposite the inner wall of the particular end of the manifold 36 onto which the container 34 is connected. Inlets 53a and 53b can be seen in FIG. 9b.

[0339] In operation, a pharmaceutical formulation enters flow channel 51 through inlet 53a for delivery to a patient.

[0340] Additionally, sleeve 86 deflects any air bubbles formed at the distal end of catheter 50 and floating adjacent catheter 50, preventing them from entering flow path 51 through inlet 53a. Instead, the air bubbles enter lower portion 39 of manifold 36 through inlet 53b (best seen at 9b). In this particular arrangement, venting means 99 is provided to relieve any excess pressure or remove air bubbles that may be present in manifold 36.

[0341] In the arrangement shown in the figures (e.g., FIG. 4 ), the dilution chamber 32 includes a container 34 adapted to be selectively displaced between an inflated state and a deflated state. In the inflated state, the container 34 allows for storage of a diluent for receiving the drug. In the deflated state, the container 34 forces any remaining drug contained in the container 34 to be delivered to the patient. In the arrangement shown in the figures, the dilution chamber 32 includes a syringe 62. The dilution chamber 32 also includes a plunger 64. The plunger 64 may be referred to as a second plunger. The plunger 64 is adapted to be selectively displaced to displace the container 34 between the inflated state and the deflated state to expel any remaining portion of the drug into the patient. The plunger 64 is configured to be selectively displaced along the longitudinal axis of the dilution chamber 32.

[0342] 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 configurations 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 infusion rate and a lower maximum infusion rate than the 10 ml chamber 32, but at a cost. This cost is offset by the fact that the fraction of drug delivered to the patient at any point during the infusion is

number

[0343] 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 so as 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 complete, any drug remaining in the dilution chamber 32 is discarded.

[0344] 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 of 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.

[0345] 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 a full therapeutic dose in a relatively short time and (2) enabling detection of submaximal adverse reactions in patients. For unwitnessed infusions (i.e., left on the ward), a Sadleir function over 60 to 120 minutes and with a 100 ml volume and a 20 ml dilution chamber may be more appropriate.

[0346] However, infusion duration can be limited by several factors. The first factor is the maximum infusion rate that a typical size intravenous cannula (i.e., 22 g) can tolerate. The second factor is that the maximum infusion rate of 20 ml / hour for most infusion drivers 14 results in a commonly used minimum Sadleir function infusion duration of 20 minutes for a 50 ml infusion volume and a 20 ml dilution chamber 32.

[0347] According to a second embodiment of the present disclosure, the infusion driver 14 delivers the drug via conduit 30a to the dilution chamber 32 and then to the patient via conduit 30b, which is fluidly connected to the patient (see FIG. 3). The processor 16 also executes code that implements a specific algorithm for driving the syringe driver 17 to deliver the pharmaceutical formulation (contained in the syringe 15) to the patient, as determined by the Sadleir function.

[0348] The device 10 can be used to administer a full therapeutic dose of any drug (active ingredient such as a medication) 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.

[0349] 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:

[0350] Drug test doses in patients not suspected of being hypersensitive to the drug being administered to them, where 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 of detecting unexpected hypersensitivity, allowing the infusion process to be stopped before the dose that would 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 does not develop tolerance and produce a negative reaction because of the particular manner in which the therapeutic dose is administered. Thus, this particular scenario typically produces what is referred to as unintended acute desensitization.

[0351] Drug challenge in a patient suspected of having a hypersensitivity reaction due to a particular drug, and in which it would be advantageous to confirm that the particular drug administered was the cause of the reaction, device 10 is used to administer a therapeutic dose of drug in a particular manner that increases the ability or probability that, if a hypersensitivity reaction occurs, 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.

[0352] Drug desensitization in patients 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., by providing a relatively low dose at the beginning of the infusion process) so that tolerance to the drug is induced. This scenario is particularly useful for desensitizing patients to a particular drug.

[0353] Methods for delivering pharmaceutical formulations Tansy method 12a and 13a broadly illustrate the steps for delivery of a therapeutic dose of a drug contained in a pharmaceutical formulation delivered by an infusion driver 14. FIG.

[0354] 12a and 12b illustrate a method according to a first embodiment of the present disclosure. In a 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 the infusion modeling function.

[0355] 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.

[0356] 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 the patient (without using the dilution chamber 32).

[0357] 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 .

[0358] As shown in FIG. 12a, the operator enters the following via the keyboard 26 of the injection driver 14: 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 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.

[0359] The operator then provides the pharmaceutical formulation to the patient's entry point, a step referred to as the priming step.

[0360] The operator then activates the injection driver 14 via a command through the keyboard 26 .

[0361] 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

[0362] 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 time 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.

[0363] 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 for both methods (Tansy method and conventional (constant infusion over 30 minutes) method).

[0364] Furthermore, Figures 15a and 15b illustrate the clear demarcation in time of clinically relevant magnitude of cumulative drug administration when using the Tansy method.

[0365] However, as shown in Figure 15, 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. 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% 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.

[0366] In contrast, the Tansy method begins with a relatively low infusion rate and continuously increases the infusion rate. Specifically, using the Tansy method results 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 six-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 six minutes, as is a 10% cumulative dose. This approximately six-minute interval (relative to 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 FIGS. 15 and 16.

[0367] In relation to unique feature (b) listed above, Figure 14a illustrates the rate of drug administration using a logarithmic scale, comparing a traditional constant infusion method with the Tansy method. This demonstrates that when using the Tansy method for a 30-minute infusion, the rate of drug administration changes every two minutes (this rate doubles in this particular configuration). In particular, the Tansy method has the following characteristics: the rate of drug administration is 0.01% of the final infusion rate at 3.425 minutes into the infusion, 0.1% of the 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% at 16.72 minutes, 10% at 23.35 minutes, and 100% at 30 minutes (see Figure 16).

[0368] As shown above, for a 30 minute infusion, the flow rate doubles every 2 minutes. However, the flow rate fluctuations can be adjusted by varying the duration of the infusion (see Figures 19a and 19b). As shown in Figure 19b, as the duration of the infusion increases, the rate fluctuations decrease, and as the duration of the infusion decreases, the flow rate fluctuations increase.

[0369] The following outlines a general formula for the cumulative volume of pharmaceutical formulation provided at each time point during an infusion according to the first embodiment (i.e., using the Tansy method):

number

[0370] As mentioned above, the medication delivery system 1 may include the medication delivery device 10 described above. The medication delivery system 1 may also include an infusion device. The infusion device includes 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 operate an infusion device actuator (e.g., infusion driver 14) to control the medication delivery device 10 to deliver medication according to the Tansy method.

[0371] In particular, the program instructions may include programming at least one infusion device processor to receive a volume input (V) indicative of the volume of the pharmaceutical formulation. 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, volumetric 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. Throughout this disclosure, volume input (V p ) may correspond to the volume of the pharmaceutical formulation.

[0372] 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 a user-provided input. For example, the time input (i) may be entered using the user interface 22. Alternatively, the time input (i) may be obtained from the infusion device memory.

[0373] 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 the infusion device memory.

[0374] 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, wherein each pharmaceutical formulation output volume corresponds to a volume of 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 the start of an associated infusion step to a second time corresponding to the end of the associated infusion step.

[0375] The Tansy function T(t) may be defined by:

number

[0376] In the formula, V p is the volume input, t is the time, and i is the time input.

[0377] Determining the pharmaceutical formulation output volume for each of a number of infusion steps includes calculating:

number

[0378] 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 for the respective infusion step. Determining the target flow rate for each infusion step may include dividing the pharmaceutical formulation output volume for the respective infusion step by the length of the respective 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.

[0379] 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. 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.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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 that of 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 20a, 22b, and 22c.

[0384] Improved accuracy (i.e., the ability 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, directing the pharmaceutical formulation to the dilution chamber 32 provides a diluted pharmaceutical formulation.

[0385] 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 results in the pharmaceutical formulation exiting the dilution chamber 32 having 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 increase throughout the duration of the injection (see FIG. 26c for an example using a 10 ml dilution chamber with a 50 mL injection 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 pharmaceutical formulation (drug) concentration (due to dilution in the dilution chamber 32).

