Drug delivery systems, devices and methods

Abstract

An example of the present application discloses a drug delivery device comprising a first plunger, a second plunger, and a container configured to receive at least a portion of the second plunger and the first plunger. The container and the second plunger define a diluent chamber configured to receive a diluent. The container defines a diluent chamber opening. The first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation. The second plunger comprises a one-way valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber. The one-way valve is configured to move from a closed position to an open position upon application of a force exceeding a valve threshold force to an inlet side of the valve. The valve threshold force is less than the sum of the second plunger breakaway force and the first plunger breakaway force.

Description

[Technical field]

[0001] The described embodiments relate to systems, devices, and methods for delivering mixed fluids. In particular, the described embodiments relate to systems, devices, and methods for administering pharmaceutical formulations. [Background technology]

[0002] Administering pharmaceutical preparations (such as intravenous drugs) to patients can involve many risks. This risk is particularly relevant for patients with drug hypersensitivity reactions to certain intravenous drugs. Drug hypersensitivity reactions to certain intravenous drugs are typically difficult, if not impossible, to predict. In particular, the specific dose of a drug that may induce a drug hypersensitivity reaction in a certain patient is difficult to predict before administration of the drug.

[0003] To reduce the risk that any patient will suffer a fatal reaction to the drug, one method of administering certain intravenous drugs is to give the patient a specific dose (called a test dose) that will cause a submaximal adverse reaction. The test dose is delivered prior to delivery of the therapeutic dose of the drug.

[0004] Upon detection of any submaximal or minor adverse reactions in response to the test dose, administration of the intravenous drug may be immediately discontinued to minimize the risk of the development of a more severe adverse reaction, or ultimate death of the patient.

[0005] However, the practice of administering test doses is not routine or recommended, especially for the following reasons: -The test dose that typically induces a submaximal response is typically on the order of 0.01%-0.1% of the therapeutic dose given to the patient, and preparation of this amount of test dose is time consuming and difficult. The test dose that will elicit a detectable submaximal response will vary between patients and can range from 0.01% to 100% of the therapeutic dose. For example, for a particular patient, a detectable submaximal response may occur at any one of 0.01%, 1%, 10% or 100% of the therapeutic dose, and this will vary between patients.

[0006] Among other reasons, these make it difficult or even impossible for clinicians to select the appropriate test dose to conduct trials to see whether adverse reactions occur during administration of the therapeutic dose. In particular, administering a relatively small test dose may not cause adverse reactions in the patient, but administering a relatively large dose (above a certain threshold specific to each patient) may cause life-threatening adverse reactions. This reaction may lead to the death of the patient. Thus, administering the test dose may lead to the life-threatening condition that the provision of the test dose was intended to alleviate.

[0007] Due to the difficulty in determining what specific percentage of the therapeutic dose should be administered to the patient as a test dose for that particular patient, the current practice is to administer the intravenous drug via a constant infusion (either a short "push" or a constant infusion over a fixed period of time). This has similar risks as those listed above. Administering a therapeutic dose of a drug without determining whether the patient is hypersensitive or allergic to that particular drug could result in administering a lethal drug dose to the patient or cause a serious adverse reaction.

[0008] Furthermore, currently, any test dose that can be administered to a patient is necessarily administered prior to and separately from the infusion of the therapeutic dose that a particular patient requires. The preparation of separate test doses requires the preparation of multiple pharmaceutical formulations for each test dose, and also for the therapeutic dose. This process is cumbersome, and therefore test doses are typically not provided to patients. Instead, therapeutic doses are provided to patients without testing the patient's reaction to the drug. This increases the risk that a particular patient (having a drug hypersensitivity reaction to a particular drug) may suffer a fatal condition while receiving this particular drug. This is especially true because current methods for administering the full therapeutic dose (a "push" or constant infusion over a fixed period of time) provide a relatively large dose at the beginning of the infusion process compared to what is typically required to cause a severe adverse reaction. This does not allow clinicians enough time to detect that a patient receiving an infusion of a pharmaceutical formulation is experiencing an adverse (i.e., negative) reaction to the drug.

[0009] Any discussion of documents, acts, materials, devices, articles or the like which has been included in this specification should not be construed as an admission that any or all of such matters form part of the prior art or were general general knowledge in the field relevant to this disclosure as they existed prior to the priority date of each of the appended claims.

[0010] Throughout this specification the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Summary of the Invention

[0011] Throughout this specification the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0012] A first aspect of the present disclosure provides a drug delivery device, the drug delivery device 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, the container and the second plunger defining a diluent chamber configured to receive a diluent, the container defining a diluent chamber opening, the first plunger, the container and the second plunger defining an activator chamber configured to receive a pharmaceutical formulation, the second plunger comprising a one-way valve configured to allow flow of the pharmaceutical formulation from the activator chamber to the diluent chamber and to prevent flow of fluid from the diluent chamber to the activator chamber.

[0013] A second aspect of the present disclosure provides a drug delivery device, the drug delivery device comprising a first plunger, a second plunger, and a container configured to receive at least a portion of the second plunger and the first plunger, the container and the second plunger defining a diluent chamber configured to receive a diluent, the container defining a diluent chamber opening, the first plunger, the container, and the second plunger defining an activator chamber configured to receive a pharmaceutical formulation, the second plunger comprising a one-way valve configured to control a flow of the pharmaceutical formulation from the activator chamber to the diluent chamber, the one-way valve configured to move from a closed position to an open position upon application of a force exceeding a valve threshold force to an inlet side of the valve, the valve threshold force being less than a sum of a breakaway force of the second plunger and a breakaway force of the first plunger, the drug delivery device being operable to push the pharmaceutical formulation through the one-way valve into the diluent chamber and mix it from the activator chamber with the diluent in the diluent chamber, and push the mixed diluent and pharmaceutical formulation out of the diluent chamber through the diluent chamber opening. Mixing of the diluent and the pharmaceutical formulation in the dilution chamber may occur simultaneously as the diluted pharmaceutical formulation is expelled from the dilution chamber through the dilution chamber opening.

[0014] A third aspect of the present disclosure provides a drug delivery device, the drug delivery device 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, the first plunger configured to seal with the container to provide a first seal, the second plunger configured to seal with the container to provide a second seal, the container and the second plunger define a diluent chamber configured to receive a diluent, the container defines a diluent chamber opening, the first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation, the second plunger comprises a one-way valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber, and a breakaway force of the second plunger is greater than a breakaway force of the first plunger.

[0015] The first, second or third aspect of the disclosure may have any of the following additional features.

[0016] The container can define an activator chamber opening and an activator chamber port comprising an activator chamber port opening. The activator chamber port can be positioned on a side of the container between the activator chamber opening and the dilution chamber opening, for example, between an initial position of the first plunger and an initial position of the second plunger.

[0017] The valve threshold force may be less than the breakaway force of the second plunger. The first plunger may have a concave surface facing the second plunger. The second plunger may have a convex surface facing the first plunger and a convex surface facing the dilution chamber opening.

[0018] The first and second plungers may be shaped such that when the first plunger is moved into contact with the second plunger, there is an air gap between the first and second plungers. The air gap may act as an air bubble trap. The second plunger may partially conform to the shape of the first plunger to minimize wastage of the pharmaceutical formulation while also allowing space for any air bubbles to become trapped between the first and second plungers when the first plunger is moved into contact with the second plunger.

[0019] In some embodiments, the distal end of the container defines a dilution chamber opening, the second plunger is movable toward the distal end of the container to an end position where the second plunger cannot move further toward the distal end of the container, and the second plunger is shaped such that at the end position there is a gap between at least a portion of the second plunger and the distal end of the container to prevent suction forces attaching the second plunger to the distal end of the container. The second plunger may have a different shape or profile than the distal end of the container to prevent suction of the second plunger into the distal end of the container.

[0020] The second plunger may partially conform to the distal end of the container to minimize waste of the pharmaceutical formulation and / or diluent when the second plunger is moved into contact with the distal end of the container to expel the contents of the dilution chamber. Because the second plunger partially conforms to the distal end of the container when the second plunger is moved into contact with the distal end of the container, a gap still exists between at least a portion of the second plunger and the distal end of the container to prevent suction forces that attach the second plunger to the distal end of the container.

[0021] In some embodiments, the side of the second plunger facing the distal end of the container includes a first portion that abuts the distal end of the container at an end position and a second portion that does not abut the distal end of the container at an end position.

[0022] The one-way valve may be a duckbill valve.

[0023] In some embodiments, the one-way valve is contained within a main body of the second plunger, the main body including at least one outlet opening, and the main body including at least one internal channel leading from an outlet of the one-way valve to the at least one outlet opening.

[0024] In some embodiments, the main body of the second plunger includes at least two exit openings.

[0025] In some embodiments, the at least two exit openings are configured to generate a first jet of the pharmaceutical formulation directed toward a first corner of the dilution chamber and a second jet of the pharmaceutical formulation directed toward a second corner of the dilution chamber as the pharmaceutical formulation is forced out of the activator chamber through the one-way valve.

[0026] In some embodiments, the device is configured such that the first and second jets of the pharmaceutical formulation repel each other on an inner surface of the dilution chamber, thereby facilitating reverse mixing of the pharmaceutical formulation and the diluent within the dilution chamber.

[0027] In some embodiments, the one-way valve is a duckbill valve having a slit substantially perpendicular to a line joining a first and a second of the at least two outlet openings.

[0028] In some embodiments, the main body of the second plunger includes three outlet openings.

[0029] In some embodiments, a middle opening of the three exit openings is configured to generate a third jet of the pharmaceutical formulation that is directed towards the dilution chamber opening.

[0030] In some embodiments, the second plunger has a length along the longitudinal axis of the container of at least 9 mm.

[0031] In some embodiments, the first plunger comprises a plunger lumen extending between the first plunger lumen opening and the second plunger lumen opening for delivering the pharmaceutical formulation into the active agent chamber through the plunger lumen.

[0032] In some embodiments, a plunger lock is further provided for fixing the position of the first plunger relative to the container so that the first plunger cannot move further into the container, and optionally the plunger lock may include a first groove for receiving a protrusion (e.g., a flange) of the first plunger and a second groove for receiving a protrusion (e.g., a flange) of the container.

[0033] In some embodiments, the container has markings that indicate a starting position where the second plunger will be positioned within the container at the start of an injection.

[0034] A fourth aspect of the present disclosure provides a drug delivery device according to any of the above claims in combination with a conduit device, the conduit device comprising: a conduit device housing including a first housing port, a second housing port, and a conduit connecting the first housing port and the second housing port, the first housing port including a first connector configured to connect to a dilution chamber outlet opening, and the second housing port including a second connector configured to connect to a tube connecting to a patient.

[0035] A fifth aspect of the present disclosure provides a method of preparing a drug delivery device according to the above aspect, the method comprising: a) filling the diluent chamber with a diluent; and b) filling the active agent chamber with a pharmaceutical formulation.

[0036] In some embodiments, the diluent chamber is filled with a diluent before the active agent chamber is filled with the pharmaceutical formulation.

[0037] In some embodiments, the dilution chamber is filled through a dilution chamber opening and the activator chamber is filled at an activator port on the side of the container.

[0038] In some embodiments, the activator chamber is filled with the activator before the diluent chamber is filled with the diluent.

[0039] In some embodiments, the active agent chamber is filled with the active agent through the plunger lumen of the first plunger.

[0040] In one example, prior to filling the dilution chamber, the second plunger is positioned at a start position that defines the initial volume of the dilution chamber that the dilution chamber will have at the start of injection. The second plunger may be provided to the clinician at an initial position that is the same as the start position or that is further away from the distal end of the container than the start position.

[0041] A sixth aspect of the present disclosure provides a method of preparing a drug delivery device, the drug delivery device comprising an active agent chamber, a diluent chamber, a one-way valve connecting the active agent chamber and the diluent chamber, and a diluent chamber opening, the method comprising: c) connecting the drug delivery device to an injection driver; d) attaching an extension tube of known, predetermined volume to the diluent chamber opening of the drug delivery device; and e) priming the drug delivery device by passing a pharmaceutical formulation from the activator chamber through the one-way valve into the diluent chamber, mixing with the diluent in the diluent chamber, and then through the diluent chamber opening and out into the extension tube, whereby the extension tube of known, predetermined volume is filled with the diluted pharmaceutical formulation that will form a first portion of an injection, wherein the concentration profile of the diluted pharmaceutical formulation in the extension tube follows a desired dose profile of the first portion of the injection.

[0042] In some embodiments, after priming the drug delivery device, attaching an extension tube to the patient and using an injection driver to control the drug delivery device to dilute the pharmaceutical formulation by mixing the pharmaceutical formulation with a diluent in a dilution chamber and delivering the diluted pharmaceutical formulation to the patient according to a predetermined dose profile.

[0043] A seventh aspect of the present disclosure provides a drug delivery system comprising a drug delivery apparatus as defined in any one of the preceding claims and an injection device comprising at least one injection device processor and an injection device memory storing program instructions accessible by the at least one injection device processor, the program instructions configured to cause the at least one injection device processor to control the drug delivery device to deliver a pharmaceutical formulation to a patient according to a predetermined dose profile.

[0044] In some embodiments, the injection device is configured to actuate the injection device actuator to displace the first plunger such that the pharmaceutical formulation is delivered by the drug delivery device according to a predetermined dose profile, or the injection device is configured to apply an injection pressure to the dilution chamber outlet, thereby causing displacement of the first plunger such that the pharmaceutical formulation is delivered by the drug delivery device according to a predetermined dose profile.

[0045] In some embodiments, the system further comprises an extension tube of known, predetermined volume to the drug delivery device, and the processor is configured to perform a priming process prior to the start of an injection, the priming process comprising priming the drug delivery device by passing the pharmaceutical formulation from the activator chamber through the one-way valve into the dilution chamber, mixing with the diluent in the dilution chamber, and then exiting through the dilution chamber opening into the extension tube, whereby the extension tube of known, predetermined volume is filled with the diluted pharmaceutical formulation that will form a first portion of the injection, and wherein the concentration profile of the diluted pharmaceutical formulation in the extension tube follows a desired dose profile for the first portion of the injection.

[0046] In some embodiments, a drug delivery device is provided. The drug delivery device includes a first plunger, a second plunger, and a container configured to receive at least a portion of the second plunger and the first plunger. The container and the second plunger define a diluent chamber configured to receive a diluent. The container defines a diluent chamber opening. The first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation. The second plunger includes a valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber. The first plunger includes a plunger lumen extending between the first plunger lumen opening and the second plunger lumen opening.

[0047] In some embodiments, the active agent chamber is configured to receive the pharmaceutical formulation through the plunger lumen.

[0048] In some embodiments, the first plunger comprises a first luer lock connector defining a first plunger lumen opening.

[0049] In some embodiments, the first plunger lumen opening is a plunger lumen inlet.

[0050] In some embodiments, the second plunger lumen opening is a plunger lumen outlet.

[0051] In some embodiments, the first plunger comprises a one-way valve configured to control the flow of the pharmaceutical formulation from the plunger lumen to the active agent chamber.

[0052] In some embodiments, the drug delivery device further comprises a first plunger cap configured to connect to the first plunger and cover the first plunger lumen opening.

[0053] In some embodiments, the first plunger cap comprises a second luer lock connector configured to connect with the first luer lock connector of the first plunger.

[0054] In some embodiments, the first plunger includes an air lumen extending between the first and second air lumen openings.

[0055] In some embodiments, the first plunger and the second plunger are each configured to be displaced relative to a longitudinal axis of the container.