[0386] Furthermore, because the pharmaceutical formulation is delivered to the dilution chamber 32 rather than directly to the patient, a remainder of the pharmaceutical formulation will remain in the conduit 30 and the dilution chamber 32 at the end of the pharmaceutical formulation administration process. The remainder of the pharmaceutical formulation (contained in the dilution chamber 32) can be administered, for example, by either 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 described above, in accordance with the second embodiment of the present disclosure, in the arrangement shown in the figures, the dilution chamber 32 includes a syringe that allows the volume of the dilution chamber 32 to be reduced by depressing the plunger of the syringe. The dilution chamber 32 may include a second plunger (i.e., part of the syringe).

[0387] The dose in the dilution chamber 32 at the end of the injection process (V r ) is the volume of the drug administered (V p ) and the volume of the dilution chamber (V d ) in the dilution chamber 32 at the end of the drug administration process. r ) is given by:

number

[0388] Comparing the Tansy and Sadleir methods, the specific amount of drug remaining in the dilution chamber 32 (at the end of the infusion process) and not delivered relative to the dose delivered via the Sadleir method is less than the total 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

[0389] This is obtained by multiplying the dose delivered by the Tansy method by Equation 3 above, using the formula: Equation 3 is referred to as the correction factor.

[0390] The variations in the administration rate of the drug (active ingredient) in the Tansy and Sadleir methods are 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.

[0391] In particular, for a 10 ml dilution chamber with a 50 ml primary drug infusion (or a 20 ml dilution chamber with a 100 ml primary drug infusion), at the end of the infusion, 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.

[0392] 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.

[0393] An advantage of the Sadleir method used in conjunction with device 10 incorporating dilution chamber 32 is that the minimum flow rate of pharmaceutical formulation exiting infusion driver 14 is orders of magnitude greater than that of the Tansy method, thereby improving the ability to accurately administer medication and reducing the total amount of pharmaceutical formulation. As noted above, infusion driver 14 is unable to provide adequate infusion rates at relatively low flow rates, such as the initial infusion rate using the Tansy method. The Sadleir method also reduces the maximum flow rate required, reducing the required size of the patient's intravenous cannula and improving patient tolerance.

[0394] The Sadleir method accomplishes this by using the dilution chamber 32 of the apparatus 10 in accordance with the second embodiment of the present disclosure.

[0395] The accuracy of the Sadleir function's estimation of the volume administered in the first minute achieves a significant figure of 3 when the algorithm used to calculate the volume operates on a time interval of 1 / 600 of a minute, or even shorter (see Figure 16 for the volume in the first minute of a 30-minute infusion from a 50 ml syringe with a 10 ml dilution chamber).

[0396] The Sadleir method delivers a known fraction of the Tansy protocol dose that increases proportionally at a similar rate when using the same pharmaceutical formulation concentration. The Sadleir function is calculated by numerical approximation of a nonlinear function, and this calculation is described in detail below.

[0397] 13a, 13b, and 13c illustrate a method according to a second embodiment of the present disclosure, in which a pharmaceutical formulation is delivered to a patient via a dilution chamber 32 according to variations in the flow rate determined by a Sadleir function according to equation (6) introduced below. FIG. 13d illustrates, for each interval n (having an interval duration of 1 / 1200 minutes), the values ​​of the flow rate, concentration in the dilution chamber, and % dose determined by the Sadleir function.

[0398] 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.

[0399] 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 will be delivered to the patient using the dilution chamber 32.

[0400] 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.

[0401] Referring to FIG. 13 a, the operator provides input via the keyboard 26 of the injection driver 14 . a) The volume of 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 (i) over which the pharmaceutical formulation will be administered in minutes (also referred to as the duration of the 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 iterated), 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.

[0402] 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

[0403] The processor 16 executes instructions that execute an algorithm for calculating the rate or volume of the starting interval and the rate or volume of the τ×i interval during the injection process according to the algorithm illustrated in FIG. 13b, which is performed by the python3 software instructions (software) shown in FIG. 28.

[0404] Processor 16 executes instructions that implement an algorithm to calculate the start interval velocity using equation (4) above for delivery of pharmaceutical formulation to dilution chamber 32 during the time period -1 / τ~0. The subtraction of equation 4 is shown in a later step below.

[0405] 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 .

[0406] 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.

[0407] For example, at time 0 and before 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.

[0408] Once the concentration in the dilution chamber 32 at time 0 is calculated, the flow rate during the first interval (n=1) is calculated by the processor 16 via equation 13 shown in Figure 13b. This means that the same pharmaceutical formulation properties (concentration of drug, volume of pharmaceutical formulation to be administered (V)) are used in the injection driver syringe. 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

[0409] The dose obtained by this multiplication is the dose of the modified Tansy function, or D mtf and is defined in Figure 13b.

[0410] After the flow rate for interval n=1 is 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 Figure 13b. This equation estimates the concentration of drug in dilution chamber 14 at the end of interval n (n=1 in this example) by dividing the amount of drug in the dilution chamber 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, where n=0 or the starting interval at this point), the particular dose that entered dilution chamber 32 during interval n, and the particular dose that left dilution chamber 32 during interval n.

[0411] 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.

[0412] In particular, the flow rate between each successive interval (S n ) results in the same dose being given to the patient as when using the Tansy method, 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 infusion. The infusion rate is calculated using the formula

number

[0413] Subtraction of the priming dose onset rate equation 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).

[0414] 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. Figure 17, particularly Figures 17b and 17d, illustrate the flow rate determined by the Sadleir function over a particular period of a 30-minute injection duration for different values ​​of τ (60 and 1200, respectively).

[0415] 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.

[0416] The optimal starting infusion flow rate (for a 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 noted above, infusion driver 14 is known not to accurately deliver pharmaceutical formulations at relatively low flow rates, such as those that occur when using the Tansy function, and therefore increasing the flow rate at which pharmaceutical formulations exit infusion driver 14 (i.e., active agent chamber 98) increases the accuracy of the pharmaceutical formulation administration process.

[0417] Figure 17a (tau = 60, i = 30 min, V p = 50 mL, V d As can be seen from Figure 17b, the lowest starting section rate (17.2) results in a lower concentration in the dilution chamber at the end of this section, resulting in a higher S1 rate, but a lower subsequent rate. In Figure 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).

[0418] Figures 17c and 17d show graphs plotting the flow rate as determined by the Sadleir function over a specific period of time for a number of cases with different starting flow rates than those in 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.

[0419] 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 largest 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 largest minimum flow rate.

[0420] 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 Figure 17e. The ideal starting dose or rate before the infusion process is initiated would be the starting step (S(0)) equal to the infusion rate of the first leg (S(1st Leg)), such that S(0) = S(1). initiating ) resulting in an infusion rate of

[0421] When the size of the interval (1 / τ) over which the Sadleir function is repeated 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 selected, 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.

[0422] Furthermore, after the start-up interval, the injection process will begin.

[0423] The flow rate during the first interval of the Sadleir function is determined by the D calculated based on the concentration in the dilution chamber 32 after the initial dose is given. mtf (t)1 (as defined above).

[0424] The infusion time is divided into τ x * 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.

[0425] 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 (second embodiment of the present disclosure), or:

number

number

number

number

[0426] 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 the drug from the primary drug container (C p ) is given by multiplying

number

number

number

[0427] The speed of the starting section (S(0)) should be equal to the speed of the first section (S(1)) as explained earlier.

[0428] The rate of the first interval (S(1)) is the ratio of the equivalent interval of injection (from time zero to time 1 / τ minutes) and the dilution chamber V d Concentration C d(0) and the dose of the 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

[0429] The initial concentration in the dilution chamber is determined by dividing the dose given during the start step (n=0) into the volume V of the dilution chamber. 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 initial step is equal to the initial step rate (S(0)) multiplied by the duration of the interval (1 / τ min), or:

number

[0430] From the above equation 16, if the speed of the section (S1) is given, C d(0) Substituting gives the following:

number

[0431] When rearranged,

number

number

[0432] Since S(0) = S(1), S(0) × S(1) = S(0). 2 :

number

number

number

number

[0433] 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

[0434] V mtf (t)1 is the integral of the modified tansy (rate) function from 0 to 1 / τ minutes, so

number

number

number

number

[0435] 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 (n=1) of the Sadleir method. The initiation step is performed before injection:

number

number

number

number

number

number

number

[0436] 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

[0437] For the same configuration but with τ = 1 / 1200 min, the priming rate (duration of 1 / 1200 min) is = 2.25526 ml / min).

[0438] FIG. 18 illustrates the volume administered in the first minute using the Sadleir method using a 30 minute infusion from a 50 ml syringe with a 10 ml dilution chamber.