[0056] In some embodiments, a second plunger is disposed between the first plunger and the dilution chamber opening.

[0057] In some embodiments, the container defines an inner container surface and the first plunger includes 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.

[0058] In some embodiments, the first plunger comprises a first plunger O-ring, the first plunger O-ring comprising a first plunger sealing surface.

[0059] In some embodiments, the container defines an inner container surface and the second plunger includes 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.

[0060] In some embodiments, the second plunger comprises a second plunger O-ring, the second plunger O-ring comprising a second plunger sealing surface.

[0061] In some embodiments, the valve comprises an inlet side and an outlet side.

[0062] 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.

[0063] 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.

[0064] In some embodiments, the valve is biased towards a closed position.

[0065] In some embodiments, the valve comprises a number of flaps configured to separate upon application of pressure to the inlet side.

[0066] In some embodiments, the drug delivery device further comprises a conduit configured to be fluidly connected to the dilution chamber opening, the conduit having a predetermined volume.

[0067] In some embodiments, the drug delivery device further comprises a dilution chamber port cap configured to connect to the container to cover the dilution chamber opening.

[0068] In some embodiments, the first plunger is configured to seal with the container to provide a first seal.

[0069] In some embodiments, the second plunger is configured to seal with the container to provide a second seal.

[0070] In some embodiments, the breakaway force of the second plunger is greater than the breakaway force of the first plunger.

[0071] In some embodiments, a drug delivery device is provided. The drug delivery device includes a first plunger, a second plunger, and a container configured to receive at least a portion of the second plunger and the first plunger. The container and the second plunger define a diluent chamber configured to receive a diluent. The container defines a diluent chamber opening. The first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation. The second plunger includes a valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber.

[0072] In some embodiments, a drug delivery device is provided. The drug delivery device comprises a first plunger, a second plunger, and a container configured to receive at least a portion of the second plunger and the first plunger. The container and the second plunger define a diluent chamber configured to receive a diluent. The container defines a diluent chamber opening. The first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation. The second plunger comprises a valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber. The valve is configured to move from a closed position to an open position upon application of a force exceeding a valve threshold force to an inlet side of the valve. The valve threshold force is less than the sum of the second plunger breakaway force and the first plunger breakaway force.

[0073] In some embodiments, the valve threshold force is less than the breakaway force of the second plunger.

[0074] In some embodiments, the opening force of the valve is less than the breakaway force of the second plunger.

[0075] In some embodiments, the valve is configured to move from an open position to a closed position when a force applied to the inlet side of the valve is removed.

[0076] In some embodiments, a drug delivery device is provided. The drug delivery device includes a first plunger, a second plunger, and a container configured to receive at least a portion of the second plunger and the first plunger. The first plunger is configured to seal with the container to provide a first seal. The second plunger is configured to seal with the container to provide a second seal. The container and the second plunger define a diluent chamber configured to receive a diluent. The container defines a diluent chamber opening. The first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation. The second plunger includes a valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber. A breakaway force of the second plunger is greater than a breakaway force of the first plunger.

[0077] In some embodiments, the container defines an activator chamber opening.

[0078] In some embodiments, the container defines an activator chamber port that comprises an activator chamber port opening.

[0079] In some embodiments, the first plunger includes a first number of O-rings.

[0080] In some embodiments, the second plunger includes a second number of O-rings.

[0081] In some embodiments, the second number is greater than the first number.

[0082] In some embodiments, one or more of the first number of O-rings comprises a first O-ring with a first diameter and a first O-ring groove with a first groove width.

[0083] In some embodiments, one or more of the second number of O-rings comprises a second O-ring with a second diameter and a second O-ring groove with a second groove width.

[0084] In some embodiments, the second diameter is greater than the first diameter.

[0085] In some embodiments, the second plunger comprises a valve device configured to control the flow of the pharmaceutical formulation from the activator chamber to the diluent chamber, the valve device comprising a valve.

[0086] In some embodiments, the second plunger comprises a second valve.

[0087] In some embodiments, the valve and the second valve are configured to control the flow of the pharmaceutical formulation from the activator chamber to the dilution chamber.

[0088] In some embodiments, a drug delivery device is provided. The drug delivery device includes a first plunger, a second plunger, a container configured to receive at least a portion of the second plunger and the first plunger, and at least one resistance element configured to resist displacement of the second plunger when the first plunger is displaced. The container and the second plunger define a diluent chamber configured to receive a diluent. The container defines a diluent chamber opening. The first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation. The second plunger includes a valve configured to control a flow of the pharmaceutical formulation from the active agent chamber to the diluent chamber.

[0089] In some embodiments, the container defines an activator chamber opening.

[0090] In some embodiments, the at least one resistance element comprises a second plunger O-ring.

[0091] In some embodiments, the second plunger comprises a second plunger O-ring.

[0092] In some embodiments, the first plunger includes a first number of first plunger O-rings.

[0093] In some embodiments, one or more of the first number of first plunger O-rings comprises a first plunger O-ring with a first diameter and a first plunger O-ring groove with a first groove width.

[0094] In some embodiments, one or more of the second number of second plunger O-rings comprises a second plunger O-ring with a second diameter and a second plunger O-ring groove with a second groove width.

[0095] In some embodiments, the second diameter is greater than the first diameter.

[0096] In some embodiments, the second groove width is smaller than the first groove width.

[0097] In some embodiments, the second plunger comprises a valve device configured to control the flow of the pharmaceutical formulation from the activator chamber to the diluent chamber, the valve device comprising a valve.

[0098] In some embodiments, the second plunger comprises a second valve.

[0099] In some embodiments, the valve and the second valve are configured to control the flow of the pharmaceutical formulation from the activator chamber to the dilution chamber.

[0100] In some embodiments, the valve is configured to move from a closed position to an open position upon application of a force on the inlet side of the valve that exceeds a valve threshold force.

[0101] In some embodiments, the valve threshold force is less than the sum of the second plunger breakaway force and the first plunger breakaway force.

[0102] In some embodiments, the breakaway force of the second plunger is greater than the breakaway force of the first plunger.

[0103] In some embodiments, a conduit device is provided. The conduit device comprises a housing comprising a first housing port, a second housing port, and a conduit connecting the first housing port and the second housing port. In some embodiments, the first housing port comprises a first connector and the second housing port comprises a second connector.

[0104] In some embodiments, the conduit is coiled within the housing.

[0105] In some embodiments, the conduit has a predetermined volume.

[0106] In some embodiments, the housing further comprises a collar extending in a direction parallel to the longitudinal direction of the conduit device and spaced apart from the second connector.

[0107] In some embodiments, the collar is configured to engage the container.

[0108] In some embodiments, the first connector is a third luer lock connector configured to connect to a dilution chamber port that defines a dilution chamber opening.

[0109] In some embodiments, the second connector is a fourth luer lock connector.

[0110] In some embodiments, a drug delivery system is provided that includes any one of the drug delivery device embodiments described above and any one of the conduit device embodiments described above.

[0111] In some embodiments, a drug delivery system is provided. The drug delivery system comprises any one of the drug delivery apparatus and the injection device described above. The injection device comprises 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 and configured to cause the at least one injection device processor to actuate the injection device actuator to displace the first plunger such that the pharmaceutical formulation is delivered by the drug delivery device.

[0112] In some embodiments, a drug delivery system is provided, comprising any one of the drug delivery apparatus embodiments and an infusion device described above, 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 and configured to cause the at least one infusion device processor to control the infusion device to apply an injection pressure to the dilution chamber outlet such that the pharmaceutical formulation is delivered by the drug delivery device, thereby causing a displacement of the first plunger.

[0113] Embodiments of the present disclosure will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0114] [Figure 1A] FIG. 1 is a perspective view of a drug delivery system according to some embodiments. [Figure 1B] FIG. 2 is a block diagram of the drug delivery system shown in FIG. 1, according to some embodiments. [Diagram 2] 1 is a cross-sectional side view of a drug delivery device according to some embodiments. [Diagram 3] FIG. 3 is a perspective view of the drug delivery device of FIG. 2, in which a portion of the reservoir of the drug delivery device is transparent. [Figure 4]FIG. 1 is a perspective view of a drug delivery system according to some embodiments. [Figure 5A] 1 illustrates a method of operation of a drug delivery system, according to some embodiments. [Figure 5B] 1 illustrates a method of operation of a drug delivery system, according to some embodiments. [Figure 5C] 1 illustrates a method of operation of a drug delivery system, according to some embodiments. [Figure 5D] 1 illustrates a method of operation of a drug delivery system, according to some embodiments. [Figure 5E] 1 illustrates a method of operation of a drug delivery system, according to some embodiments. [Figure 6] 1-5E illustrate methods of operation of the drug delivery device of FIG. 1-5E, according to some embodiments. [Figure 7] 1-5E illustrate another method of operation of the drug delivery device of FIG. 1-5E, according to some embodiments. [Figure 8] 1A-5E illustrate methods for preparing the drug delivery devices of FIGS. 1-5E, according to some embodiments. [Figure 9] 1-5E illustrate another method for preparing the drug delivery device of FIG. 1-5E, according to some embodiments. [Figure 10] 1 illustrates a drug delivery device having a first plunger having a concave surface facing the second plunger, and a second plunger having a convex surface facing the first plunger and a convex surface facing the distal end of the container, according to some embodiments. [Figure 11] 1 illustrates a cap for a primary plunger and a support structure for the cap, according to some embodiments. [Figure 12] 1 illustrates a drug delivery device comprising a plunger lumen, according to some embodiments. [Figure 13A] 13 is a schematic diagram of a cross-section of the drug delivery device of FIG. 12 according to some embodiments. [Figure 13B] 13 is a schematic diagram of a cross-section of the drug delivery device of FIG. 12 when filled with a diluent and a pharmaceutical formulation, according to some embodiments. [Figure 14]12-13B, according to some embodiments. [Figure 15] 1 illustrates an embodiment of a medication delivery device comprising an alternative first plunger and an alternative second plunger, according to some embodiments. [Figure 16] 16 illustrates a method of preparing the drug delivery device of FIG. 15 according to some embodiments. [Figure 17] 1 illustrates a method of preparing a drug delivery device, according to some embodiments. [Figure 18] 1 illustrates another method of preparing a drug delivery device, according to some embodiments. [Figure 19A] 1A-1D show side views of a drug delivery device with a plunger in different positions, according to some embodiments. [Figure 19B] 1A-1D show side views of a drug delivery device with a plunger in different positions, according to some embodiments. [Figure 20A] 1 shows a side view of a drug delivery device with an O-ring in a first state according to some embodiments. [Figure 20B] 1 illustrates a side view of another drug delivery device with an O-ring in a first state according to some embodiments. [Figure 20C] 1 illustrates a cross-sectional view of an O-ring according to some embodiments. [Figure 21] 1 shows a side view of a drug delivery device in a first state according to some embodiments. [Figure 22] 1 shows a side view of a drug delivery device with protrusions in a first state according to some embodiments. [Figure 23] 1 is a partial cross-sectional side view of a drug delivery device according to some embodiments. [Figure 24] 1 is a partial cross-sectional side view of a drug delivery device according to some embodiments. [Figure 25A] 1 illustrates a second plunger according to some embodiments. [Figure 25B] 13 illustrates another second plunger according to some embodiments. [Figure 25C]1 illustrates a plunger according to some embodiments. [Figure 25D] 1 illustrates a plunger according to some embodiments. [Figure 26] 1 illustrates a medication delivery device having a first plunger and a second plunger shaped to provide an air trap, according to some embodiments. [Figure 27] 1 illustrates a second plunger having a single outlet according to some embodiments. [Figure 28] 13 illustrates a second plunger having two outlets according to some embodiments. [Figure 29A] 13 illustrates a second plunger having two outlets according to some embodiments. [Figure 29B] FIG. 13 illustrates a top view of a second plunger having two outlets and a horizontal duckbill valve, according to some embodiments. [Figure 29C] FIG. 13 illustrates a top view of a second plunger having two outlets and a vertical duckbill valve, according to some embodiments. [Figure 30A] 13 shows a jet of pharmaceutical formulation being released through two outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 30B] 13 shows a jet of pharmaceutical formulation being released through two outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 30C] 13 shows a jet of pharmaceutical formulation being released through two outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 30D] 13 shows a jet of pharmaceutical formulation being released through two outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 30E] 13 shows a jet of pharmaceutical formulation being released through two outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 30F]13 shows a jet of pharmaceutical formulation being released through two outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Diagram 31] FIG. 13 illustrates a perspective view of a second plunger having three outlets, according to some embodiments. [Diagram 32] FIG. 13 illustrates a cross-sectional view of a second plunger having three outlets, according to some embodiments. [Figure 33A] 13 shows a jet of pharmaceutical formulation being released through three outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 33B] 13 shows a jet of pharmaceutical formulation being released through three outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 33C] 13 shows a jet of pharmaceutical formulation being released through three outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 33D] 13 shows a jet of pharmaceutical formulation being released through three outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 33E] 13 shows a jet of pharmaceutical formulation being released through three outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Figure 33F] 13 shows a jet of pharmaceutical formulation being released through three outlets of the second plunger into the dilution chamber, mixing the pharmaceutical formulation with the diluent, according to some embodiments. [Diagram 34] 13 illustrates the internal structure of a second plunger having multiple channels and outlets according to some embodiments. [Diagram 35] 1 illustrates a drug delivery system, according to some embodiments. [Diagram 36] 1 illustrates a pump having a primary inlet and a secondary inlet that may be connected to a conduit device or a drug delivery device, according to some embodiments. [Figure 37]1 shows a perspective view of a conduit device and a portion of a drug delivery device, according to some embodiments. [Figure 38] 38 shows a perspective view of the channel device and drug delivery apparatus of FIG. 37 according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0115] The present disclosure relates to a system for administering a pharmaceutical formulation. In particular, several embodiments of a drug delivery device for administering a pharmaceutical formulation are disclosed.

[0116] It will be understood that the term "active agent" used in the description may correspond to or may be referred to as an "active ingredient" or "drug". That is, throughout this disclosure, the terms "active ingredient", "active agent", and "drug" are used to describe the active agent to be administered to the patient. In some embodiments, a pharmaceutical formulation may be delivered to the patient. The pharmaceutical formulation may include an active agent. The pharmaceutical formulation may also include one or more other components. 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. In some embodiments, the pharmaceutical formulation may include a diluent. That is, in some embodiments, the pharmaceutical formulation may include an active agent, a solvent, and / or a diluent. The pharmaceutical formulation may include a particular concentration of the active agent. This may be referred to as the active agent concentration. The pharmaceutical formulation may be a solution. It will be understood that in some embodiments, the term "drug" used in the description may correspond to the active agent of the "pharmaceutical formulation".

[0117] Drug Delivery Systems 1A, 1B, 4, and 5A-5E show a system 1 according to some embodiments. In some embodiments, the system 1 is a fluid delivery system 1. In some embodiments, the system 1 is a drug delivery system 1. The drug delivery system 1 comprises a fluid delivery device 2. The fluid delivery device 2 is configured to mix fluids and deliver the mixed fluid. In some embodiments, the fluid delivery device 2 is in the form of a drug delivery device 2. FIGS. 2, 3, 6, and 7 show a drug delivery device 2 according to some embodiments.

[0118] The drug delivery system 1 is configured to provide a pharmaceutical formulation to a patient. The drug delivery system 1 is configured to provide a pharmaceutical formulation according to a target flow rate that approximates a flow rate delivery function. In some embodiments, the drug delivery system 1 is configured to provide a pharmaceutical formulation according to a target flow rate as described in International Patent Application No. PCT / AU2020 / 051363, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the drug delivery system 1 is configured to provide a pharmaceutical formulation according to a target flow rate as described in Australian Provisional Patent Application No. 2021 / 901792, the contents of which are incorporated herein by reference in their entirety. The target flow rate may change over time.

[0119] As described in PCT / AU2020 / 051363 and Australian Provisional Patent Application No. 2021 / 901792, the injection device may be configured to control a drug delivery device to intravenously deliver a pharmaceutical formulation to a patient, the injection device comprising a processor and a memory storing instructions executable by the processor to cause the drug delivery device to deliver the pharmaceutical formulation to the patient according to a predetermined dose profile, the predetermined dose profile 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, or desensitization of the patient to the pharmaceutical formulation, during a first stage of administering the therapeutic dose.

[0120] In some examples, the predetermined dose profile is such that the dose rate changes over a predetermined infusion time. In some examples, the cumulative dose delivered to the patient increases at a rate that increases exponentially or increases over time over at least a portion of the predetermined infusion time. In some examples, the dose profile is such that there is a first period during which the cumulative dose reaches 0.01% and 0.1% of the therapeutic dose and a second period during which the cumulative dose reaches 0.1% and 1% of the therapeutic dose, the first period and the second period being selected from the group consisting of at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, between 2 minutes and 10 minutes, and at least a potential period of adverse reactions.

[0121] The processor of the infusion device may control the drug delivery device to deliver the pharmaceutical formulation according to a predetermined profile by controlling the infusion device. For example, the infusion device may drive a pump or may be controlled to drive a plunger of the drug delivery device such that the pharmaceutical formulation is delivered according to a predetermined dose profile. For example, the processor may divide a predetermined infusion time into several infusion steps and determine a target flow rate or target delivery volume for each infusion step such that the predetermined dose profile is realized when the actuator is controlled according to the target flow rate or target delivery volume of each infusion step. The target flow rate or target delivery volume of the infusion steps of the predetermined dose profile may be determined by referring to a look-up table stored in memory or calculated in real time. In either case, the cumulative dose of drug delivered to the patient starts at a very low level and increases over the course of the infusion, and in some cases, the dose rate increases as the infusion progresses. The infusion may last, for example, 20 to 180 minutes. The dose rate may be relatively low and increases slowly only over the initial part of the infusion, for example the first 10 minutes of the infusion.

[0122] For many injection drivers, it may be difficult to accurately deliver low injection rates. Thus, in some examples, the drug delivery device may include an active agent chamber that discharges the pharmaceutical formulation into a separate diluent chamber that contains a diluent, and the diluted pharmaceutical formulation may then flow to the patient through a conduit, such as an extension tube. In this way, the pharmaceutical formulation may be significantly diluted at the beginning of the injection, so that a higher dose rate can be used while delivering a low injection rate. The concentration of the pharmaceutical formulation in the diluent chamber and delivered to the patient may vary and increase over at least a portion of the injection. One convenient implementation is a drug delivery device in the form of a syringe with a pair of plungers that define an active agent chamber and a diluent chamber, as described in more detail below.

[0123] The drug delivery system 1 comprises an injection device 3 (such as a syringe driver, a peristaltic pump, a volumetric pump, or a similar drug injection pump). The injection device 3 comprises or may be in the form of an injection driver 3. The injection device 3 comprises or may be in the form of a vacuum injection device 3. When the injection device 3 comprises or is in the form of a vacuum injection device 3, the injection device 3 may apply an injection pressure (i.e., a vacuum pressure 61) to the dilution chamber opening 53, thereby causing a displacement of the first plunger 13, such that the pharmaceutical formulation is delivered by the drug delivery apparatus 2. The pharmaceutical formulation may be delivered at a target flow rate.

[0124] The infusion device 3 comprises a control unit for controlling the rate at which the infusion device 3 delivers the pharmaceutical formulation from the drug delivery device 2 to the patient. The control unit comprises hardware and software for controlling the infusion device 3. The software comprises a number of instructions for executing an algorithm designed to calculate a flow rate dependent on a flow delivery function. In some embodiments, the flow delivery function characterizes the flow rate at which the pharmaceutical formulation is provided to the patient by the drug delivery device 2. Figure 1B shows a block diagram of the drug delivery system 1.

[0125] The drug delivery device 2 comprises a first plunger 13. The first plunger 13 may also be referred to as a primary plunger. The drug delivery device 2 comprises a second plunger 14. The second plunger 14 may also be referred to as a separate plunger. The drug delivery device 2 comprises a container 11. The container 11 may also be referred to as a barrel 11. The container 11 is configured for receiving the second plunger 14. The container 11 is configured to receive at least a portion of the first plunger 13. This may be a distal portion of the first plunger 13.

[0126] The second plunger 14, when received in the container 11, defines two chambers in the container 11. In particular, the second plunger 14, when received in the container 11, defines a first chamber 15 and a second chamber 25. The first chamber 15 is configured to store a first fluid. The first fluid may be a solution including an activator and a solvent. The activator may be as described herein. The solvent may be as described herein. The first chamber 15 may be referred to as an activator chamber 15. The second chamber 25 is configured to store a second fluid. The second fluid may be a diluent. The diluent may be as described herein. The second chamber 25 may be referred to as a mixing chamber 25 or a diluent chamber 25. In particular, the container 11 and the second plunger 14 together define a diluent chamber 25. The diluent chamber 25 is configured to receive a diluent. The first plunger 13 , the container 11 and the second plunger 14 together define an activator chamber 15 .

[0127] The active agent chamber 15 is configured to receive an active agent. In some embodiments, the active agent can be a solid (e.g., a crystalline form or a powder). In such cases, the active agent chamber 15 can be configured to receive a solvent. The solvent is configured to dissolve the solid active agent. Thus, the pharmaceutical formulation includes the active agent dissolved in the solvent. That is, the pharmaceutical formulation includes a solution including the active agent and the solvent.

[0128] In some embodiments, the active agent chamber 15 is configured to receive a pharmaceutical formulation. As described herein, the pharmaceutical formulation may be a solution comprising the active agent (if dissolved) and a solvent. In such a case, the active agent chamber 15 is configured to receive the pharmaceutical formulation as a solution comprising the active agent and a solvent.

[0129] The second plunger 14 is configured to allow flow of the fluid (e.g., a pharmaceutical formulation) contained in the active agent chamber 15 into the diluent chamber 25. The diluent chamber 25 contains a diluent for mixing with the pharmaceutical formulation (or active agent) flowing from the active agent chamber 15.

[0130] The second plunger 14 includes a valve 39. The valve 39 may also be referred to as a valve means 39. The valve 39 is configured to control the flow of the pharmaceutical formulation from the activator chamber 15 into the diluent chamber 25. In other words, the second plunger 14 includes a valve 39 configured to control the flow of the pharmaceutical formulation from the activator chamber 15 to the diluent chamber 25. The diluent chamber 25 is close to the distal end of the container 11, and the activator chamber 15 is further away from the distal end of the container. As shown in FIG. 6, during use, the pharmaceutical formulation can be discharged from the activator chamber 15 through the valve 39 into the diluent chamber 25 and discharged from the diluent chamber 25 through the diluent chamber opening 51. The diluent chamber opening 51 can be connected to a conduit 23, such as an extension tube, leading to a patient. In this way, the pharmaceutical formulation can be mixed with the diluent in the diluent chamber, and the diluted pharmaceutical formulation can be released from the device and delivered intravenously to the patient. Fluid may be continuously forced through the chamber and out the dilution chamber opening so that mixing of the pharmaceutical formulation and diluent within the dilution chamber may occur simultaneously as the diluted pharmaceutical formulation is released through the dilution chamber opening.

[0131] In Figures 5A-5D and 6, the diluent chamber 25 is toward the distal end of the container 11 and the activator chamber 15 is toward the proximal end. Because the order of the chambers is different in the examples of the present disclosure, this arrangement differs from prior art dual chamber syringes where the diluent chamber is at the proximal end and the activator chamber is at the distal end. In some examples, the medical delivery devices of the present disclosure may be provided with empty diluent and activator chambers that are filled by the clinician. This differs from prior art dual chamber syringes where the syringe is provided with an activator chamber at the distal end pre-filled with a solid drug and a diluent chamber at the proximal end pre-filled with a diluent.

[0132] The valve 39 is a one-way valve that allows the flow of fluid from the activator chamber 15 to the diluent chamber 25, but prevents the flow of fluid from the diluent chamber into the activator chamber. The valve 39 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 13. Alternatively, the pressure may be applied via the first plunger 13. In at least the particular arrangement shown in Figures 1-8, the valve 39 comprises a duckbill valve 41. The duckbill valve 41 comprises a plurality of flaps 43 that separate from one another to open the duckbill valve 41 when pressure is applied to the first plunger 13. When pressure applied to the first plunger 13 is removed, the flaps 43 return to their original state to close the duckbill valve 41 and prevent backflow of the pharmaceutical formulation into the activator chamber 15.

[0133] The valve 39 (or valve means 39) comprises an inlet side 45 and an outlet side 47. The valve 39 (or valve means 39) is configured to move from a closed position to an open position when pressure is applied to the inlet side 45. Pressure may be applied to the inlet side 45 of the valve 39 (or valve means 39) by longitudinally displacing (or actuating) the first plunger 13 in the container 11 to displace the pharmaceutical formulation. The valve 39 (or valve means 39) is configured to move from an open position to a closed position when the pressure applied to the inlet side is removed. The valve 39 (or valve means 39) may be configured to move from a closed position to an open position when the pressure applied to the inlet side 45 exceeds a pressure threshold. The valve 39 (or valve means 39) may be configured to move from an open position to a closed position when the pressure applied to the inlet side 45 falls below a pressure threshold.

[0134] The valve 39 (or valve means 39) is biased towards a closed position. The valve 39 (or valve means 39) comprises a number of flaps 43 configured to separate when pressure is applied to the inlet side 45. The first plunger 13 is configured to contact the second plunger 14 when all or a majority of the pharmaceutical formulation in the active agent chamber 15 is transferred to the dilution chamber 25. Further actuation of the first plunger 13 will also result in the movement of the second plunger 14. Thus, actuation of the first plunger 13 causes the movement of the second plunger 14, causing the pharmaceutical formulation in the dilution chamber 25 to be output by the drug delivery device 2.

[0135] The container 11 includes at least one first port 49. The first port 49 may be referred to as a container fill port 49. The first port 49 may be referred to as an active agent chamber port 49. This may be because the first port 49 may provide access to the active agent chamber 15 of the drug delivery device 2. The active agent chamber port 49 defines an active agent chamber port opening 54. The active agent chamber port opening 17 is an opening in the container 11 that provides access to the active agent chamber 15 and / or the interior of the container 11. The drug delivery system 1 includes a first port cap 50. The first port cap 50 is configured to cover the active agent chamber port 49. The first port cap 50 may be referred to as an active agent chamber port cap 50.

[0136] The container includes a second port 51. The second port 51 may be referred to as a container exit port 51. The second port 51 may also be referred to as a dilution chamber port 51. The dilution chamber port 51 defines a dilution chamber opening 53. The dilution chamber opening 53 is an opening in the container 11 that allows access to the dilution chamber 25 and / or the interior of the container 11. The drug delivery system 1 includes a second port cap 52. The second port cap 52 may be referred to as a container exit port cap 52. The second port cap 52 may be referred to as a dilution chamber port cap 52. The dilution chamber port cap 52 is configured to cover the dilution chamber port 51.

[0137] Container fill port 49 allows for filling of container 11 with a pharmaceutical formulation. Diluent chamber port 51 allows for either (1) submitting diluent chamber 25 with a diluent or (2) allowing a mixture of active agent and diluent (pharmaceutical composition) to exit container 11 (specifically, from diluent chamber 25) for delivery to a patient.

[0138] As mentioned above, the container 11 includes an activator chamber opening 17. The activator chamber opening 17 is configured to receive at least a portion of the first plunger 13. In particular, the activator chamber 15 includes an activator chamber opening 17. The activator chamber port opening 49 may be considered as a second activator chamber opening. In other words, the activator chamber 15 may be said to include a second activator chamber opening configured to receive a pharmaceutical agent. The activator chamber port opening 49 is defined in a wall of the container 11. The activator chamber 15 may be filled with a pharmaceutical agent by introducing the pharmaceutical agent into the activator chamber 15 through the second activator chamber port opening 49. The activator chamber port 49 may therefore be referred to as an activator chamber inlet.

[0139] As mentioned above, the container 11 includes a dilution chamber port 51. In particular, the dilution chamber 25 includes a dilution chamber port 51. Thus, the second port 51 may be referred to as the dilution chamber port 51. The dilution chamber port 51 includes a dilution chamber opening 53. Thus, the dilution chamber port 51 may be considered as an exit port 51 of the drug delivery device 2 and / or the dilution chamber 25.

[0140] In the arrangement shown in the figure, the activator chamber port 49 and the diluent chamber port 51 are shown to include male luer lock connectors (i.e., first luer lock connectors). In alternative arrangements, for example, the activator chamber port 49 and / or the diluent chamber port 51 may include female luer lock connectors (i.e., second luer lock connectors).

[0141] The activator chamber port cap 50 may include a complementary luer lock connector to the luer lock connector of the activator chamber port 49. The activator chamber port cap 50 prevents fluid flow through the activator chamber port 49 while connected to the activator chamber port 49. The diluent chamber port cap 52 may include a complementary luer lock connector to the luer lock connector of the diluent chamber port 51. The diluent chamber port cap 52 prevents fluid flow through the diluent chamber port 51 while connected to the diluent chamber port 51.

[0142] The first plunger 13 and the second plunger 14 are each configured to be displaced relative to the longitudinal axis 21 of the container 11. The second plunger 14 is disposed between the first plunger 13 and the dilution chamber opening 53 (and the dilution chamber port 51). The second plunger 14 is disposed between the activator chamber port 49 (and the activator chamber port opening) and the dilution chamber opening 53.

[0143] The container 11 defines an inner container surface 55. The first plunger 13 includes a first plunger sealing surface 57. The first plunger 13 is configured to seal with the inner container surface 55. In particular, the first plunger 13 is configured to seal with the inner container surface 55 to prevent fluid flow between the inner container surface 55 and the first plunger sealing surface 57. The first plunger 13 is configured to seal with the first plunger sealing surface 57.

[0144] The second plunger 14 includes a second plunger sealing surface 59. The second plunger 14 is configured to seal with the inner container surface 55. In particular, the second plunger sealing surface 59 is configured to seal with the inner container surface 55 to prevent fluid flow between the inner container surface 55 and the second plunger sealing surface 59. The second plunger 14 is configured to seal with the second plunger sealing surface 59.

[0145] The drug delivery device 2 may comprise a conduit 23. The conduit 23 is configured to be fluidly connected to the dilution chamber opening 53. The conduit 23 has a predetermined volume. That is, the length and the internal surface area of ​​the conduit 23 are sized such that the conduit 23 defines a predetermined volume. Thus, the conduit 23 can hold or store a volume of the diluted pharmaceutical formulation before it is delivered to the patient. The conduit 23 may be referred to as a minimum volume extension tube. The conduit 23 is configured to maintain a first volume of injection to be delivered to the patient. The first injection volume may be prepared by a priming process at a rate that will result in effective mixing in the dilution chamber 25. This is possible because during this time no pharmaceutical formulation is delivered to the patient. Thus, during priming, a different flow rate may be used for the first volume while driving the mixed fluid exiting the dilution chamber 25 to the end of the conduit 23. Although the conduit 23 of the drug delivery device 2 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.