[0439] The accuracy of the Sadleir function's estimation of the volume administered in the first minute achieves a significant figure of 3 when repeated up to a time interval of 1 / 1200 of a minute (see Figure 18 for the volume in the first minute of a 30 minute infusion from a 50 ml syringe with a 10 ml dilution chamber).

[0440] Calculating the speed of subsequent sections As noted above, calculating the infusion rate value for each subsequent interval occurring after the initial 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 that infusion rate (the subsequent infusion rate) is being 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 multiplying by a "correction factor," see Equation 16a in FIG. 13b below), assuming the drug concentration calculated by Equation 9 below (Equation 14 in FIG. 13b): mtf ) is calculated as the injection rate required to deliver the volume of fluid in the dilution chamber 32 containing

[0441] The concentration in dilution chamber 32 at the end of a particular subsequent interval n is approximated as the amount of drug in dilution chamber 32 at the end of the subsequent interval n divided by the volume of dilution chamber 32. The amount of drug in dilution chamber 32 at the end of the subsequent interval n is approximated by:

[0442] The amount of drug in the dilution chamber 32 at the start of an interval (dilution chamber volume) multiplied by the dilution chamber drug concentration at the end of the previous interval (C d(n-1) ) multiplied by

[0443] The amount of drug that entered the dilution chamber during this interval (infusion rate (S n ) multiplied by the interval duration (1 / tau) to calculate the concentration of the drug in the pharmaceutical formulation (C p ) multiplied by , and added to

[0444] 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 subtracted from it the amount of drug that left the dilution chamber 32 during

[0445] therefore,

number

[0446] Dilution chamber concentration (C d(n) ) can be simplified to:

number

[0447] 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

[0448] As noted above, using the Sadleir function instead of the Tansy function results in the administration of a dose that is less than the dose administered at any point during the Tansy function. The dose according to the Sadleir function is reduced by multiplying the dose determined by the Tansy function by a correction factor.

number

[0449] 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.

[0450] The number of subsequent intervals is divided by the duration of the infusion (in minutes) to give the number of intervals per minute (τ), which gives a total of (i × τ) intervals over each interval of the infusion period (time(n-1) / τ to time(n / τ) minutes, see Figure 13d.

[0451] 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.

[0452] The integral of the Tansy function is calculated as follows:

number

number

number

[0453] The administered volume for each interval (calculated above) is converted to a dose by multiplying this volume by the concentration of drug in syringe 15. The calculated value of the dose is then reduced to account for the fact that the total dose administered to the patient using device 10 using the Sadleir method is less than the total dose injected from syringe 15 due to a portion of the drug remaining in dilution chamber 32 at the end of the injection. The dose reduction 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

[0454] Therefore, the dose administered by the modified Tansy function (Sadleir function) for each interval is given by:

number

number

[0455] 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 the dilution chamber 32 with the pharmaceutical formulation. This is done via the start step noted above, and 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

[0456] This injection, which takes place during the start-up period, has a volume V d The resulting concentration in the dilution chamber 32 after the initiation interval is given by:

number

number

[0457] 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 ) is used as the calculation. This is calculated as follows:

number

number

number

[0458] The concentration of drug in the dilution chamber 32 at the end of interval n is then calculated using the following formula:

number

[0459] 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 the volume that will result in the same dose as the Tansy function multiplied by the correction factor.

number

[0460] 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.

[0461] It is important to note that the above-described process (illustrated in FIGS. 13b and 13d) provides rate values ​​determined by the Sadleir function, which provides the curve (Sadleir theoretical curve) shown for the specific example (for 50 mL of pharmaceutical formulation using a 10 mL dilution chamber) in FIGS. 20b (for various infusion durations) and 20c (the first 10 minutes of a 30-minute infusion), and in FIGS. 22a, 22b, and 22c (for a 30-minute infusion). 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. (In FIGS. 20b and 20c, flow rate refers to the rate (ml / min) at which the infusion driver 14 injects the pharmaceutical formulation from the syringe 15 into the conduit 30a, dilution chamber 32, and conduit 30b of the Sadleir device 10.)

[0462] 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 provide the same or approximately the same 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.

[0463] 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 that moves the diluted pharmaceutical formulation from the outlet of the dilution chamber 38 to the patient's intravenous access point.

[0464] In a first priming step, conduit 30a is filled with the pharmaceutical formulation by opening multi-way valve 42 to the atmosphere and operating infusion driver 14 to purge the drug into multi-way valve 42. Infusion driver 14 is stopped and multi-way valve 42 is actuated to prevent contact between conduit 30a and the atmosphere and open dilution chamber 32 to deliver the pharmaceutical formulation to reservoir 34 of dilution chamber 32.

[0465] 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. During this step, the drug is not administered to the patient; therefore, the alternating flow rates must be taken into account when calculating the patient's dosage.

[0466] 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.

[0467] 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 and varying the flow rate as the infusion continues.

[0468] 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.

[0469] In fact, programmable infusion devices (such as syringe drivers or peristaltic pumps or similar drug infusion pumps) typically cannot provide pharmaceutical formulations in a continuous manner (with infinitely 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 the adverse effect of latency between steps (disruption of infusion between each step). Note that in the Sadleir method, even a series of constant or ramp rate infusion steps will result in continuously varying active ingredient (drug) administration rates due to the continuously changing concentration of the pharmaceutical formulation exiting dilution chamber 32.

[0470] According to this embodiment of the present disclosure, several methods for approximating a 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 Sadleir function approximation process using a constant or ramp infusion method over the first 4 minutes of a 30 minute infusion, using 40 steps of 45 second duration.

[0471] As shown in Figures 12 and 13, the Tansy (Figures 23b and 23c) and Sadleir (Figures 24b, 24c, 25a, and 25b) methods each involve defining a volume of injection steps that are performed sequentially over the duration of the injection. Each step has a specific duration during which a specific amount of pharmaceutical formulation is provided. In a particular configuration, these steps will provide a similar volume as the Tansy or Sadleir function over an equivalent time interval of the injection.

[0472] As noted above, a specific amount of pharmaceutical formulation will be provided during each of these steps. The specific amount of pharmaceutical formulation to be provided during each particular step will depend on the specific amount of pharmaceutical formulation determined by the Tansy or Sadleir function that must be provided during the time interval of a particular infusion interval; in particular, as described below, this specific amount is calculated using the amount determined for each particular interval at the corresponding specific moment of time during the infusion process as determined by the Tansy (see FIG. 12b) or Sadleir (see FIG. 13c) function.

[0473] 12b and 13c illustrate how to approximate the Tansy and Sadleir functions, respectively, to deliver a pharmaceutical formulation to a patient.

[0474] As shown in Figure 12b in connection with the Tansy method, after calculating the actual amount (volume) of pharmaceutical formulation to be delivered during a particular time period for 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).

[0475] A priming step would then commence by delivering sufficient pharmaceutical formulation to the patient to fill the conduit 30a with pharmaceutical formulation up to the point of the patient's intravenous access point. At this stage, the infusion process may commence by delivering the calculated amount of pharmaceutical formulation for each step to the patient during each step. Once the infusion period has elapsed, the infusion process is stopped.

[0476] As shown in Figure 13c for the Sadleir method, after calculating the actual amount of pharmaceutical formulation to be infused during a specific period of each step, a first priming step would be initiated by delivering enough pharmaceutical formulation to fill conduit 30a with pharmaceutical formulation, followed by a second priming step to present dilution chamber 32 and conduit 30b for the diluted pharmaceutical formulation to reach the patient.

[0477] The infusion process can 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 can be delivered to the patient during each step until the completion of the infusion process.

[0478] 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 infusion period has elapsed, the infusion process is stopped and the remaining pharmaceutical formulation is delivered to the patient, for example, by collapsing the dilution chamber 32 as described above with respect to the device 10 depicted in Figures 1-11.

[0479] An alternative configuration of the Sadleir method to approximate the active ingredient dosing rate of the Tansy method.

[0480] In an alternative arrangement of the Sadleir method, the device may include 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 results in drug being present in the dilution chamber 32 at the completion of 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 reciprocal of a "correction factor", i.e.

number

[0481] "Increased Concentration Sadleir Method" includes the use of the second embodiment of the present disclosure, which increases the concentration of the active ingredient in a pharmaceutical formulation compared to that of an equivalent (same Vp and i) Tansy method. The active ingredient concentration in the pharmaceutical formulation is increased by:

number

number

[0482] A further alternative arrangement of the second embodiment of the present disclosure, which provides the same active ingredient dosing profile as the equivalent Tansy method when increased volume infusions are not contraindicated, is the "increased volume Sadleir method." The increased volume Sadleir method uses the same infusion duration and pharmaceutical formulation active ingredient concentration compared to the equivalent Tansy method, but uses a larger volume of pharmaceutical infusion and a higher rate of infusion to deliver the same active ingredient dosing as the equivalent Tansy method. The higher infusion volume is calculated by an iterative function described below, and the higher infusion rate is calculated using a modification of the Sadleir function. At the end of the infusion period, any solution in the dilution chamber 32 is discarded. Relative to an equivalent Tansy function using a 50 mL injection over 30 minutes, the "Increasing Volume Sadleir Method" involves an injection of 59.98 mL when using a 10 mL dilution chamber 32, an injection of 69.38 mL when using a 20 mL dilution chamber 32, or an injection of 77.75 mL when using a 30 mL dilution chamber 32. (See Figures 29b, 29c, 29d, and 29e for injection rates and injection volumes over the 30 minute injection time duration.) As illustrated in Figure 29f, the same dosage of active ingredient (drug) is delivered to the patient over the duration of the injection compared to the equivalent Tansy method.

[0483] The algorithm (to calculate the required total injection volume of pharmaceutical formulation at the same concentration as an equivalent Tansy injection, but to deliver the same dose of active ingredient at any time during the "increasing volume Sadleir" injection) is an iterative process. p refers to the volume of pharmaceutical formulation used in an equivalent Tansy injection, and V d refers to the volume of the dilution chamber of the device. The volume of active ingredient injected into the dilution chamber during injection is determined by the value V input into the algorithm (Kelly function). p becomes larger than

[0484] The algorithm for calculating the infusion rate for the "increasing volume Sadleir method" is depicted in Figure 29a. The infusion rate is higher than the equivalent (same Cp, Vd, i) Sadleir function, which causes a greater rate of increase in dilution chamber drug concentration over time. Over each interval n of the infusion, a volume of diluted pharmaceutical formulation is delivered that would give the same dose as the equivalent (same Cp, i) Tansy function, rather than the same dose as the modified Tansy function. As a result, the infusion rate is higher and a greater total volume (v) is delivered over the infusion period. At the completion of the infusion process, any drug remaining in the dilution chamber is discarded.

[0485] Figure 29a depicts a flowchart illustrating the modified Sadleir function applied to calculate the infusion rate for the "Increasing Volume Sadleir Method." This is similar to the Sadleir function and method, except that the equation for determining the starting rate omits the "correction factor," and equations 13 and 15 calculate the rate of infusion using the Tansy function dose rather than the modified Tansy function dose.

[0486] The rates and volumes delivered over the course of a 30 minute infusion using the "Increasing Volume Sadleir Method" with various dilution chamber volumes and that would administer the same active ingredient dosage over the infusion period as the equivalent Tansy method are illustrated in Figures 29b, 29c, 29d, 29e, and 29f.

[0487] Figures 29b and 29c illustrate the cumulative volume infused using an alternative embodiment of the second embodiment of the present disclosure (the "Increasing Volume Sadleir Method") with various dilution chamber volumes (10 mL, 20 mL, and 30 mL), with Figure 29c illustrating the first 15 minutes of a 30-minute infusion. Compared to the equivalent Tansy method, a larger volume of pharmaceutical formulation is used, and an equivalent dose of drug is administered to the patient at any time during the infusion.

[0488] Figures 29d and 29e illustrate infusion rates using an alternative embodiment of the second embodiment of the present disclosure (the "Increasing Volume Sadleir Method") with various dilution chamber volumes (10 mL, 20 mL, and 30 mL), with Figure 29e illustrating the first 10 minutes of a 30-minute infusion. The infusion rate is higher for the alternative embodiment than for the Tansy Method, and an equivalent dose of drug is administered to the patient at any time during the infusion.

[0489] FIG. 29f illustrates similar active ingredient dosing over the infusion period using the "increasing volume Sadleir method" with various dilution chamber volumes compared to the equivalent Tansy method.

[0490] When the Sadleir method is used with increased pharmaceutical formulation concentrations and increased injection volumes, as described above, an alternative arrangement may include a container 34 (having a dilution chamber 32 that does not have the ability to be selectively displaced between expanded and deflated states (i.e., has a fixed volume)).

[0491] Approximating infusion using an infusion pump capable of discrete infusion steps ("pump steps")

[0492] During operation, the processor 16 will execute instructions of the code (e.g., similar to FIG. 27 (Tansy method) or FIG. 28 (Sadleir method)) to obtain a specific amount of pharmaceutical formulation to be provided during each particular step; in particular, executing the instructions will calculate an amount (theoretical amount) of pharmaceutical formulation to be delivered during a specific time period for each interval determined by the Tansy or Sadleir function, and this theoretical amount of pharmaceutical formulation will be used to calculate an actual amount of pharmaceutical formulation to be delivered during a specific time period for each step. The actual amount of pharmaceutical formulation delivered during each step may be an average of the theoretical amount of pharmaceutical formulation to be delivered over a time period determined by the Tansy or Sadleir function, as described below.

[0493] The first method is to use an injection driver 14 that is capable of injecting a series of constant rate injection steps (see Figures 25a and 25b). This method is referred to as the constant step method.

[0494] The first configuration of the constant step method ("average constant step") is to set the flow rate of the pharmaceutical formulation from the syringe driver during each step as the average of the value at the start of the step and the value at the end of the corresponding step as determined by a Tansy or Sadleir function.

[0495] A second configuration of the constant step method (the "mid-value constant step" method) is to make the flow rate of the pharmaceutical formulation delivered during each step equal the flow rate at the midpoint of the corresponding period (halfway between the start and end of the step) as determined by a Tansy or Sadleir function.

[0496] A third configuration of the constant step method ("corrected constant step") is to set the flow rate of the pharmaceutical formulation as the flow rate that would deliver the same volume as would be delivered during the duration of the period according to the corresponding Tansy or Sadleir function.

[0497] The second method is to use an injection driver 14 that can deliver a series of ramp-step injections. This method is referred to as the ramp-step method.

[0498] Figure 24a is a table of two example values ​​of the Sadleir function approximation for a 50 mL infusion of a pharmaceutical formulation over 30 minutes using a 10 mL dilution chamber and a τ of 1200 / min. The first column lists the integration interval (n) at the boundary of each step, the second column lists the infusion step that begins at that point, and the third column lists the infusion time that has elapsed at that point. The starting rate of the ramp rate program infusion step is indicated ("Ramp Rate"), and the linear increase or decrease in rate until it reaches the starting rate of the subsequent step is given in the fourth column. The values ​​of this ramp rate approximation for the volume delivered over each step ("Interval Volume") and the equivalent Tansy function percentage of the total dose ("Cumulative Dose %) are given in the fifth and sixth columns, respectively. In column 7, the approximate step rate of the Sadleir function using a 90 second constant rate infusion step is given for each step ("Constant Rate"), and in columns 8 and 9, the volume delivered over each step (Interval Volume) and the percentage of the total dose ("Cumulative Dose %") for the equivalent Tansy function.

[0499] A first configuration of the ramp step method is to use a pump capable of delivering a series of ramp steps, each step beginning at one first speed and linearly decreasing or increasing to a second speed at the end of each step (see Figures 24b, 24c, and 24d).

[0500] The actual amount of pharmaceutical formulation delivered at the beginning of each step is defined as the amount of pharmaceutical formulation determined by the Tansy or Sadleir function at the beginning of each corresponding interval. To calculate the total volume of each step, the rate variation between the end and start of each step is assumed to vary linearly (either decreasing or increasing).

[0501] However, the total volume calculated for each step using (1) the actual infusion rate of the pharmaceutical formulation delivered at the beginning and end of each step, and (2) assuming a linear variation in flow rate, does not correspond to the theoretical volume as determined by the Tansy or Sadleir function because the variation in flow rate between the beginning and end of each interval as determined by the Tansy and Sadleir functions is not a linear variation; instead, the curve representing this particular variation in flow rate is concave in shape. Thus, the flow rate for each step is reduced to match (1) the actual volume delivered during each step by the infusion driver 14, and (2) the volume delivered during each interval as determined by the Tansy or Sadleir function.