[0146] The injection device 3 comprises a computer system 5. The injection device 3 comprises a drive mechanism 9. The drive mechanism 9 may comprise a syringe driver. The drive mechanism 9 is controlled by the computer system 5. In particular, the computer system 5 is adapted to control the drive mechanism 9 in order to deliver a drug (contained in the drug delivery apparatus 2) to the patient in a specific manner, for example according to a flow rate delivery function.

[0147] The computer system 5 comprises at least one processor 27. The computer system 5 comprises a memory 29. The memory 29 may be in the form of random access memory (RAM). The computer system 5 comprises a data storage device 31. The computer system 5 comprises a user interface 33. The user interface 33 may include a display 35 and / or a keyboard 37. Certain components of the computer system 5 may communicate with one or more other components of the computer system 5 and / or the infusion device 3 via a system bus 39.

[0148] The at least one processor 27 is configured to execute the infusion device program instructions stored in memory 29 to cause the infusion device to function as described herein. In other words, the infusion device program instructions are accessible by the at least one processor 27 and are configured to cause the at least one processor 27 to function as described herein.

[0149] In some embodiments, the infusion device program instructions are in the form of program code. The at least one processor 27 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.

[0150] The memory 29 may comprise one or more volatile or non-volatile memory types. For example, the memory 29 may include one or more of a random access memory (RAM), a read only memory (ROM), an electrically erasable programmable read only memory (EEPROM), or a flash memory. The memory 29 is configured to store program code accessible by the at least one processor 27. The program code may include executable program code modules. In other words, the memory 29 is configured to store executable code modules configured to be executable by the at least one processor 27. The executable code modules, when executed by the at least one processor 27, cause the at least one infusion device processor 27 to perform certain functions, as described herein.

[0151] If the injection device 3 comprises a vacuum injection device 3 or is in the form of a vacuum injection device 3, the injection device 3 can apply an injection pressure (i.e., vacuum pressure 61) to the dilution chamber opening, thereby causing displacement of the first plunger 13, so that the pharmaceutical formulation is delivered by the drug delivery apparatus 2 at a target flow rate.

[0152] In some embodiments, the injection device 3 is configured to actuate the first plunger 13. The injection device 3 may be configured to actuate the injection device actuator to displace the first plunger 13 such that the pharmaceutical formulation is delivered by the drug delivery apparatus 2. The pharmaceutical formulation may be delivered at a target flow rate.

[0153] The computer system 5 may optionally include a drug library and database containing a maximum allowable drug administration rate for each particular drug that may be infused into the patient. If the expected drug delivery rate during use of the infusion device 3 (e.g., during execution of the flow rate delivery function) exceeds the maximum allowable drug administration rate, the infusion rate will be reduced according to the maximum allowable infusion rate such that the concentration of the drug leaving the dilution chamber 25 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.

[0154] During the method of injecting a pharmaceutical formulation according to the method of the present disclosure, the drug library may be accessed by computer system 5 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.

[0155] The processor 27 may execute instructions for controlling the drive mechanism 9 of the infusion device 3 to deliver the drug according to, for example, any of the flow rate delivery functions. The code executed by the processor 27 may be stored in the memory 29 of the computer system 5 or may be provided from an external source through the data storage device 31. This software will include instructions for controlling the drive mechanism of the infusion device 3 such that the pharmaceutical formulation exits the drug delivery apparatus 2 at a particular flow rate that matches or approximates the infusion rate of the pharmaceutical formulation as dictated by the flow rate delivery function.

[0156] Figures 4 and 5A-5E show a drug delivery apparatus 2 attached to an injection device 3, thereby forming a drug delivery system 1. The injection device 3 of Figures 4 and 5A-5E is in the form of a syringe driver 3. Figure 6 shows a first method 600 of operation of the drug delivery apparatus 2 according to some embodiments. The first method 600 of operation of the drug delivery apparatus 2 of Figures 5A-6 includes actuating the first plunger 13 by applying a force to the first plunger in a direction parallel to the longitudinal axis 21 of the drug delivery apparatus 2. The force is applied by an injection driver 9 contacting and pushing the first plunger 13. Figures 5A-6 show some steps involved in emptying the active agent chamber 15 and the dilution chamber 25 according to the first method 600.

[0157] 5A-5E, preparation of a pharmaceutical composition (i.e., a solution to be delivered by drug delivery device 2) involves depressing first plunger 13 such that the pharmaceutical formulation contained in active agent chamber 15 is delivered into diluent chamber 25 and mixes (via valve 39) with the diluent contained in diluent chamber 25. In FIG. 6, this step is shown at 602 and 604.

[0158] At 602, the drug delivery device 2 is in a priming state, in which the active agent chamber 15 is filled with the pharmaceutical formulation, the diluent chamber 25 is filled with diluent and the conduit 23 is primed with diluent.

[0159] 5A-5C and 602 and 604, the injection device 3 engages and actuates the first plunger 13. The injection device 3 actuates the first plunger 13 in a direction parallel to the longitudinal axis 21 of the drug delivery device 2. In Figs. 5A-5C and 604, the primary plunger 13 is pushed by the injection device 3 to deliver the pharmaceutical formulation into the diluent chamber 25 in cooperation with the valve means 39 to provide a specific mixing profile in the diluent chamber 25 to allow the pharmaceutical formulation to be properly mixed with the diluent.

[0160] When the pharmaceutical formulation contained in the active agent chamber 15 is delivered into the dilution chamber 25, mixing occurs to produce a pharmaceutical composition (in this case, a diluted pharmaceutical formulation), which is then delivered to the conduit 23 for injection into the patient. As the pharmaceutical composition is delivered into the conduit 23, the concentration of the active agent in the dilution chamber 25 increases as the pharmaceutical formulation is delivered into the dilution chamber 25 during injection.

[0161] In Figures 5D and 5E, and at 606-610 in Figure 6, the active agent chamber 15 is emptied; that is, the first plunger 13 is in contact with the second plunger 14, and further actuation of the first plunger 13 causes movement of the second plunger 14. Movement of the second plunger 14 displaces fluid in the dilution chamber 25 (i.e., the diluted pharmaceutical formulation, or pharmaceutical composition) through the dilution chamber port 51. The fluid in the dilution chamber 25 is displaced into the conduit 23 for delivery to the patient.

[0162] To deliver the pharmaceutical composition to the patient, the first plunger 13 is pushed (with the second plunger 14 abutting the primary plunger 13) in such a manner that the pharmaceutical composition is delivered according to a particular profile. In particular, the first plunger 13 is driven based on a particular algorithm.

[0163] Initially, the first plunger 13 is driven based on a particular algorithm and before the conduit 23 is fluidly connected to the patient, the injection device 3 is operated to drive the first plunger 13 in such a manner as to fill (i.e., prime) the conduit 23 so that it is fluidly connected to the patient for delivery of the pharmaceutical composition.

[0164] Alternatively, in some embodiments, the conduit 23 is filled with diluent before the first plunger 13 is driven based on a particular algorithm and the conduit 23 is fluidly connected to the patient. The injection device 3 may then deliver the volume required to displace the volume of diluent in the conduit 23 to the patient and fill the conduit 23 with the diluted pharmaceutical formulation before the first plunger 13 is driven based on a particular algorithm.

[0165] FIG. 7 illustrates a second method 700 of operation of the drug delivery device 2, according to some embodiments. The second method 700 of operation of the drug delivery device 2 includes actuating the first plunger 13 by applying a vacuum pressure 61 to the diluent chamber port 51. The force may be applied by a vacuum pump of the injection driver 3. The vacuum pressure 61 applies a force to the first plunger 13. The force moves the first plunger 13 towards the second plunger 14 in a direction parallel to the longitudinal axis 21 of the drug delivery device 2. FIG. 7 illustrates a number of steps involved in emptying the active agent chamber 15 and the diluent chamber 25 according to the second method 700.

[0166] At 702, the drug delivery device is in a priming state, in which the active agent chamber 15 is filled with the pharmaceutical formulation, the diluent chamber 25 is filled with diluent and the conduit 23 is primed with diluent.

[0167] At 704, the injection device 3 applies a vacuum pressure 61 to the dilution chamber port 51. The vacuum pressure 61 may be applied via the conduit 23. As described herein, the drug delivery device 2 is configured such that the first plunger 13 is moved by the vacuum pressure 61. The first plunger 13 is initially moved by the vacuum pressure 61 without significant movement of the second plunger 14. At 704, the first plunger 13 moves, thereby displacing the pharmaceutical formulation from the active agent chamber 15 through the valve 39 and into the dilution chamber 25. The movement of the first plunger 13 also displaces the pharmaceutical composition (i.e., the diluted pharmaceutical formulation in the dilution chamber 25) through the dilution chamber port 51. The drug delivery device 2 is shown at 704 in a first intermediate state. In the first intermediate state, the first plunger 13 has partially emptied the pharmaceutical formulation from the active agent chamber 15.

[0168] At 706, the first plunger 13 contacts the second plunger 14. The injection device 3 continues to apply vacuum pressure 61 causing movement of both the first plunger 13 and the second plunger 14. Movement of the first plunger 13 and the second plunger 14 displaces fluid in the dilution chamber 25 (pharmaceutical composition) through the dilution chamber port 51.

[0169] At 708, the first plunger 13 and the second plunger 14 are both moved by the vacuum pressure 61. The drug delivery device 2 is shown at 708 in a second intermediate state. In the second intermediate state, the first plunger 13 and the second plunger 14 have partially emptied the pharmaceutical composition from the dilution chamber 25.

[0170] At 710, the second plunger 14 contacts the container 11. In particular, the second plunger 14 contacts the distal end 63 of the container 11. At this point, both the activator chamber 15 and the diluent chamber 25 are empty.

[0171] Method 800 for preparing drug delivery device 2 Figure 8 shows a method 800 for preparing the drug delivery device 2 of Figures 1-5E, according to some embodiments. At 802, the drug delivery device 2 is in an initial state. In the initial state, the first plunger 13 is in contact with the second plunger 14. Furthermore, the second plunger is in contact with the distal end 63 of the container 11.

[0172] The clinician covers the active agent chamber port 49 with the active agent chamber port cap 50. The clinician connects the fill conduit 65 to the diluent chamber port 51 of the drug delivery device 2. The fill conduit 65 may include a luer lock connector complementary to the luer lock connector of the diluent chamber port 51. The fill conduit 65 may be in the form of a needle.

[0173] The clinician inserts the distal end of the fill conduit 65 into the diluent container 67. The diluent container 67 contains a diluent. The clinician inserts the distal end of the fill conduit 65 into the diluent stored in the diluent container 67.

[0174] At 804, the clinician moves the first plunger 13 away from the diluent chamber port 51. Moving the first plunger 13 away from the diluent chamber port 51 pulls the second plunger 14 along with the first plunger 13 away from the diluent chamber port 51 because a substantially airtight seal exists between the first plunger 13 and the second plunger 14. Moving the first plunger 13 away from the diluent chamber port 51 also draws diluent from the diluent container 67 into the drug delivery device 2.

[0175] Moving the first plunger 13 away from the diluent chamber port 51 increases the volume of the diluent chamber 25. The increased diluent chamber 25 volume is occupied by diluent that is withdrawn through the second outlet 51. The clinician moves the first plunger 13 (and the second plunger 14) away from the diluent chamber port 51 to the initial diluent chamber plunger position. The diluent chamber 25 is the initial diluent chamber volume when the first plunger 13 is in the initial diluent chamber plunger position. The initial diluent chamber volume may relate to the volume of diluent that will be provided to the patient during an injection. For example, the initial diluent chamber volume may be greater than the volume of diluent that will be provided to the patient during an injection.

[0176] At 806, the clinician removes the fill conduit 65 from the diluent chamber port 51. The clinician moves the drug delivery device 2 so that the diluent chamber port 51 faces in the upward direction 69. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to move any air bubbles that may be present in the diluent in the diluent chamber 25 toward the diluent chamber port 51. The clinician then moves the first plunger 13 (and the second plunger 14) toward the diluent chamber port 51 to the diluent chamber plunger position, thereby pushing excess air out of the diluent chamber port 51. The diluent chamber 25 is the diluent chamber injection volume when the first plunger 13 is in the diluent chamber plunger position. The injection volume of the diluent chamber may relate to the volume of diluent that will be provided to the patient during injection. For example, the injection volume of the diluent chamber may correspond to the volume of diluent that will be provided to the patient during injection.

[0177] At 808, the clinician covers the diluent chamber port 51 with a diluent chamber port cap 52. The diluent chamber port cap 52 may include a luer lock connector that is complementary to the luer lock connector of the diluent chamber port 51. The diluent chamber port cap 52 prevents fluid flow through the diluent chamber port 51 while connected to the diluent chamber port 51.

[0178] The clinician removes the activator chamber port cap 50 from the activator chamber port 49. The clinician connects the outlet of the filling syringe 71 to the activator chamber port 49. The filling syringe 71 contains the pharmaceutical formulation to be used for injection in the filling syringe chamber 72.

[0179] At 810, the clinician actuates the filling syringe plunger 73 of the filling syringe 71. Actuation of the filling syringe plunger 73 displaces the pharmaceutical formulation through the outlet of the filling syringe 71 and into the drug delivery device 2. The pharmaceutical formulation applies pressure to the first plunger 13, causing displacement of the first plunger 13 within the container 11. The pressure applied by the pharmaceutical formulation moves the first plunger 13 away from the second plunger 14.

[0180] Alternatively, the clinician can move the first plunger 13 away from the second plunger 14, increasing the volume of the active agent chamber 15. This creates a vacuum pressure at the outlet of the filling syringe 71, displacing the pharmaceutical formulation from the filling syringe 71 into the active agent chamber 15.

[0181] Moving the first plunger 13 away from the second plunger 14 increases the volume of the active agent chamber 15. The increased volume of the active agent chamber 15 is occupied by the pharmaceutical formulation. The first plunger 13 is moved to an initial active agent chamber first plunger position. The active agent chamber 15 is the initial active agent chamber volume when the first plunger 13 is in the initial active agent chamber first plunger position. The initial active agent chamber volume may relate to the volume of the pharmaceutical formulation that will be provided to the patient during injection. For example, the initial active agent chamber volume may be larger than the volume of the pharmaceutical formulation that will be provided to the patient during injection.

[0182] At 812, the clinician removes the filled syringe 71. The clinician moves the drug delivery device 2 so that the first port 51 faces generally in the upward direction 69. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to move any air bubbles that may be in the pharmaceutical formulation in the activator chamber 15 toward the activator chamber port 49. The clinician then moves the first plunger 13 toward the activator chamber plunger position toward the activator chamber port 49, thereby pushing any air remaining in the activator chamber 15 through the activator chamber port 49. The activator chamber 15 is at the activator chamber injection volume when the first plunger 13 is at the activator chamber plunger position. The activator chamber injection volume may relate to a volume of the pharmaceutical formulation that will be provided to the patient during an injection. For example, the injection volume of the activator chamber may correspond to a volume of the pharmaceutical formulation that will be provided to the patient during an injection.

[0183] At 814, the clinician covers the active agent chamber port 49 with the active agent chamber port cap 50. The drug delivery device 2 may be stored for a later injection or may be used in an injection.

[0184] Method 900 for preparing a drug delivery device 2 9 illustrates a method 900 of preparing the drug delivery device 2 of FIGS. 1-5E, according to some embodiments. At 902, the drug delivery device 2 is in an initial state. In the initial state, the first plunger 13 is in contact with the second plunger 14. Furthermore, the second plunger 14 is in contact with the distal end 63 of the container 11. In the initial state, the activator chamber port cap 50 and the diluent chamber port cap 52 are not connected to the drug delivery device 2.