[0502] A second arrangement of the ramp step method ("corrected ramp step") is to define the starting and ending velocities at each step as Tansy or Sadleir rates, as described above, and then calculate the delivered volume as determined by the Tansy or Sadleir function for all intervals except the first, since most of the error in the Sadleir function occurs in the first interval. All rates from the start of the second interval are reduced by the percentage of the delivered volume over the intended volume over this period due to discrepancies resulting from assuming linear variation rather than variation according to a concave curve as determined by the Tansy or Sadleir function.

[0503] The ending velocity of the first step is defined as this corrected starting velocity of the second step. The starting velocity of the first step is then defined as the velocity at which this first step ramp function would result in delivering the same volume as would be given by the Sadleir function over the first interval (see Figures 24b and 24c).

[0504] Different rates over time for three constant step approximations of the Sadleir function are illustrated in Figures 25a and 25b, and the percentage of cumulative dose administered versus infusion time for five approximations of the Sadleir function, and compared to the theoretical Sadleir curve, is given for the first 3 minutes of a 30-minute infusion in Figures 25c and 25d. (The five different flow rate approximations include two different approximations using infusions with ramped rate steps, or three different approximations using constant rate steps, with infusion steps occurring every 0.75 minutes over the 30-minute infusion, with a total infusion volume of 50 ml, 40 steps, and τ = 1200.) The pharmaceutical dose administered by the Sadleir device using these protocols depends on the concentration of drug exiting the dilution chamber 32 and entering the patient and the speed at which the infusion driver 14 drives the diluted pharmaceutical formulation from the dilution chamber 32 into the patient.

[0505] Reference is now made to Figure 23, which refers to an implementation of the first embodiment of the present disclosure.

[0506] Figure 23a is a table of the instantaneous rate of the Tansy function at various times during a 60-minute infusion of 1000 mL of pharmaceutical formulation, and the values ​​at which the infusion device approximates this function using either 40 constant rate steps or 40 ramp rate steps. The two methods illustrated include 40 constant rate steps or 40 ramp rate steps. The table contains programmed values ​​for 40 infusion steps of 45 seconds duration, with either a constant rate step ("Constant Rate" column) or a rate that changes linearly from the rate at the start of one step to the rate at the start of the next step ("Ramp Rate" column). The volume delivered over each step interval ("Step Volume" column), the cumulative volume delivered ("Cumulative Volume"), and the dose (percentage of pharmaceutical formulation, "Cumulative % Dose") over each step interval are also given.

[0507] Figures 23b (linear y-axis scale) and 23c (logarithmic y-axis scale) illustrate the flow rates of two approximations of the Tansy function using 40 injection steps over a 30-minute 1000 ml injection. One approximation ("Constant Rate Step") uses 40 constant rate injection steps, while the other ("Ramp Rate Step") uses 40 injection steps where the rate increases linearly over the duration of each step to give an equivalent volume of the Tansy function, with starting and ending velocities proportional to the Tansy function rate at those times.

[0508] This particular implementation, related to the first embodiment of the present disclosure, includes the following: a) a therapeutic dose of the pharmaceutical formulation over an appropriate time frame (in this case 30 minutes) is administered to the patient; b) A large volume of solution (1000 ml) is used to reduce imprecision in the early stages of the injection.

[0509] The equipment used to carry out this particular realization is a relatively large capacity computer controlled peristaltic pump acting as an infusion driver 14 with a 1000 ml syringe 15 containing the pharmaceutical formulation to be administered to the patient via conduit 30a to a three-way stopcock attached to the patient's intravenous access (conduit 30b).

[0510] An example of software instructions in the python3 language used with the computer system 12 to calculate variables for operating the infusion driver 14 is provided in Figure 27. Figure 27 shows software code written in python3 for calculating values ​​that can be sent to the infusion device to implement the Tansy method (first embodiment of the present disclosure). These can be manually entered into the infusion device for either a constant or ramp infusion step, or they can be sent to the microprocessor through various means. This software generates infusion step rates and volumes that can be manually entered via the keypad 26 or stored on the external memory drive 20 along with additional software instructions depending on the characteristics of the computer system 12.

[0511] For this particular implementation, the initial variables entered by the operator into the injection driver 14 are: a) Injection time (i) = 30 minutes b) Injection volume (V p )=1000ml c) 40 steps for a 30 minute infusion

[0512] 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 rest 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.

[0513] In this implementation, a ramp step program and a constant step program are performed and compared with each other in the graph illustrated in FIG. 23b.

[0514] The volume delivered by the Tansy function is then calculated for each interval, as described with reference to Figures 12a and 12b. The flow rate for each programmed infusion step of the infusion driver 14 is then calculated for each constant step program and ramp step program.

[0515] For a constant step program, the infusion rate (ml / min) is equal to the rate over the interval that would result in the same volume being delivered that would be delivered by the calculated Tansy function over the same infusion period.

[0516] For a ramp step program, the infusion driver 14 can deliver a flow rate over an infusion step that starts at one rate and linearly decreases or increases to a terminal rate. The next infusion step then starts at this terminal rate and linearly increases or decreases to the terminal rate for that step. This process is repeated over and over for all infusion steps.

[0517] A ramp step program is initially calculated so that the starting value of each infusion step corresponds to the same flow rate as the Tansy function interval at that point in the infusion process. The program calculates a larger volume of pharmaceutical formulation during each step than would be determined by the Tansy function, as a result of the linear rather than nonlinear variation in flow rate as in the Tansy function.

[0518] The process of modifying the ramp rate to more closely follow the Tansy function is described below. a) calculating the volume of pharmaceutical formulation that all ramp rates (in this particular example, there are 40 ramp steps) will over-deliver a volume (which will be referred to as V2) when compared to the volume V1 determined by the Tansy function over the duration of the infusion process; b) multiplying the start and end flow rates by the quotient V1 / V2; c) Correct for the pause between each injection step - this is only applicable if the flow rate is interrupted between injection steps. In particular, if the pump has a 250 second pause between each step (each step having a 45 second duration), a correction is needed to ensure that the flow rate is always increased to give similar volumes as determined by the Tansy function by multiplying each flow rate value by 45 / (45-0.250).

[0519] In operation, the three-way stopcock (which receives the conduit 30a coming from the infusion driver 14 and extends to a three-way stopcock attached to the patient's intravenous access) is opened to atmosphere to prime the conduit 30a by initiating a first priming program (e.g., 0.5 ml over 30 seconds) to provide the pharmaceutical composition to the patient's entry point.

[0520] The infusion driver 14 is then deactivated and the three-way valve is closed, directing the pharmaceutical formulation to the patient.

[0521] Subsequently, the injection driver 14 is restarted as described with reference to Figures 12a and 12b, and once the injection process is complete, the injection driver 14 is stopped.

[0522] Inspection of the graphs in Figures 23b and 23c reveals that the flow rates determined by the Tansy function are very low compared to those delivered by the second embodiment of the present disclosure (Sadleir function, see Figures 22b and 22c), even though a relatively large volume of intravenous fluid is used to dilute the drug. In particular, it is not until approximately 14 minutes that 1 ml of pharmaceutical formulation is delivered to the patient. The flow rates in the later parts of the injection process are relatively high, and these relatively high flow rates can be addressed (reduced), for example, by either (1) selecting a longer injection duration (e.g., 60 or 120 minutes) or (2) a smaller volume of pharmaceutical formulation (e.g., 250 or 500 ml).

[0523] The above implementation administers a therapeutic dose of a pharmaceutical formulation over an appropriate time frame and uses a large volume of solution (1000 ml) to reduce imprecision in the early stages of the injection process.

[0524] Furthermore, as noted above, the infusion rate is relatively low during the first half of the infusion process, which allows for a wide range of test doses to be administered to the patient that may detect a negative reaction in a patient (not known to be allergic to the pharmaceutical product), resulting in identification of the patient as allergic to the drug being infused into the patient. This infusion process is also particularly useful (1) in situations where it is suspected that the patient may be allergic to the drug (drug challenge), or (2) for inducing hyposensitization in patients who may or may not be previously suspected to be allergic to the drug (drug hyposensitization).

[0525] Reference is now made to Figure 26, which refers to an implementation of the second embodiment of the present disclosure.

[0526] The equipment used to perform this particular implementation is a Chemyx200 syringe driver serving as injection driver 14 with a 60 ml syringe 15 containing 53 ml of pharmaceutical formulation (e.g., Simacid blue dye used as a spectroscopic marker in this case). The pharmaceutical formulation is to be administered to the patient via conduit 30a (minimum volume extension tubing with a volume of 0.3 ml) extending from syringe 15 to a multi-way stopcock (minimum volume extension tubing with a volume of 2.0 ml) attached to dilution chamber 32 attached to conduit 30b attached to the patient's venous access.

[0527] An example of software instructions in the python3 language used with the computer system 12 to calculate variables for operating the infusion driver 14 is provided in Figure 28. Figure 28 shows software code written in python3 for calculating values ​​that can be sent to the infusion device to implement the Sadleir method (a second embodiment of the present disclosure). These can be manually entered into the infusion device for either a constant or ramp infusion step, or they can be sent to the microprocessor through various means. This software generates infusion step rates and volumes that can be manually entered via the keypad 26 or stored on the external memory drive 20 along with additional software instructions depending on the characteristics of the computer system 12.

[0528] The dilution chamber 32 in this particular implementation comprises a catheter 50 having three equally spaced 0.25 mm diameter perforations (items 58a-58c in FIG. 9b) around the upper aspect of a sleeve 68 that expands during use to form an oval balloon at the end of the catheter. The perforations are oriented 60 degrees above the horizontal toward the inlet 53 and outlet 38 of the manifold 36. The arrangement, as shown in FIGS. 2 and 3, provides for the dilution chamber 32 to be oriented in a vertical fashion.

[0529] For this particular implementation, the initial variables entered by the operator into the injection driver 14 are: a) Injection time (i) = 30 minutes b) Injection volume (V p )=50ml c) Dilution chamber (V d )=10ml d) Number of intervals per minute (τ) = 1200 gives a total of 36,000 intervals during an injection process with a duration of 30 minutes. e) Syringe 15(C d ) = 2% / ml of total therapeutic dose

[0530] 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). For this illustration, a ramp step program was used, but equivalent dosing can be achieved with a constant step program (see FIG. 25c). The infusion driver 14 provides a 250 ms pause (rest period) between infusion steps.

[0531] For the Sadleir function approximation process, 40 steps were chosen for a 30 minute injection (each step was 0.745833 minutes long due to a 0.250 second pause between each step).

[0532] Additionally, the Tansy function of 50 ml of pharmaceutical formulation over a 30-minute infusion time was calculated to determine the dose to be delivered at each point in the infusion process. The 30-minute infusion period was divided into 36,000 intervals of 0.0008333 minutes (1 / 1200 of a minute). The volume determined by the Tansy function for each interval was then calculated. This volume was used to calculate the dose of drug delivered in each interval (interval volume multiplied by the concentration of drug in the dilution chamber (Cd)).

[0533] The dose for each leg of the infusion was then corrected by a correction factor to obtain the corrected Tansy function (D mtf ) is calculated. Specifically, the dose delivered in each leg of the Tansy function infusion protocol is reduced by multiplying each dose by a "constant fraction." This constant fraction is (1) the total dose of active ingredient minus the amount of active ingredient remaining in the dilution chamber at the end of the infusion process using the Sadleir method, divided by (2) the total dose of active ingredient. This is then calculated as:

number

[0534] For a 50 ml injection dose using a 10 ml dilution chamber, the fraction of the total dose remaining in the dilution chamber at the completion of the 50 ml injection is 0.1987. The "constant fraction" is 0.80135 (Equation 3). Reducing the dose administered in each interval ensures that injections according to the Sadleir method are carried out over the same duration as would be determined by the Tansy method.

[0535] The flow rate determined by the Sadleir function was calculated for each of the 36,000 intervals (occurring during the 30-minute injection process) to determine the patient's D mtf Determine the flow rate required to ensure that the patient receives the same dose as calculated for .

[0536] At this stage, the infusion driver 14 is programmed to approximate the flow rate delivered by the infusion driver 14 to the flow rate determined by the Sadleir function calculated above.

[0537] To approximate the Sadleir function in an infusion driver 14 that can provide a limited number of infusion steps, the amount of pharmaceutical formulation delivered over each programmed infusion step is calculated. Specifically, as shown in FIG. 13c with respect to equation (10), the volume of pharmaceutical formulation in each infusion step is equal to the sum of the volumes of pharmaceutical formulation delivered during the 900 corresponding intervals of the Sadleir function. The number 900 is obtained by dividing (a) the total number of intervals (36,000) used in calculating the flow rate value determined by the Sadleir function by (b) the number of infusion steps (40), i.e., 36000 / 40=900. Therefore, the number of intervals (used in calculating the flow rate value determined by the Sadleir function) per infusion step is 900.

[0538] The flow rate for each programmed infusion step of the infusion driver 14 (Chemyx200 infusion pump) is then calculated.

[0539] For constant step programs, the flow rate (ml / min) of each infusion step is such that the volume of pharmaceutical formulation delivered during each infusion step is equal to the total volume of pharmaceutical formulation delivered during the corresponding 900 interval (delivered during the specified period of each step), calculated using the Sadleir function.

[0540] For a ramp step program, the infusion driver 14 may deliver a flow rate over an infusion step (occurring over a specific period of time) that begins at a first flow rate and linearly decreases or increases to a second flow rate. The next infusion step would begin at the second rate and linearly increase or decrease to reach the final rate for that infusion step. This process continues for each step of the infusion process.

[0541] The ramp step program is initially calculated so that the first flow rate of each infusion step (occurring during a specific time period) is equal to the starting flow rate of the 900 interval (occurring during a specific time period) used to calculate the flow rate determined by the Sadleir function, and the second flow rate of each infusion step is equal to the starting flow rate of the next 900 interval (occurring during the subsequent infusion step period). The flow rate fluctuations occurring during the specific time period of each infusion step will either linearly decrease or increase from the first flow rate to reach the second flow rate. This approximation is only an approximation because the Sadleir function is not a linear function; therefore, the volume of pharmaceutical formulation delivered during a specific time period, as determined by the Sadleir function, will not equal the volume delivered by the infusion driver 14 during the specific time period.

[0542] In particular, the volume delivered by the injection driver 14 during a certain period of time is greater than the volume determined by the Sadleir function during a certain period of time. In the first injection step, the difference between both volumes is greatest.

[0543] The process for correcting the above inaccuracies is as follows: a) Calculate the volume (V2) administered by the ramp step program from injection step 2 to the final injection step (step 40). b) Calculate the (V1) volume associated with the Sadleir injection for the corresponding injection interval (interval 901-36000). c) Multiply the velocity at the end of each ramp step by V1 / V2 (and therefore the starting velocity for the subsequent sections 2-40). d) Calculate the volume associated with the Sadleir function for the interval corresponding to the first ramp step (interval 1-900). Set the starting rate of the first ramp step to deliver the same volume over the step as the Sadleir function (i.e., adjust from 2.255 ml / min to 0.158 ml / min). e) Correcting for pause periods (during which delivery of pharmaceutical formulation is interrupted) between adjacent injection steps; in particular, since the injection driver 14 in this implementation has a pause period of 0.250 seconds between injection steps (each injection step of 45 seconds duration), for this particular pause period, the flow rate is always multiplied by 45 / (45-0.250) to ensure that a similar volume of pharmaceutical formulation, as determined by the Sadleir function, is delivered to the injection process across each injection step.

[0544] In operation, the multi-way valve is opened to atmosphere to prime the conduit 30a and a first priming step is initiated (eg, 0.5 ml over 30 seconds).

[0545] The multi-way valve is then actuated to initiate a second priming step, directing the pharmaceutical formulation into the dilution chamber 32, delivering the mixed, diluted pharmaceutical formulation from the dilution chamber 32 to the patient, and then stopping. In this implementation, this requires the injection of 1.96 ml of pharmaceutical formulation, depending on the volume of the conduit 30b between the dilution chamber 32 and the patient. To enhance mixing within the dilution chamber 32 of the diluent originally contained therein and the delivered pharmaceutical formulation, the flow rate is alternated between a rapid flow rate (e.g., 1 ml / min) and a slow flow rate (e.g., 0.1 ml / min). As noted above, these flow rate changes do not affect the amount of pharmaceutical formulation provided to the patient due to the mixing that occurs prior to the injection process.

[0546] At this stage, a ramp step program is initiated to initiate the infusion process and deliver the pharmaceutical formulation to the patient. At the end of the infusion process, the infusion driver 14 is stopped and the pharmaceutical composition remaining in the dilution chamber 32 is delivered to the patient by collapse of the dilution chamber.