[0185] At 904, the clinician moves the first plunger 13 away from the diluent chamber port 51. Moving the first plunger 13 away from the diluent chamber port 51 pulls the second plunger 14 along with the first plunger 13 away from the diluent chamber port 51 because a substantially airtight seal exists between the first plunger 13 and the second plunger 14. The clinician pulls the first plunger 13 away from the diluent chamber port 51 and through the activator chamber port 49.

[0186] As the first plunger 13 is moved through the activator chamber port 49, the substantially airtight seal between the first plunger 13 and the second plunger 14 is broken by the activator chamber port 49. That is, air can enter the drug delivery device between the first plunger 13 and the second plunger 14 via the activator chamber port opening 54. Thus, the second plunger 14 stops moving with the first plunger 13 as the first plunger 13 moves further away from the diluent chamber port 51. The second plunger 14 is left in the diluent chamber plunger position.

[0187] At 906 and 908, the clinician fills the diluent chamber 25 with diluent using a first filling syringe 71. The first filling syringe 71 includes a first filling syringe chamber 72 that contains the diluent. The first filling syringe 71 includes a first filling syringe conduit 75, which may be, for example, a needle. At 906, the clinician inserts the first filling syringe conduit 75 into the diluent chamber port 51.

[0188] At 908, the clinician actuates the first fill syringe plunger 73 to displace diluent from the first fill syringe chamber 72, through the first fill syringe conduit 75, and into the diluent chamber 25. The outer diameter of the first fill syringe conduit 75 is smaller than the inner diameter of the opening of the diluent chamber port 51. Thus, any air bubbles present in the diluent when displaced into the diluent chamber 25 can pass through the first fill syringe conduit 75 and out of the diluent chamber 25 during filling.

[0189] At 910, the clinician covers the second outlet 51 with the diluent chamber port cap 52. The clinician then moves the first plunger 13 to the activator chamber plunger position. The activator chamber plunger position corresponds to the required amount of pharmaceutical preparation (i.e., the required volume of the activator chamber 15).

[0190] At 912, the clinician fills the active agent chamber 15 with a pharmaceutical formulation using a second filling syringe 71A. The second filling syringe 71A includes a second filling syringe chamber 72A that contains the pharmaceutical formulation. The second filling syringe 71A includes a second filling syringe conduit 75A, which may be, for example, a needle. The clinician inserts the second filling syringe conduit 75A into the active agent chamber port 49.

[0191] The clinician actuates second filling syringe plunger 73A to displace the pharmaceutical formulation from second filling syringe chamber 72A through second filling syringe conduit 75A and into activator chamber 15. The outer diameter of second filling syringe conduit 75A is smaller than the inner diameter of activator chamber port opening 54. Thus, any air bubbles present in the pharmaceutical formulation when displaced into activator chamber 15 can pass through second filling syringe conduit 75A during filling and out of activator chamber port opening 54.

[0192] At 914, the clinician covers the active agent chamber port 49 with the active agent chamber port cap 50. The drug delivery device 2 is then in a storage state where it can be stored for a later injection or used in an injection.

[0193] Drug delivery device 2 with a concave first plunger and a biconvex second plunger FIG. 10 shows an example of a drug delivery device 2 in which the first and second plungers have a particular shape. Like reference numbers indicate like parts to the previous figures. The first plunger 13 has a concave surface 13A facing the second plunger. The second plunger 14 may be described as biconvex, having a convex surface 14A facing the first plunger and a convex surface 14B facing the distal end of the reservoir and dilution chamber opening 51. The dilution chamber opening may be closed by attaching an end cap 52 to prevent the escape of fluid from the opening. In this example, the valve 39 projects outwardly from the second plunger 14. This may help maintain separation of the second plunger from the distal end of the reservoir 11. In other examples, the valve 39 may not project outwardly. In still other examples, the valve 39 may be entirely contained within the second plunger to protect the valve 39 from distortion due to contact with the reservoir wall or the dilution chamber opening 51. The first plunger 13 may include a gasket portion and a shaft 94 extending from the gasket portion back to the proximal end of the container 11. The shaft 94 may have a lumen 93 to allow for fluid flow through the first plunger 13 and into the active agent chamber 15. The lumen 93 may be used, for example, to fill the active agent chamber 15 with a pharmaceutical formulation or to aspirate air from the active agent chamber 15.

[0194] The opposing surfaces 13A, 14A of the first and second plungers may at least partially coincide with one another. This minimizes or prevents the pharmaceutical formulation from being trapped between the first and second plungers, thereby minimizing wastage of the pharmaceutical formulation. Because the surface 14B of the second plunger facing the dilution chamber opening 52 is concave, this may help minimize wastage of the pharmaceutical formulation, as it allows all or most of the fluid to be expelled from the dilution chamber as the second plunger moves into contact with the distal end of the container, particularly if the inner surface of the distal end of the container 11 is convex. Further examples of concave first plungers and biconvex second plungers are described below in FIG. 26.

[0195] FIG. 11 shows an example of a cap 107 that may be attached to the distal end of the first plunger 13. As shown, the cap 107 is attached to the shaft 94 of the first plunger 13. The cap 107 may have multiple struts 107A-107C or other support structure to prevent bending of the cap 107 when the first plunger is pushed into the container 11. This helps improve the accuracy of the device, as bending of the cap 107 can cause inaccuracies and make it difficult to move the first plunger to a desired position when filling the device or during injection. The cap 107 may further include a central portion 107D within the struts, which may be threaded into the plunger lumen. The cap 107 may have an end plate 107E supported by posts 107A-107C, which may form a surface against which a syringe-driven actuator or a clinician can press to move the first plunger 13 towards the distal end of the container 11.

[0196] Drug delivery device 2 with plunger lumen 93 Figure 12 shows a perspective view of a cross section of another embodiment of a drug delivery device 2, according to some embodiments. Figure 13A is a schematic cross-sectional view of the drug delivery device 2 of Figure 12 when empty. Figure 13B is a schematic cross-sectional view of the drug delivery device 2 when filled with a diluent and a pharmaceutical formulation.

[0197] 12, 13A and 13B, the drug delivery device 2 comprises several features similar or the same as other embodiments of the drug delivery device 2 described herein. It will be understood that the drug delivery device 2 of FIG. 12 may comprise features and / or components of other embodiments of the drug delivery device 2 described herein.

[0198] The drug delivery device 2 comprises a first plunger 13. The drug delivery device 2 comprises a second plunger 14. The drug delivery device 2 comprises a container 11. The container 11 is configured to receive the second plunger 14. The container 11 is configured to receive at least a portion of the first plunger 13. The container 11 and the second plunger define a diluent chamber 25 configured to receive a diluent. The diluent chamber 25 may be as described herein with reference to other embodiments of the drug delivery device 2. The first plunger 13, the container 11, and the second plunger 14 define an active agent chamber 15. The active agent chamber 15 is configured to receive a pharmaceutical formulation. The active agent chamber 15 may be as described herein with reference to other embodiments of the drug delivery device 2.

[0199] The container 11 comprises a dilution chamber port 51. The dilution chamber port 51 defines a dilution chamber opening 53. The dilution chamber port 51 and / or the dilution chamber opening 53 are configured to allow a flow of fluid into and out of the dilution chamber 25 and / or the container 11. The dilution chamber port 51 and / or the dilution chamber opening 53 may be the same as or similar to the dilution chamber port 51 and / or the dilution chamber opening 53 described herein with reference to other embodiments of the drug delivery device 2. The drug delivery device 2 comprises a dilution chamber port cap 52. The dilution chamber port cap 52 may be the same as or similar to the dilution chamber port cap 52 described herein with reference to other embodiments of the drug delivery device 2. The dilution chamber port cap 52 is configured to connect to the container 11 and cover the dilution chamber opening 53.

[0200] The second plunger 2 comprises a valve 39. The valve 39 is configured to control the flow of the pharmaceutical formulation from the active agent chamber 15 to the diluent chamber 25. The valve 39 may be the same as or similar to the valves 39 described herein with reference to other embodiments of the drug delivery device 2. For example, the valve 39 comprises a valve inlet side 45 and a valve outlet side 47. The valve 39 is configured to move from a closed position to an open position when pressure is applied to the inlet side 45, as described herein. The valve 39 is configured to move from an open position to a closed position when pressure applied to the inlet side 45 is removed, as described herein.

[0201] The first plunger 13 includes a plunger lumen 93. The plunger lumen 93 extends between a first plunger lumen opening 95 and a second plunger lumen opening 97. The plunger lumen 93 extends through a shaft 94 of the first plunger 13. The shaft 94 may also be referred to as a rod. In use, the plunger lumen 93 is generally parallel to the longitudinal axis 21 of the drug delivery device 2. The active agent chamber 15 is configured to receive a pharmaceutical formulation through the plunger lumen 93.

[0202] The first plunger lumen opening 95 is a plunger lumen inlet. The first plunger lumen opening 95 is configured to receive a pharmaceutical formulation to be provided through the plunger lumen 93. The second plunger lumen opening 97 is a plunger lumen outlet. The second plunger lumen opening 97 is configured to allow the pharmaceutical formulation in the plunger lumen 93 to flow into the active agent chamber 15.

[0203] The first plunger 13 includes a first plunger connector 96. The first plunger connector 96 is in the form of a first luer lock connector. The first plunger connector 96 defines a first plunger lumen opening 95.

[0204] The first plunger 13 includes a first plunger O-ring 99. The first plunger O-ring 99 includes a first plunger sealing surface 101. The first plunger 13 is configured to seal with the vessel 11 to provide a first seal. In particular, the first plunger sealing surface 101 is configured to seal with the inner vessel surface 55 to prevent fluid flow between the inner vessel surface 55 and the first plunger sealing surface 101.

[0205] Alternatively, in some embodiments, the first plunger 13 comprises a first plunger sealing portion. The first plunger sealing portion may be an elastomeric portion. The first plunger sealing portion may be as described herein. The first plunger sealing portion may be configured to seal with the inner container surface 55 to prevent fluid flow between the inner container surface 55 and the first plunger sealing surface 101. In some embodiments, the first plunger sealing portion comprises a protruding portion. The protruding portion may extend around the circumference of the first plunger 13. The protruding portion may be configured to seal with the inner container surface 55 to prevent fluid flow between the inner container surface 55 and the first plunger sealing surface 101.

[0206] The first plunger 13 includes a one-way valve (not shown). The one-way valve may be disposed at the distal end 64 of the first plunger 13. For example, the one-way valve may define a second plunger lumen opening 97 when open. The one-way valve advantageously allows fluid to flow through the plunger lumen 93 from the first plunger lumen opening 95 to the activator chamber 15 once the fluid has entered the activator chamber 15 without flowing in the reverse direction.

[0207] The drug delivery device 2 includes a first plunger cap 107. The first plunger cap 107 is configured to connect to the first plunger 13. In particular, the first plunger cap 107 is configured to connect to the first plunger 13 and cover the first plunger lumen opening 95. The first plunger cap 107 is configured to connect to the first plunger connector 96. Thus, the first plunger cap 107 may include a complementary connector (e.g., a complementary luer lock connector) of the first plunger connector 96. In the illustrated embodiment, the first plunger cap 107 includes a second luer lock connector configured to connect with the first luer lock connector of the first plunger 13 (i.e., the luer lock connector of the first plunger connector 96).

[0208] The second plunger 14 is disposed between the first plunger 13 and the dilution chamber opening 53. The second plunger 14 includes a second plunger O-ring 103. The second plunger O-ring 103 includes a second plunger sealing surface 105. The second plunger 14 is configured to seal with the vessel 11 to provide a second seal. In particular, the second plunger sealing surface 105 is configured to seal with the inner vessel surface 55 to prevent fluid flow between the inner vessel surface 55 and the second plunger sealing surface 105.

[0209] Alternatively, in some embodiments, the second plunger 14 comprises a second plunger sealing portion. The second plunger sealing portion may be an elastomeric portion. The second plunger sealing portion may be as described herein, for example, with reference to FIGS. 27A and 27B. The second plunger sealing portion may be configured to seal with the inner container surface 55 to prevent fluid flow between the inner container surface 55 and the second plunger sealing surface 105. In some embodiments, the second plunger sealing portion comprises a protruding portion. The protruding portion may extend around the circumference of the second plunger 14. The protruding portion may be configured to seal with the inner container surface 55 to prevent fluid flow between the inner container surface 55 and the second plunger sealing surface 105.

[0210] The first plunger 13 is configured for displacement within the container 11 relative to a longitudinal axis 21 of the container 11. The second plunger 14 is configured for displacement within the container 11 relative to a longitudinal axis 21 of the container 11.

[0211] The breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13, as described in more detail herein. The valve threshold force of the valve 39 is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14, as described in more detail herein. For example, this approach may be used when the injection device is a vacuum pump. In some embodiments, the valve threshold force is less than the breakaway force of the second plunger 14. For example, this approach may be used when the injection device is a syringe driver. The valve threshold force is the force required to open the valve. Because the valve is part of the second plunger, when the valve is open and fluid is flowing through the valve, this fluid flow applies some force to the second plunger in the direction of the fluid flow. This force on the second plunger caused by the flow of fluid through the open valve is referred to as the valve opening force. The valve opening force may be proportional to the resistance of the open valve. The device may be designed so that the opening force, even at high flow rates, is less than the breakaway force of the second plunger 14, so that the second plunger is not displaced by high flow rates through the valve.

[0212] The drug delivery device 2 comprises a conduit (not shown). The conduit is configured to be fluidly connected to the dilution chamber opening 53. The conduit has a predetermined volume. The conduit of the drug delivery device 2 shown with respect to Figure 12 may be similar or the same as the conduit 23 described elsewhere herein.

[0213] As shown in Figures 13A and 13B, the first plunger 13 includes a distal end 64. The distal end 64 of the first plunger 13 is configured to contact the second plunger 14. The distal end 64 of the first plunger 13 is convex, e.g., conical. The distal end 64 of the first plunger 13 includes an apex 66. The distal end 64 of the first plunger 13 includes a base 68. In the illustrated configuration, the apex 66 is in a central portion of the distal end 64 of the first plunger 13. The apex 66 is closer to the valve 39 of the second plunger 14 than the base 88. The apex 66 is closer to the diluent chamber port 51 than the base 68.

[0214] The second plunger 14 includes a proximal end 70. The proximal end 70 of the second plunger 14 is configured to contact the first plunger 13. The proximal end 70 of the second plunger 14 may be concave, e.g., have an inverted conical profile. That is, the proximal end 70 of the second plunger 14 defines a recess, e.g., a conical recess. The proximal end 70 of the second plunger 14 is configured to receive the convex, e.g., conical, distal end 64 of the first plunger 13. In another example, the distal end 66 of the first plunger may be concave and the proximal end 70 of the second plunger may be convex, as depicted in FIGS. 10 and 26.

[0215] Method 1400 for preparing a drug delivery device 2 Figure 14 illustrates a method 1400 for preparing a drug delivery device 2 as described with reference to Figures 12-13B, according to some embodiments, for preparing a drug delivery device 2 including a plunger lumen 93 as described herein.

[0216] At 1402, the drug delivery device 2 is in an initial state. In the initial state, the first plunger 13 is in contact with the second plunger 14. Furthermore, the second plunger 14 is in contact with the distal end 63 of the container 11. In the initial state, the dilution chamber port cap 52 is connected to the drug delivery device 2.

[0217] At 1404, the clinician removes the first plunger cap 107. The clinician connects the filled syringe 71 to the first plunger connector 96.

[0218] At 1406, the clinician fills the active agent chamber 15 with a pharmaceutical formulation using a first filling syringe 71. The first filling syringe 71 includes a first filling syringe chamber 72 that contains the pharmaceutical formulation. The clinician actuates the first filling syringe plunger 73 to displace the pharmaceutical formulation from the first filling syringe chamber 72, through the plunger lumen 93, and into the active agent chamber 15.

[0219] At 1408, the clinician removes the first filling syringe 71 and moves the drug delivery device 2 so that the diluent chamber port 51 faces in the upward direction 69. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to move any air bubbles that may be in the pharmaceutical formulation in the active agent chamber 15 towards the valve 39 and the diluent chamber port 51. The clinician then moves the first plunger 13 towards the diluent chamber port 51. This displaces any air bubbles that may be present in the pharmaceutical formulation from the valve 39 and the second outlet 51.

[0220] At 1410, the clinician moves the first plunger 13 away from the second outlet 51. This also moves the second plunger 14 away from the second outlet 51, thereby creating a volume of the dilution chamber 25.

[0221] At 1412, the clinician fills the diluent chamber 25 with diluent using a second filling syringe 71A. The second filling syringe 71A includes a second filling syringe chamber 72A that contains the diluent. The second filling syringe 71A includes a second filling syringe conduit 75A, which may be, for example, a needle. The clinician inserts the second filling syringe conduit 75A into the diluent chamber port 51.

[0222] The clinician actuates the second fill syringe plunger 73A to displace diluent from the second fill syringe chamber 72A through the second fill syringe conduit 75A and into the diluent chamber 25. The outer diameter of the second fill syringe conduit 75A is smaller than the inner diameter of the diluent chamber opening 53. Thus, any air bubbles present in the diluent when displaced into the diluent chamber 25 can pass through the second fill syringe conduit 75A and out of the diluent chamber 25 during filling.

[0223] At 1414, the clinician covers the dilution chamber port 51 with the dilution chamber port cap 52. The drug delivery device 2 is then in a storage state and can be stored for a later injection or can be used in an injection.

[0224] Alternative First Plunger 13 and Second Plunger 13 Configurations 13A and 13B, the first plunger 13 includes a conical distal end 64 and the second plunger 14 includes a proximal end 70 having an inverted conical profile configured to receive the conical distal end 64 of the first plunger 13. FIG. 15 illustrates an embodiment of a drug delivery device 2 including an alternative first plunger 13 and an alternative second plunger 14.

[0225] The distal end 80 of the first plunger 13 of the drug delivery device 2 of FIG. 15 is configured to contact the second plunger 14. However, in this case, the distal end 70 of the second plunger 14 is conical. The distal end 70 of the second plunger 14 comprises an apex 76. The distal end 70 of the second plunger 14 comprises a base 78. In the illustrated configuration, the apex 76 is at a central portion of the proximal end of the second plunger 14. The apex 76 is further away from the valve 39 of the second plunger 14 in a direction parallel to the longitudinal axis 21 than the base 78. Similarly, the apex 76 is further away from the diluent chamber port 51 in a direction parallel to the longitudinal axis 21 than the base 78.

[0226] The first plunger 13 includes a proximal end 80. The proximal end 80 of the first plunger 13 is configured to contact the second plunger 14. The proximal end 80 of the first plunger 13 has an inverted conical profile. That is, the proximal end 80 of the first plunger 13 defines a conical recess. The proximal end 80 of the first plunger 13 is configured to receive the conical proximal end 70 of the second plunger 14.

[0227] Method 1600 for preparing a drug delivery device 2 Figure 16 illustrates a method 1600 for preparing a drug delivery device 2 as described with reference to Figure 15 according to some embodiments, namely, for preparing a drug delivery device 2 comprising a second plunger 14 having a proximal end 70 with a conical profile and a first plunger 13 having a distal end with an inverted conical profile configured to receive the proximal end 70 of the second plunger, as described herein.

[0228] At 1602, the drug delivery device 2 is in an initial state. In the initial state, the first plunger 13 is in contact with the second plunger 14. Furthermore, the second plunger 14 is in contact with the distal end 63 of the container 11. In the initial state, the dilution chamber port cap 52 is connected to the drug delivery device 2.

[0229] At 1604, the clinician removes the first plunger cap 107. The clinician connects the filled syringe 71 to the first plunger connector 96.

[0230] At 1606, the clinician fills the active agent chamber 15 with a pharmaceutical formulation using a first filling syringe 71. The first filling syringe 71 includes a first filling syringe chamber 72 that contains the pharmaceutical formulation. The clinician actuates the first filling syringe plunger 73 to displace the pharmaceutical formulation from the first filling syringe chamber 72, through the plunger lumen 93, and into the active agent chamber 15.

[0231] At 1808, the clinician removes the first filling syringe 71. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to displace any air bubbles that may be present in the pharmaceutical formulation in the active agent chamber 15 toward the second plunger lumen opening 97 of the first plunger 13. Because the distal end 80 of the first plunger 13 has an inverted cone profile, the air in the pharmaceutical formulation accumulates in the second plunger lumen opening 97 of the first plunger 13. The clinician then moves the first plunger 13 toward the diluent chamber port 51. This displaces any air bubbles that may be present in the pharmaceutical formulation from the plunger lumen 93 and the first plunger lumen opening 95 of the first plunger 13. Alternatively, the clinician may remove the air before removing the first filling syringe 71. To accomplish this, the clinician may actuate the first filling syringe plunger 73 to create a vacuum pressure and draw air into the first filling syringe 71 .

[0232] At 1610, the clinician reconnects the first plunger cap 107 to the first plunger connector 96. The clinician removes the diluent chamber port cap 52 from the diluent chamber port 51. The clinician moves the first plunger 13 away from the second outlet 51. This also moves the second plunger 14 away from the second outlet 51, thereby creating a volume of the diluent chamber 25.

[0233] At 1612, the clinician fills the diluent chamber 25 with diluent using a second filling syringe 71A. The second filling syringe 71A includes a second filling syringe chamber 72A that contains the diluent. The second filling syringe 71A includes a second filling syringe conduit 75A, which may be, for example, a needle. The clinician inserts the second filling syringe conduit 75A into the diluent chamber port 51.

[0234] The clinician actuates the second filling syringe plunger 73A to displace diluent from the second filling syringe chamber 72A through the second filling syringe conduit 75A and into the diluent chamber 25. The outer diameter of the second filling syringe conduit 75A is smaller than the inner diameter of the opening of the diluent chamber port 51. Thus, any air bubbles present in the diluent when displaced into the diluent chamber 25 can pass through the second filling syringe conduit 75A and out of the diluent chamber 25 during filling.

[0235] At 1614, the clinician covers the dilution chamber port 51 with the dilution chamber port cap 52. The drug delivery device 2 is then in a storage state and can be stored for a later injection or can be used in an injection.

[0236] Various exemplary methods have been described above in which the drug delivery device is provided to the clinician (e.g., from a factory or storage location) with the activator chamber and the diluent chamber empty, and the clinician fills the chambers prior to use. Two further exemplary methods of filling the activator chamber and the diluent chamber will now be described with reference to Figures 17 and 18.

[0237] In both of these exemplary methods, prior to filling the dilution chamber, the second plunger 14 (also referred to as the "separation plunger") is positioned in a starting position that defines the initial volume of the dilution chamber 25 that the dilution chamber will have at the start of injection.

[0238] The device may be provided to the clinician (e.g., from a factory or storage) with the second plunger 14 in an initial position that is the same as the starting position, or in an initial position that is further from the distal end of the container than the starting position. If the initial position is not the same as the starting position, the clinician moves the second plunger to the starting position as a first part of the filling process. This movement of the second plunger before filling the active agent and diluent chamber ensures that any high compression of the separation plunger against the walls of the syringe that may have occurred during storage can be broken, and also ensures that the clinician has confirmed that the secondary plunger is in the correct starting position before use. If the initial position of the second plunger is the same as the starting position, there are fewer steps to fill the device, but still helps ensure that the secondary plunger is in the correct starting position before injection.

[0239] The container 11 may have markings indicating the starting position that the second plunger will be positioned in the container at the start of an injection. This assists the clinician in locating the second plunger and moving it to the starting position if the second plunger is not in the starting position. The container may also have markings indicating the initial position of the second plunger (if the initial position is different from the starting position) and / or the starting position of the first plunger that the first plunger will have at the start of an injection.

[0240] In some examples, the starting position is positioned such that the dilution chamber has a volume of 10 mL when the second plunger is in the starting position. In some examples, the initial position of the second plunger is in a position that provides a dilution chamber volume of 15 mL. In this case, the clinician moves the second plunger from the 15 mL mark to the 10 mL mark.

[0241] 17, the first plunger 13 is retracted and the end cap 52 is removed prior to injecting the pharmaceutical formulation into the active agent chamber 15. This allows air to escape from the open end of the syringe as the pharmaceutical formulation is injected.

[0242] With reference to FIG. 17, in a first step 17-1, the drug delivery device is received by the clinician. The device has an empty diluent chamber and an empty activator chamber. The clinician may remove the device from the sterile packaging at this stage. In a second step 17-2, the end cap 52 is cut off and the first plunger 13 is pushed further into the container to push the second plunger to a starting position (through air pressure in the gap between the first and second plungers). The starting position may be indicated by marking on the container. In other examples, the device may be provided with the second plunger already in the starting position. In block 17-3, the plunger lumen cap (also referred to as the "axial filling cap") is cut off and the first plunger is then retracted to the starting position of the first plunger. The starting position of the first plunger may be marked, for example, on the container 11 or may be found by retracting the first plunger until a gasket or other portion of the first plunger contacts a lip, flange or protrusion of the container, thereby stopping retraction of the first plunger. The first plunger may be retracted without moving the second plunger because air can flow through the plunger lumen and into the activator chamber 15 between the first and second plungers.

[0243] In step 17-4, the pharmaceutical formulation is injected into the active agent chamber, for example, by connecting a pharmaceutical formulation syringe containing the pharmaceutical formulation to the plunger lumen and injecting the pharmaceutical formulation through the plunger lumen into the active agent chamber. In this step, the device is positioned (e.g., held) with the dilution chamber opening facing upward.

[0244] In step 17-5, end cap 52 is replaced over the dilution chamber opening. The device is then rotated in the opposite direction so that the dilution chamber opening faces downward, and the pharmaceutical formulation syringe is used to remove (e.g., aspirate) any air bubbles that have formed in active agent chamber 25.

[0245] In step 17-6, the plunger lumen cap is replaced on the plunger lumen. In step 17-7, the pharmaceutical formulation syringe may be disconnected from the dilution chamber opening.

[0246] In step 17-8, diluent is injected into the diluent chamber. For example, end cap 25 may be removed from the diluent chamber opening and a diluent syringe used to inject diluent into the diluent chamber through the diluent chamber opening. In step 17-9, the diluent syringe may be removed from the diluent chamber opening, degassing may be performed, and end cap 25 may be replaced over the diluent chamber opening.

[0247] The filling method shown in Figure 18 is similar to that of Figure 17, with the main difference being that the end cap 52 is in place and the first plunger 13 is adjacent to the second plunger 2 prior to injecting or aspirating the pharmaceutical formulation into the active agent chamber. Aspirating by moving the plunger rod 94 away from the drug chamber (and the end cap 52 is in place over the end of the syringe) helps ensure that no positive pressure is created in the active agent chamber that could inadvertently inject the pharmaceutical formulation into the empty diluent chamber.

[0248] In steps 18-1 and 18-2, the end cap 25 is removed and the first plunger is moved to move the second plunger to the starting position, similar to step 32-2 of FIG. 32. In step 18-3, the end cap 25 is replaced over the dilution chamber opening. In step 18-4, the plunger lumen cap is removed from the plunger lumen. In step 18-5, the device is positioned with the dilution chamber opening facing upwards and the pharmaceutical formulation syringe is used to inject the pharmaceutical formulation into the activator chamber through the plunger lumen, and any remaining air in the activator chamber is aspirated downwards and drawn into the pharmaceutical formulation syringe. In step 18-6, the device is reoriented so that the dilution chamber opening faces downwards and air is aspirated from the activator chamber into the pharmaceutical formulation syringe. In step 18-7, the plunger lumen cap is replaced over the plunger lumen and the end cap 25 is removed from the dilution chamber opening. In step 18-8, the device is reoriented so that the diluent chamber opening faces upward. A diluent syringe is then connected to the diluent chamber opening. In step 18-9, the diluent syringe is used to inject diluent into the diluent chamber and aspirate air bubbles from the diluent chamber. In step 18-10, the end cap 25 may be replaced over the diluent chamber opening.

[0249] Alternative configurations of drug delivery device 2 In some embodiments, one or more features of the drug delivery device 2 may be tailored to provide specific functional characteristics. Figures 19A-24 show several alternative configurations of the drug delivery device 2. The embodiments of the drug delivery device 2 shown in each of Figures 19-24 may be the same or similar in at least some respects to the drug delivery device 2 described above. For example, the embodiments of the drug delivery device 2 shown in each of Figures 19A-24 include a first plunger 13, a second plunger 14, a container 11, a valve 39 (or valve means), and a dilution chamber port 51. At least one or more of the first plunger 13, the second plunger 14, the one-way valve 39 (or valve means), the container 11, and the dilution chamber port 51 may be as described herein (e.g., with reference to one or more of the preceding embodiments), except with respect to any differences described in the relevant disclosure.

[0250] As previously mentioned, an alternative configuration of the drug delivery device 2 described with reference to Figures 19A-24 may comprise a container 11. The container 11 is configured to receive the second plunger 14 and at least a portion of the first plunger 13. The container 11 and the second plunger 14 define a diluent chamber 25. The diluent chamber 25 is configured to receive a diluent. The second port 51 may be referred to as a diluent chamber port 51. The container 11 defines a diluent chamber opening 51. The first plunger 13, the container 11, and the second plunger 14 define an active agent chamber 15 configured to receive a pharmaceutical formulation. In Figure 19A, the first plunger 13 and the second plunger 14 are in a pre-injection state in the starting position that they have at the start of the injection. In Figure 19B, the first plunger 13 has been moved further into the container 11 so as to contact the second plunger 14.

[0251] While Figures 19A-24 show a first plunger having a convex distal surface facing the second plunger and a second plunger having a flat proximal surface facing the first plunger, this arrangement may be modified such that the first plunger has a concave distal surface and the second plunger has a convex proximal surface, for example, as described elsewhere in this application and shown in Figures 10 or 26. Additionally, while the device shown in Figures 19A-24 has an activator port 49 and an activator port cap 50 on the side of the container, this arrangement may be modified such that there is no activator port 49 and no activator port cap 50. The activator port 49 may be used to fill the activator chamber, but if the activator port 49 is not present, the activator chamber may be filled in other ways, for example, through a proximal opening of the container 11 (e.g., when the first plunger is removed), through the plunger lumen of the first plunger, or the device may be provided with the activator chamber pre-filled.

[0252] The first plunger 13 is configured to seal with the container 11 to provide a first seal. The first seal may be as described herein. The second plunger 14 is configured to seal with the container 11 to provide a second seal. The second seal may be as described herein. The container 11 includes an activator chamber opening 17 as described herein.

[0253] The second plunger 14 includes a one-way valve 39. The valve 39 is configured to control the flow of the pharmaceutical formulation from the active agent 15 chamber to the diluent chamber 25, as described herein. The valve 39 is configured to move from a closed position to an open position when a force exceeding a valve threshold force is applied to an inlet side of the valve 39. The valve 39 is configured to move from an open position to a closed position when the force applied to the inlet side of the valve 39 is removed.