[0547] An illustration of the effectiveness of mixing drugs in the dilution chamber using the Sadleir method in two configurations (with and without bubble traps) of the dilution chamber 32 with the manifold 36 and catheter 50 (illustrated in Figures 6, 7, and 8) is presented in Figures 26c and 26d for a 50 mL infusion over 30 minutes using a ramp step method with 40 infusion steps of 45 seconds each to approximate the Sadleir function. In these examples, the flexible sleeve 68 of the catheter 50 (see Figure 8c) was perforated at three equal intervals of 30g (0.25 mm) perforation angles at 60 degrees above the horizontal.

[0548] An illustration of a desired dosing profile over the infusion period for implementation, ensuring temporal separation of cumulative dose and dosing rate by orders of magnitude, is illustrated in Figures 26b and 26c, and Figure 26d.

[0549] As noted above, the infusion rate of Sadleir and Tansy is relatively low during most of the beginning of the infusion process. This allows for the administration of a wide range of test doses that can identify negative reactions in patients (who are not known to be allergic to the drug) simultaneously with the actual process of infusing the pharmaceutical formulation. This can lead to the identification that the patient is allergic to the drug being infused, and the infusion can be stopped before the patient receives a dose that would result in a more severe or fatal reaction. This infusion process is also particularly useful (1) in situations where it is suspected that the patient may be allergic to the drug (drug challenge) or (2) for inducing hyposensitization in patients who may or may not be previously suspected to be allergic to the drug (drug hyposensitization).

[0550] Alternative Drug Delivery Systems 30-47, which illustrate particular configurations of a drug delivery system 91 including a drug delivery device 90, according to certain embodiments of the present disclosure.

[0551] 30 , in some embodiments, a drug delivery system 91 includes a drug delivery apparatus 90 and an injection device 93. The injection device 93 is illustrated in the form of a syringe driver 17. The injection device 93 may be similar to or the same as the previously described injection device 14. In some embodiments, the drug delivery apparatus 90 includes 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 apparatus 90 also includes 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.

[0552] The presence of the separation plunger 94 within the container 96 defines two chambers within the container 96, specifically a first chamber 98 (an activator 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 to or the same as the diluent chamber 32 described above. The first plunger 92, the container 96, and the second plunger 94 together define an activator chamber 98. The activator chamber 98 is configured to receive a pharmaceutical formulation.

[0553] 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., an active agent) contained in active agent chamber 98 to flow into dilution chamber 100. Dilution 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 to prepare a pharmaceutical composition (diluted pharmaceutical formulation) that is delivered to a patient.

[0554] According to this embodiment of the disclosure, the second plunger 94 comprises a valve means 102 (sometimes referred to as a 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 .

[0555] 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 within 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 toward a closed position. The valve 102 (or valve means 102) includes a plurality of flaps 106. The plurality of flaps 106 are 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 has been transferred to the dilution chamber 100. Further actuation of the first plunger 92 also results in movement of the second plunger 94. Thus, actuation of the first plunger 92 causes movement of the second plunger 94, causing the pharmaceutical formulation in the dilution chamber 100 to be output by the drug delivery device 90.

[0556] Furthermore, the container 96 includes 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) the mixing chamber to be filled with a diluent or (2) the mixture of the active agent and the diluent (pharmaceutical composition) to exit the container 96 (particularly, from the mixing chamber 100) for delivery to the patient. The container 96 includes a first active agent chamber opening 103 configured to receive at least a portion of the first plunger 92. Particularly, the active agent chamber 98 includes the active agent chamber opening 103. The inlet port 108 can be considered a second active agent chamber opening configured to receive the pharmaceutical formulation. In other words, the active agent chamber 98 can be said to include a second active agent chamber opening configured to receive the pharmaceutical formulation. The second active agent chamber opening (inlet port 108) is defined in the wall of the container 96. The activator chamber 98 may be filled with the pharmaceutical formulation by introducing the pharmaceutical formulation into the activator chamber 98 through a second activator chamber opening (i.e., first port 108). Accordingly, the first port 108 may be referred to as an activator 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.

[0557] In the arrangement shown in the figures, the inlet and outlet ports 108 and 110 (and the inlet and outlet ports 118 and 120) are shown as male luer lock connectors, although in alternative arrangements, the inlet ports, such as 108 and 118, may comprise female luer lock connectors.

[0558] First plunger 92 and second plunger 94 are each configured to be displaced relative to the longitudinal axis of container 96. Second plunger 94 is disposed between first plunger 92 and dilution chamber opening 110 (i.e., outlet port 110). Second plunger 94 is disposed between inlet port 108 (second activator chamber opening) and dilution chamber opening 110.

[0559] 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.

[0560] 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.

[0561] The drug delivery device 91 includes 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 internal surface area of ​​the conduit 30a are dimensioned so 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 first injection volume to be delivered to the patient. The first injection volume can be prepared by a priming process at a rate that results in effective mixing in the dilution chamber 110. This is possible because no pharmaceutical formulation is delivered to the patient during this time. Thus, a different flow rate 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.

[0562] FIG. 31 illustrates a process for presenting the container 96 of the drug delivery device 90 with an active agent and a diluent.

[0563] 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.

[0564] Once the mixing chamber 100 is filled with a corresponding amount of diluent, the outlet 110 is closed to allow the activator chamber 98 to fill.

[0565] Filling the active agent chamber 98 includes opening the inlet port 108 to deliver the pharmaceutical formulation into 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 pharmaceutical formulation has been delivered into the active agent chamber 98.

[0566] 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.

[0567] Preparing the drug delivery device 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.

[0568] 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 with 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.

[0569] As shown in Figure 34a, preparation of a pharmaceutical composition includes depressing primary plunger 92 to deliver the pharmaceutical formulation contained in active agent chamber 98 into diluent chamber 100 and mix with the diluent contained in diluent chamber 100. Primary plunger 92 is depressed by syringe driver 17 in such a manner that the pharmaceutical formulation is delivered into mixing chamber 100 in cooperation with valve means 102 to provide a specific mixing profile within mixing chamber 100 to enable proper mixing of the pharmaceutical formulation with the diluent.

[0570] When the pharmaceutical formulation contained in the active agent chamber 98 is delivered into the dilution chamber 100, mixing occurs to produce 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 the primary plunger 92) in a manner such that the pharmaceutical composition is delivered according to a specific profile. In particular, the primary plunger 92 is driven based on a specific algorithm.

[0571] 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 such a manner as to fill (i.e., prime) the conduit 30a so that it is fluidly connected to the patient for delivery of the pharmaceutical composition.

[0572] One advantage of priming the conduit 30a (as described in the immediately preceding paragraph) is 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 containing the diluted active agent.

[0573] Another advantage of priming conduit 30a is that while priming conduit 30a (prior to delivering any pharmaceutical composition to the patient), the active agent can be driven into 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 dilution chamber 100 before delivering any pharmaceutical composition to the patient.

[0574] Syringe driver 17 is adapted to drive primary plunger 92 in a particular manner. For example, syringe driver 17 may comprise processing means for executing an algorithm for driving primary plunger 92 in a particular manner to obtain a particular mixing profile as well as a delivery profile of the pharmaceutical composition.

[0575] Sadleir method The drug delivery system 91 described above can be controlled to deliver a pharmaceutical formulation to a patient in accordance with the Sadleir method. As described above, the drug delivery system 91 includes a drug delivery apparatus 90 and an injection device 93. As described above, the injection device 93 includes at least one injection device processor and an injection device memory. 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.

[0576] In particular, the program instructions may include programming the at least one infusion device processor to receive a concentration input (C ) indicative of the concentration of the pharmaceutical formulation in the active agent chamber. 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 ) can 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.

[0577] The program instructions may also include programming the at least one infusion device processor to receive a volume input (V) indicating the volume of the pharmaceutical formulation. 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, volumetric 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.

[0578] The program instructions may also include providing the at least one injection device processor with a dilution chamber volume input (V) indicating the volume of the dilution chamber 100. d ) and a 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 injection device memory. Throughout this disclosure, the dilution chamber volume input (V d ) may correspond to the volume of the associated dilution chamber.

[0579] 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 a user-provided input. 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.

[0580] 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 over which the infusion modeling function will be numerically approximated over the time window. 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 the infusion device memory. Throughout this disclosure, the infusion number input (τ) may correspond to the number of infusion intervals per minute over which an associated function (e.g., a Sadleir function) is calculated.