[0254] The breakaway force of the plunger in the syringe may be considered as the force required to break the static friction of the plunger. In the context of the drug delivery device 2, the breakaway force of the first plunger 13 may be considered as the force required to break the static friction of the first plunger 13 (i.e., the static friction between the first plunger 13 and the container 11). That is, the breakaway force of the first plunger 13 may be considered as the force required to cause the first plunger 13 to move when the first plunger 13 is stationary. A breakaway force may be considered when the active agent chamber 15 contains a pharmaceutical formulation and / or when the diluent chamber 25 contains a diluent. The breakaway force of the first plunger 13 may be referred to as the first plunger breakaway force. The breakaway force of the first plunger 13 may be referred to as the first breakaway force.

[0255] The breakaway force of the second plunger 14 may be considered as the force required to break the static friction of the second plunger 14 (i.e., the static friction between the second plunger 14 and the container 11). That is, the breakaway force of the second plunger 14 may be considered as the force required to cause the second plunger 14 to move when the second plunger 14 is stationary. A breakaway force may be considered when the active agent chamber 15 contains a pharmaceutical formulation and / or when the diluent chamber 25 contains a diluent. The breakaway force of the second plunger 14 may be referred to as the second plunger breakaway force. The breakaway force of the second plunger 14 may be referred to as the second breakaway force.

[0256] The valve threshold force may be less than the sum of the breakaway force of the second plunger 14 and the breakaway force of the first plunger. In some embodiments, the valve threshold force is less than the sum of the second plunger 14 and the first plunger 13 breakaway forces. In other words, the valve threshold force is less than the sum of the second breakaway force and the first breakaway force. Such a configuration may be beneficial when the injection device 3 is a vacuum injection device 3. That is, such a configuration may be beneficial when the injection device 3 applies a vacuum pressure 61 to the diluent chamber port 51 of the drug delivery device 2. In such a case, when the vacuum pressure 61 exerts a force on the valve 39 sufficient to open the valve 39, the second plunger 14 does not move.

[0257] As mentioned above, the injection device 3 may apply a vacuum pressure 61 to the diluent chamber port 51 of the drug delivery apparatus 2. The vacuum pressure 61 applies a vacuum force to the fluid (i.e., diluent) in the diluent chamber 25. Because the fluid in the diluent chamber 25 is generally incompressible, the vacuum force is also applied to the second plunger 14. If the vacuum force exceeds a valve force threshold (thereby opening the valve 39), the vacuum force may be transferred to the fluid (i.e., pharmaceutical formulation) in the active agent chamber 15 via the valve 39 of the second plunger 14. When the vacuum force is applied to the outlet side 47 of the valve 39, the valve 39 may open and the vacuum force 61 may be transferred to the pharmaceutical formulation in the active agent chamber 15. Also, because the pharmaceutical formulation is a fluid, it is generally incompressible. Therefore, the vacuum force is also applied to the first plunger 13.

[0258] The vacuum force is sufficient to open the valve 39, thereby causing movement of the first plunger 13. The vacuum pressure 61 therefore draws the pharmaceutical formulation into the dilution chamber 25. Control of the vacuum pressure 61 thereby allows control of the flow rate of the pharmaceutical formulation into the dilution chamber 25.

[0259] The valve threshold force may be less than the breakaway force of the second plunger 14. This ensures that the second plunger 14 remains stationary while the pharmaceutical formulation is being drawn from the active agent chamber 15 by the vacuum pressure 61. In some embodiments, the breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13.

[0260] Note that because the fluids in each of the diluent chamber 25 and activator chamber 15 are incompressible, in order for the second plunger 14 to be moved by the vacuum pressure before the valve 39 opens, the vacuum pressure must overcome both the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14 (because both move). Because the fluids may not be completely incompressible, in some embodiments the breakaway force of the second plunger 14 must be greater than the valve threshold force.

[0261] When the valve 39 is in the open position, there is little force (at low flow rates) across the second plunger 14. This force is proportional to the resistance across the valve 39. In some embodiments, the force across the valve 39 when it is in the open position is referred to as the opening force. When the valve 39 is in the open position, the first plunger 13 moves as long as the injection device 3 can generate a vacuum pressure greater than the breakaway force of the first plunger 13.

[0262] When the valve 39 is in the open position at high flow rates, the opening force is greater; i.e., the opening force is greater at high flow rates. In some embodiments, the breakaway force of the second plunger 14 is greater than the opening force at the maximum flow rate of the injection. This ensures that the second plunger 14 does not move before the first plunger 13 contacts the second plunger 14. In some embodiments, the breakaway force of the second plunger is about 450 grams.

[0263] In some embodiments, the disengagement force of the second plunger 14 is less than a force alarm threshold. The force alarm threshold is the force at which the injection device 3 will alarm. An alarm on the injection device 3 may indicate an occlusion. In some embodiments, the force alarm threshold may be 1,200 grams.

[0264] 20A shows a side view of a drug delivery device 2 in a first state according to some embodiments. The first state may be a pre-injection state. The first state may represent a first stage of injection.

[0265] 20B shows a side view of another drug delivery device 2 in a first state, according to some embodiments. The first state may be a pre-injection state. The first state may indicate a first stage of injection.

[0266] The drug delivery device 2 shown in Figures 20A and 20B comprises a first plunger 13 and a second plunger 14. The first plunger 13 can be as described herein, at least in some embodiments. The second plunger 14 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a container 11. The container 11 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises an activator chamber 15. The activator chamber 15 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a dilution chamber 25. The dilution chamber 25 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises an activator chamber port 49. The activator chamber port 49 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a dilution chamber port 51. The dilution chamber port 51 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a valve 39. The valve 39, in at least some embodiments, can be as described herein.

[0267] 20A and 20B, in some embodiments, the first plunger 13 includes a first number of O-rings 109. The first number of O-rings 109 includes a first plunger O-ring 110. The first number of O-rings 109 are configured to provide a number of O-ring interfaces between the first plunger 13 and the container 11. The number of O-ring interfaces corresponds to the first number of O-rings 109. That is, the number of O-ring interfaces is the same as the number of O-rings in the first number of O-rings 109.

[0268] 20A and 20B, in some embodiments, the second plunger 14 includes a second number of O-rings 111. The second number of O-rings 111 includes a second plunger O-ring 112. The second number of O-rings 111 is configured to provide a second number of O-ring interfaces between the second plunger 14 and the container 11. The second number of O-ring interfaces correspond to the second number of O-rings 111. That is, the second number of O-ring interfaces is the same as the number of O-rings in the second number of O-rings 111.

[0269] In the embodiment shown in FIG. 20A, the first number is 1. That is, the first number of O-rings 109 includes one O-ring 110. The second number is greater than 1. That is, the second number of O-rings 111 includes two or more O-rings 112, 113. In particular, the second number is 2. That is, the second number of O-rings 111 includes two O-rings 112, 113. The second number is greater than the first number. The O-rings of the first number of O-rings 109 and the second number of O-rings 111 may be the same. That is, the O-rings of the first number of O-rings 109 and the second number of O-rings 111 may have the same dimensions.

[0270] In the embodiment shown in FIG. 20B, the first number is 2, i.e. the first number of O-rings 109 includes two O-rings. The second number is greater than 2, i.e. the second number of O-rings 111 includes three or more O-rings. In particular, the second number is 3, i.e. the second number of O-rings 111 includes three O-rings 112, 113. The second number is greater than the first number. The O-rings of the first number of O-rings 109 and the second number of O-rings 111 may be the same, i.e. the O-rings of the first number of O-rings 109 and the second number of O-rings 111 may have the same dimensions.

[0271] In the embodiment shown in Figures 20A and 20B, the O-rings are of comparable size, i.e., the strength of the O-ring joint provided by each O-ring is generally similar.

[0272] FIG. 20C shows a cross section of an O-ring 113, according to some embodiments. The O-ring 113 may represent one or more of the first number of O-rings 109 and / or the second number of O-rings 111. The O-ring 113 is positioned in an O-ring groove 115. The first plunger 13 may include such an O-ring groove 115. For example, one or more of the first number of O-rings 109 may be disposed in an O-ring groove as shown in FIG. 20C. Similarly, the second plunger 14 may include such an O-ring groove 115. For example, one or more of the second number of O-rings 111 may be disposed in an O-ring groove as shown in FIG. 20C.

[0273] The O-ring 113 is sized with an O-ring diameter 117. The O-ring groove 115 comprises a groove width 119. The O-ring diameter 117 may be smaller than the groove width 119. The O-ring diameter 117 may be the same as the groove width 119. The O-ring diameter 117 may be larger than the groove width 119. In some embodiments, the diameter of one of the first number of O-rings 109 is referred to as a first diameter. Similarly, the diameter of one of the second number of O-rings 111 is referred to as a second diameter. In some embodiments, the groove in which one of the first number of O-rings 109 is disposed is referred to as a first groove. The first groove may have a first groove width. Similarly, the groove in which one of the second number of O-rings 111 is disposed is referred to as a second groove. The second groove may have a second groove width.

[0274] In some embodiments, the second diameter is larger than the first diameter, i.e., the diameter of one or more of the second number of O-rings 111 is larger than the diameter of one or more of the first number of O-rings 109. This increases the breakaway force associated with the O-ring joint of the associated O-ring of the second number of O-rings 111 as compared to the breakaway force associated with the O-ring joint of the associated O-ring of the first number of O-rings 109.

[0275] Thus, providing a drug delivery device 2 such that the valve threshold force is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14 can be achieved in several ways. Similarly, providing a drug delivery device 2 such that the breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13 can be achieved in several ways by adjusting the characteristics of the first number of O-rings 109 and the second number of O-rings 111. Similarly, providing a drug delivery device 2 such that the valve opening force is less than the breakaway force of the second plunger 14 can be achieved in several ways.

[0276] In some embodiments, the breakaway force of each of the first plunger 13 and the second plunger 14 can be controlled by controlling the first number or the second number. In such cases, the dimensions associated with each O-ring can be comparable. That is, the O-ring diameter of the first number of O-rings 109 can be similar or the same as the O-ring diameter of the second number of O-rings 111. Thus, if the second number is greater than the first number, the breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13. The first number can be selected such that the valve threshold force is greater than the breakaway force of the first plunger 13.

[0277] In some embodiments, the breakaway force of each of the first plunger 13 and the second plunger 14 may be controlled by controlling the dimensions associated with the O-rings of the first number of O-rings 109 and the second number of O-rings 111. For example, the groove width of the groove of the second number of O-rings 111 may be sized smaller than the groove width of the groove of the first number of O-rings 109. In such a case, the O-ring interface provided by the second number of O-rings 111 must overcome more force, thereby increasing the breakaway force of the second plunger 14. In such a case, these dimensions may be controlled such that the breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13. Similarly, these dimensions may be controlled such that the valve threshold force is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14. Similarly, these dimensions may be controlled such that the valve threshold force is less than the breakaway force of the second plunger 14. Similarly, these dimensions may be controlled so that the opening force is less than the breakaway force of the second plunger 14 .

[0278] In some embodiments, the at least one resistance element 121 includes one or more of the second number of O-rings 111. In some embodiments, each of the second number of O-rings 111 is considered to be one of the at least one resistance element 121.

[0279] 21 shows a side view of another drug delivery device 2 in a first state, according to some embodiments. The first state may be a pre-injection state. The first state may represent a first stage of injection.

[0280] The drug delivery device 2 shown in FIG. 21 comprises a first plunger 13 and a second plunger 14. The first plunger 13 can be as described herein, at least in some embodiments. The second plunger 14 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a container 11. The container 11 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises an activator chamber 15. The activator chamber 15 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a dilution chamber 25. The dilution chamber 25 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises an activator chamber port 49. The activator chamber port 49 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a dilution chamber port 51. The dilution chamber port 51 can be as described herein, at least in some embodiments.

[0281] As described herein, the second plunger 14 comprises a valve 39. In some embodiments, the second plunger 14 comprises a valve device 149. The valve device 149 is configured to control the flow of the pharmaceutical formulation from the activator chamber 15 to the diluent chamber 25. The valve device 149 may comprise the valve 39. As described herein, the valve 39 may be a duckbill valve 41. The valve 39 may comprise a plurality of flaps 43.

[0282] In some embodiments, the valve arrangement 149 comprises a plurality of valves 39. One or more of the plurality of valves may be duckbill valves 41. One or more of the plurality of valves 39 may comprise a plurality of flaps 43. For example, the valve arrangement 149 may comprise a first valve 39A and a second valve 39B. Each of the first valve 39A and the second valve 39B is configured to control the flow of the pharmaceutical formulation from the activator chamber 15 to the diluent chamber 25.

[0283] Providing the drug delivery device 2 such that the valve threshold force is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14 may be achieved in a number of ways. Providing the drug delivery device 2 such that the valve threshold force is less than the breakaway force of the second plunger 14 may be achieved in a number of ways. Similarly, providing the drug delivery device 2 such that the breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13 may be achieved in a number of ways. Similarly, providing the drug delivery device 2 such that the valve opening force is less than the breakaway force of the second plunger 14 may be achieved in a number of ways.

[0284] In some embodiments, the disengagement force of the second plunger 14 can be controlled by controlling aspects of the valve 39 and / or the valve arrangement 149. Similarly, the opening force can be controlled by controlling aspects of the valve 39 and / or the valve arrangement 149. For example, the material from which the valve 39 is manufactured can affect the force required to open the valve 39 and also the opening force (i.e., the force across the valve 39 when the valve 39 is in the open position). Similarly, the dimensions of the flap 43 can affect the force required to open the valve 39 and also the opening force. The number of valves in the valve arrangement 149 can also affect the force required to open the valve 39 and also the opening force. Because the opening force is proportional to the resistance of each valve 39 in the valve arrangement 149, adding more valves 39 or varying the resistance of the valves 39 (e.g., by changing the cross-sectional area of ​​each valve 39 when open by changing the valve material, geometry, durometer, flap configuration, opening size, etc.) can reduce the overall resistance of the valve arrangement 149, thereby reducing the opening force.

[0285] The valve threshold force, the breakaway force of the first plunger 13, and the breakaway force of the second plunger 14 may be controlled as described herein to ensure that the valve threshold force is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14 and / or is less than the breakaway force of the second plunger 14. The valve arrangement 149 may also be controlled to ensure that the valve threshold force is less than the breakaway force of the second plunger 14. For example, the material from which the valve 39 of the valve arrangement 149 is manufactured may be altered to reduce the valve threshold force. Similarly, the opening force and breakaway force of the second plunger 14 may be controlled as described herein to ensure that the opening force is less than the breakaway force of the second plunger 14. For example, the opening force may be reduced by increasing the number of valves 39 in the valve arrangement 149 or by increasing the size of the opening of the valve 39 of the valve arrangement 149 when the valve 39 is open.

[0286] 22 shows a side view of the drug delivery device 2 in a first state according to some embodiments. The first state may be a pre-injection state. The first state may represent a first stage of injection.

[0287] The drug delivery device 2 shown in FIG. 22 comprises a first plunger 13 and a second plunger 14. The first plunger 13 can be as described herein, at least in some embodiments. The second plunger 14 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a container 11. The container 11 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises an activator chamber 15. The activator chamber 15 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a dilution chamber 25. The dilution chamber 25 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises an activator chamber port 49. The activator chamber port 49 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a dilution chamber port 51. The dilution chamber port 51 can be as described herein, at least in some embodiments. The drug delivery device 2 comprises a valve 39. The valve 39, in at least some embodiments, can be as described herein.