[0581] Throughout this disclosure, it will be understood that an infusion interval is an interval in which 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 duration. For example, a 30 s 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 numerical approximation are subject to performing infusion steps at lower resolution than those actually performed by the infusion device disclosed herein.

[0582] 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 the 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 the 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

[0583] 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.

[0584] 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.

[0585] 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.

[0586] 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 device memory. The theoretical program may be a numerical approximation as described herein.

[0587] Numerically approximating the infusion modeling function includes determining the 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.

[0588] Numerical approximation of the injection modeling function is performed by determining the starting target flow parameter (S(0) initiating ) and determining 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 initial infusion interval.

[0589] Start target flow rate (S(0) initiating ) includes calculating:

number

[0590] 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:

number

number

[0591] 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 compound 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 compound output by the drug delivery device 90 during a respective subsequent infusion interval of the numerical approximation. The subsequent pharmaceutical compound concentrations each indicate a subsequent approximate concentration of the pharmaceutical compound in the dilution chamber after a respective subsequent infusion interval.

[0592] 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. That is, each subsequent target flow rate is determined at least in part on the subsequent pharmaceutical agent concentration of the infusion segment that occurred immediately before the infusion segment of the subsequent target flow rate. Each subsequent pharmaceutical agent concentration is determined at least in part on the subsequent target flow rate of the respective subsequent infusion segment.

[0593] 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 injection intervals involved. n Determining the dose parameter D mtf (t) n This involves determining the dose parameter D mtf (t) n To determine

number

Claims

1. 1. A system for delivering an infusion of a pharmaceutical formulation to a patient, comprising: a drug delivery device comprising an activator chamber for receiving a pharmaceutical formulation and a diluent chamber for receiving a diluent, the diluent chamber being disposed in series with the activator chamber and configured to receive the pharmaceutical formulation discharged from the activator chamber; an injection device comprising an actuator that drives a plunger or pump of the drug delivery device, causing the drug delivery device to expel the pharmaceutical formulation from the active agent chamber into the diluent chamber, dilute the pharmaceutical formulation with the diluent in the diluent chamber, and simultaneously expel the diluted pharmaceutical formulation from the outlet of the diluent chamber for delivery to a patient according to a predetermined dose profile; Equipped with the predetermined dose profile is designed to deliver a therapeutic dose of the pharmaceutical formulation to the patient over a predetermined infusion time in a manner that facilitates safe detection of an adverse reaction of the patient to the pharmaceutical formulation during a first stage of administering the therapeutic dose, and the predetermined dose profile is such that the concentration of the pharmaceutical formulation in the dilution chamber increases during the process of infusion into the patient.

2. 10. The system of claim 1, wherein the predetermined dose profile is such that after 56% of the infusion time, the cumulative dose delivered to the patient is 1% or less of the therapeutic dose.

3. The system of claim 1 or 2, wherein the dilution chamber has a volume of at least 10 ml.

4. 4. The system of claim 1, wherein the predetermined dose profile has a dose rate that increases over time from 14% of the infusion time to 78% of the infusion time.

5. 5. The system of any one of claims 1 to 4, wherein the predetermined dose profile is such that 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.

6. 5. The system of claim 4, wherein the dose profile has a maximum dose rate, and the dose profile is such that the time it takes for the cumulative dose to reach 0.1%, 1%, and / or 10% of the therapeutic dose, respectively, is substantially the same as the time it takes for the dose rate to reach 0.1%, 1%, and / or 10% of the maximum dose rate.

7. 7. The system of any one of claims 1-6, wherein the predetermined dose profile is such that the cumulative dose delivered to the patient increases at an exponentially increasing or time-increasing rate over a period of time between a first time at which 0.1% of the cumulative dose is delivered to the patient and a second time at which 10% of the cumulative dose is delivered to the patient.

8. 8. The system of claim 1, wherein the predetermined dose profile has a dose rate, and wherein the predetermined dose profile is such that the dose rate increases exponentially or at a time-increasing rate over at least a portion of the predetermined infusion time.

9. 9. The system of claim 1, wherein the predetermined dose profile has a dose rate such that the dose rate increases exponentially or at a rate that increases over time during 14% to 78% of the predetermined infusion time.

10. 10. The system of claim 1, wherein the predetermined dose profile is such that there is a first period during which a cumulative dose reaches 0.01% and 0.1% and a second period during which the cumulative dose reaches 0.1% and 1% of the therapeutic dose, and wherein the first period and the second period are selected from the group comprising at least 6 minutes.

11. 11. The system of any one of claims 1 to 10, wherein the predetermined dose profile is such that the period between 0.00% and 0.01% of the therapeutic dose takes longer than 0.01% of the predetermined infusion time.

12. 12. The system of any one of claims 1 to 11, wherein the predetermined dose profile delivers the therapeutic dose over a predetermined infusion time that is between 20 minutes and 180 minutes.

13. The system of any one of claims 1 to 12, wherein the outlet of the dilution chamber is attached to an extension tube for delivering the injection to the patient.

14. 14. The system of any one of claims 1 to 13, wherein the predetermined dose profile is such that at the end of the predetermined infusion time, a portion of the therapeutic dose remains in the dilution chamber and is then delivered to the patient in a bolus by emptying the dilution chamber.

15. 14. The system of claim 13, wherein the predetermined dose profile delivers the therapeutic dose over a predetermined injection time in a manner such that the flow rate of the pharmaceutical formulation into the dilution chamber starts at a higher level, decreases to a minimum flow rate during an initial phase, and then increases.

16. the drug delivery device a first plunger; a second plunger; a container configured to receive the second plunger and at least a portion of the first plunger; the dilution chamber is defined by the container and the second plunger, the outlet of the dilution chamber comprises a dilution chamber opening defined by the container, the activator chamber is defined by the first plunger, the container, and the second plunger, the activator chamber comprises a first activator chamber opening configured to receive the at least a portion of the first plunger; 16. The system of any one of claims 1 to 15, wherein the second plunger comprises a valve configured to control the flow of pharmaceutical formulation from the activator chamber to the diluent chamber in response to an applied pressure.

17. the activator chamber comprises a second activator chamber opening in a wall of the container; 17. The system of claim 16, wherein the active agent chamber is configured to receive the pharmaceutical formulation through the second active agent chamber opening.

18. the injection device receiving a volume input (Vp) indicating a volume of the pharmaceutical formulation; receiving a time input (i) indicating a time at which the pharmaceutical formulation is to be administered; determining a number (h) of infusion steps to be performed during the time period during which the pharmaceutical formulation will be administered; determining a pharmaceutical formulation output volume for each of the infusion steps among the number of infusion steps, each pharmaceutical formulation output volume corresponding to a volume of the pharmaceutical formulation to be output by the drug delivery device during a respective infusion step; determining a target flow rate for each infusion step, each target flow rate indicating a target flow rate of the pharmaceutical formulation output by the drug delivery device during the respective infusion step, each target flow rate being determined at least in part based on the pharmaceutical formulation output volume for the respective infusion step; and actuating an injection device actuator such that the pharmaceutical formulation is output by the drug delivery device at a respective target flow rate during each injection step.

19. the injection device A concentration input (C) indicating the concentration of the pharmaceutical agent in the active agent chamber. p )and, A volume input (V) indicating the volume of the pharmaceutical formulation to be injected. p )and, A dilution chamber volume input (V d )and, receiving a time input (i) indicating a time window during which the pharmaceutical formulation is to be administered; determining a number (h) of injection steps to be performed during said time window; modeling the injection over the time window based on an injection modeling function, wherein modeling the injection comprises: modeling, including determining a target flow rate of the pharmaceutical formulation to the patient and a concentration of the pharmaceutical formulation in the dilution chamber for each of the number of infusion steps; determining an infusion volume for each of the number (h) infusion steps based at least in part on the infusion modeling function, the infusion volume indicating a volume of the pharmaceutical formulation to be output by the drug delivery device during a respective infusion step; and actuating an injection device actuator such that the determined injection volume for each injection step is output by the medication delivery device during the respective injection step.

20. 5. The system of claim 4, wherein the predetermined dose profile is such that the dose rate increases as the infusion progresses such that the time interval during which the dose rate increases by an order of magnitude is at least 6 minutes or at least 20% of the predetermined infusion time.

21. 21. The system of any one of claims 1-20, wherein the predetermined dose profile has a dose rate, and wherein the predetermined dose profile is such that, for at least a portion of the infusion, the dose rate doubles every X minutes, where X is in the range of 1.33 minutes to 12 minutes.

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