[0288] In the embodiment shown in FIG. 22, the drug delivery device 2 comprises a protrusion 147. The protrusion 147 is configured to block the displacement of the second plunger 14. In particular, the protrusion 147 is configured to block the displacement of the second plunger 14 into the diluent chamber port 51. The container 11 comprises a protrusion 147. The protrusion 147 protrudes inwardly. The protrusion 147 is an annular protrusion. The protrusion 147 extends around the interior of the container 11. The protrusion 147 is between the activator chamber port 49 and the diluent chamber port 51. The protrusion 147 can be used to increase the breakaway force of the second plunger 14.

[0289] Providing the drug delivery device 2 such that the valve threshold force is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14 may be achieved in a number of ways. Similarly, providing the drug delivery device 2 such that the breakaway force of the second plunger 14 is greater than the breakaway force of the first plunger 13 may be achieved in a number of ways. Similarly, providing the drug delivery device 2 such that the valve opening force is less than the breakaway force of the second plunger 14 may be achieved in a number of ways. In some embodiments, one or more of these are achieved at least in part by appropriately dimensioning the protrusion 147.

[0290] In some embodiments, the breakaway force of the second plunger 14 can be controlled by controlling the aspect of the protrusion. For example, the degree to which the protrusion 147 protrudes into the container 11 can be controlled. The degree to which the protrusion 147 extends into the container 11 from the inner surface 55 of the container 11 can be the protrusion dimension. This may also be referred to as the radial protrusion dimension. The thickness of the protrusion 147 in a direction parallel to the longitudinal axis 21 can be the longitudinal protrusion dimension. The protrusion dimension and the longitudinal protrusion dimension can also be controlled to control the breakaway force of the second plunger 14.

[0291] Increasing the extent to which the protrusion 147 protrudes into the container 11 can increase the breakaway force of the second plunger 14 because it must overcome the resistance force applied to the second plunger 14 by the protrusion 147. Similarly, increasing the longitudinal protrusion dimension can increase the breakaway force of the second plunger 14. Thus, the breakaway force of the second plunger 14 can be greater than the breakaway force of the first plunger 13, at least in part, as a result of the resistance to movement of the second plunger 14 provided by the protrusion 147. The dimensions of the protrusion 147 (e.g., protrusion dimension) can be controlled as described herein to ensure that the valve threshold force is less than the sum of the breakaway force of the first plunger 13 and the breakaway force of the second plunger 14. Similarly, the dimensions of the protrusion 147 can be controlled as described herein to ensure that the valve threshold force is less than the breakaway force of the second plunger 14.

[0292] In some embodiments, the resistance element 121 comprises a protrusion 147 .

[0293] The disengagement force of each of the first plunger 13 and the second plunger 14 can be controlled by controlling the number of O-rings associated with each plunger and the size of the O-rings, as described above. However, other ways of controlling the disengagement force are possible. In some examples, the disengagement force can be controlled through the number of valves, as shown in FIG. 21, or by providing a protrusion 147 that blocks movement of the second plunger, as shown in FIG. 22. In yet other examples, there can be a stop system 131 with an actuating element 133 that is movable between an engaged position that engages with a groove 139 of the second plunger to block movement of the second plunger (as shown in FIG. 19A) and a disengaged position (as shown in FIG. 19B) in which the actuating element 133 does not engage with the groove 139 of the second plunger and does not block movement of the second plunger. In yet another example (not shown), a first portion of the container inner surface near the distal end of the container and the starting position of the second plunger may have a rougher surface than a second portion of the container inner surface toward the proximal end of the container, such that the rougher first portion prevents movement of the second plunger beyond the starting position toward the distal end of the container. In yet another example, the disengagement force may be controlled by a spring between the distal end of the container and the distal face of the second plunger, or by providing an engagement member on the proximal face of the second plunger to prevent movement of the second plunger.

[0294] Second plunger 14 FIG. 24 shows a side view of a partial cross section of the drug delivery device 2, according to some embodiments. An embodiment of the second plunger 14 is shown in FIG. 23. The second plunger 14 of FIG. 23 comprises a second plunger seal portion 151. The second plunger 14 comprises a second plunger seal support portion 153. The second plunger seal support portion 153 is configured to connect to the second plunger seal portion 151. The second plunger seal support portion 153 is configured to support the second plunger seal portion 151. In some embodiments, the second plunger seal portion 151 comprises an elastomeric material. In some embodiments, the seal support portion 153 comprises a non-elastomeric or relatively rigid material (more rigid than the material of the seal portion 151). The second plunger seal support portion 153 helps the second plunger seal portion 151 maintain its shape. The second plunger seal support portion 153 may be connected to the first plunger seal portion 151 with a soft push connection. That is, the second plunger seal support portion 153 may be received by a recess in the second plunger seal portion 151. The second plunger includes a valve 39. The valve 39 may be as described herein. The second plunger 14 includes a valve connector portion 155. The valve connector portion 155 is configured to securely connect the valve 39 to the second plunger seal support portion 153.

[0295] 23 shows a side view in partial cross section of the drug delivery device 2, according to some embodiments. The second plunger 14 includes a second plunger recess 157. The second plunger recess 157 is a conical recess. The second plunger recess 157 is configured to receive the first plunger 13.

[0296] The valve 39 extends beyond the apex 159 of the second plunger 14 shown in FIGS. 23 and 24. The outer dimensions of the valve 39 may be larger than the outer dimensions of the channel of the dilution chamber port 51. Thus, the valve 39 may contact the inner surface of the container 11 as the second plunger 14 is moved toward the distal end 63 of the container. Thus, the valve 39 may prevent or minimize the extent to which the second plunger contacts the distal end 63 of the container 11. This may reduce the extent to which the second plunger 14 adheres to the distal end 63 of the container 11, thereby providing improved ease with which the second plunger 14 can be removed from the distal end 63 of the container 11 and reset, for example, for a second injection.

[0297] Furthermore, the described design of the valve 39 improves the ease with which the drug delivery device 2 can be primed. If the second plunger 14 is shaped to correspond to the shape of the distal end 63 of the container 11, the second plunger 14 may be sucked into the distal end 63 of the container 11 prior to priming, which may increase the difficulty of filling the dilution chamber 25. Providing the second plunger 14 as described may overcome this problem.

[0298] In some embodiments, the valve 39 may include a protrusion (not shown) that extends in a generally forward direction (i.e., away from the valve 39 toward the dilution chamber port 51). This protrusion may act to contact the container 11 to minimize the extent to which the second plunger 14 draws into the container 11. In some embodiments, instead of the valve 39 extending beyond the apex 159 of the second plunger 14, the valve 39 may be contained within the second plunger 14.

[0299] In some embodiments, the valve 39 is sized so that it does not contact the vessel 11. Specifically, the valve 39 does not contact the dilution chamber port 51. This reduces distortion of the valve 39 that may result from contact.

[0300] FIG. 25A illustrates a second plunger 14 according to some embodiments. The second plunger 14 of FIG. 25A includes a front portion 161. The second plunger 14 of FIG. 27A includes a rear portion 163. The front portion 161 is conical. The front portion 161 extends away from the rear portion 163 by a front portion depth 165. The rear portion 163 extends away from the front portion 161 by a rear portion depth 167. The front portion depth 165 is greater than the rear portion depth 167. In some embodiments, the front portion depth 165 is less than the rear portion depth 167.

[0301] The rear portion 163 includes a rear portion groove 168. The rear portion groove 168 includes a first angled edge 169 and a second angled edge 171. The angle between the second angled edge 171 and a longitudinal axis 173 of the second plunger 14 is greater than the angle between the first angled edge 169 and the longitudinal axis 173 of the second plunger 14.

[0302] FIG. 25B illustrates a second plunger 14 according to some embodiments. The second plunger 14 of FIG. 25B includes a front portion 161. The second plunger 14 of FIG. 25B includes a rear portion 163. In some embodiments, the front portion 161 is conical. In some embodiments, the front portion 161 is hemispherical. The front portion 161 extends away from the rear portion 163 by a front portion depth 165. The rear portion 163 extends away from the front portion 161 by a rear portion depth 167. The front portion depth 165 is less than the rear portion depth 167. In some embodiments, the front portion depth 165 is greater than the rear portion depth 167.

[0303] The rear portion 163 comprises a rear portion groove 168. The rear portion groove 168 comprises a first angled edge 169 and a second angled edge 171. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis 173 of the second plunger 14 is the same as the angle between the first angled edge 169 and the longitudinal axis 173 of the second plunger 14. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis 173 of the second plunger 14 is greater than the angle between the first angled edge 169 and the longitudinal axis 173 of the second plunger 14. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis 173 of the second plunger 14 is less than the angle between the first angled edge 169 and the longitudinal axis 173 of the second plunger 14.

[0304] Various features may be provided to inhibit or prevent the second plunger 14 from flipping or rotating out of alignment within the container 11. In some embodiments, the second plunger has a length of at least 9 mm along the longitudinal axis of the container. This helps prevent the second plunger from becoming out of alignment. This length of at least 9 mm may be, for example, the length between the distal side of the second plunger facing the dilution chamber opening and the proximal side of the second plunger facing the first plunger. In some examples, the length 167 of the portion of the second plunger that contacts the container wall may be at least 9 mm. In some examples, the length is between 9 mm and 11 mm.

[0305] In some examples, the rear portion depth 167 is greater than the front portion depth 165, which can help to bring the peripheral edge of the second plunger into contact with the inner wall of the container 11 and prevent the second plunger 14 from inverting within the container.

[0306] In some embodiments, the inner surface 55 of the container 11 may be lubricated. For example, the inner surface 55 of the container 11 may be lubricated with oil. This lubrication may reduce the likelihood of the second plunger 14 flipping or rotating out of alignment. This may be accomplished by providing an improvement in the degree to which the second plunger 14 can slide. In some embodiments, the height of the second plunger 14 (i.e., the dimension of the second plunger 14 in a direction parallel to the longitudinal axis 21g) may be increased to reduce the likelihood of the second plunger 14 flipping or rotating. In some embodiments, the size of the second plunger 14 is controlled such that the compression of the second plunger 14 is generally constant around its circumference. For example, the second plunger 14 may be sized such that the lateral compression at the leading edge of the second plunger 14 is generally the same as the lateral compression at the trailing edge of the second plunger 14. This may help prevent the second plunger from becoming out of alignment.

[0307] In some embodiments, the distal end 63 of the container 11 may be considered to define a recess, e.g., a conical depression. The second plunger 14 is described as being moved into contact with the container 11, as described herein. In some embodiments, the distal end (e.g., first portion 161) of the second plunger 14 may be convex, e.g., conical, as described herein. However, the height of the second plunger 14 may be such that the convex distal surface of the second plunger 14 (i.e., the curved surface of the front portion 161 of the second plunger 14) does not directly align, does not match, or only partially matches the inner surface of the distal end 63 of the container 11. For example, the convex (e.g., conical) shape of the distal end of the second plunger 14 and the concave (e.g., conical) depression of the distal end 63 of the container 11 may have different profiles. This may advantageously reduce the extent to which the second plunger 14 may be drawn into the container 11. This configuration may also advantageously allow the curved surface of the front portion 161 of the second plunger 14 to seal against the diluent chamber port 51. As a result, fluid exiting the valve 39 may be directed through the diluent chamber port 51 without entering the diluent chamber 25. This may be useful when filling the drug delivery device 2.

[0308] 25C and 25D show a first plunger 13 according to some embodiments. The first plunger 13 of FIG. 25C and 25D comprises a front portion 161. The first plunger 13 of FIG. 25C and 25D comprises a rear portion 163. The front portion 161 of the first plunger 13 is configured to contact the second plunger 14. The front portion 161 has a concave (e.g., inverted cone) profile. That is, the front portion 161 of the first plunger 13 defines a concave (e.g., conical) recess 193. The concave (e.g., conical) recess 193 may have a profile corresponding to a truncated cone.

[0309] Front portion 161 extends away from rear portion 163 by front portion depth 165. Rear portion 163 extends away from front portion 161 by rear portion depth 167. Front portion depth 165 is greater than rear portion depth 167. In some embodiments, front portion depth 165 is less than rear portion depth 167.

[0310] The first plunger 13 comprises a first plunger groove 168. The first plunger groove 168 comprises a first angled edge 169 and a second angled edge 171. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis of the first plunger 13 is the same as the angle between the first angled edge 169 and the longitudinal axis of the first plunger 143. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis of the first plunger 13 is greater than the angle between the first angled edge 169 and the longitudinal axis of the first plunger 13. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis of the first plunger 13 is less than the angle between the first angled edge 169 and the longitudinal axis of the first plunger 13.

[0311] FIG. 26 illustrates an embodiment of a drug delivery device 2, according to some embodiments.

[0312] In the embodiment of FIG. 26, the first plunger 13 has a concave (distal) surface 195 that faces the second plunger 14. For example, the distal surface of the first plunger 13 may define a concave recess. The concave recess may have a conical profile. The second plunger 14 has a convex (distal) surface 197 that faces the first plunger. For example, the proximal surface of the second plunger may include a frusto-conical portion 197. Although not shown in FIG. 26, the second plunger may include a valve, as previously described in other embodiments.

[0313] When the first plunger 13 contacts the second plunger 14, a gap 199 is defined between the first plunger 13 and the second plunger 14. The gap 199 allows air to accumulate within the drug delivery device 2, preventing or minimizing the extent to which air is injected into the dilution chamber 25 and / or the patient. The gap may therefore function as an air bubble trap. In some embodiments, the gap 199 may be defined by a concave (e.g., conical) recess 195 of the first plunger 13 and a frusto-conical portion 197 of the second plunger 14. While the gap 199 in FIG. 26 is formed between central portions of the plungers, in other examples the gap may have a peripheral location off to one side.

[0314] Generally, the first and second plungers may be shaped such that when the first plunger is moved into contact with the second plunger, there is an air gap between the first and second plungers. The second plunger may partially conform to the shape of the first plunger to minimize waste of pharmaceutical formulation, but the air gap allows space for air bubbles to become trapped between the first and second plungers when the first plunger is moved into contact with the second plunger.

[0315] The second plunger 14 may have a (distal) convex surface 198 facing the distal end 11A of the container 11. The distal end 11A of the container is the end of the container that defines the dilution chamber opening 51. The second plunger 14 is movable toward the distal end 11A of the container to an end position where the second plunger cannot move further toward the distal end of the container. For example, the end position of the second plunger may be a position where the second plunger 14 abuts against the distal end 11A of the container. The distal side 198 of the second plunger 14 is shaped such that, in the end position, there is a gap between at least a portion of the second plunger and the distal end of the container. The gap helps to prevent the second plunger from adhering (by suction or otherwise) to the distal end of the container. For example, the distal face of the second plunger may have a different shape or profile than the distal end of the container to prevent attraction or adhesion of the second plunger to the distal end of the container.

[0316] The distal side or face 198 of the second plunger may partially conform to the distal end of the container 11A to minimize waste of pharmaceutical formulation and / or diluent when the second plunger 14 is moved into contact with the distal end of the container to expel the contents of the dilution chamber 25 through the dilution chamber opening 51. Because the second plunger only partially conforms to the distal end of the container when the second plunger 14 is moved into contact with the distal end 11A of the container, there will still be a gap between at least a portion of the second plunger and the distal end of the container. This gap helps to prevent suction forces that attach the second plunger to the distal end of the container. This may be achieved, for example, by the distal end of the second plunger and the distal end of the container having different profiles.

[0317] To achieve this clearance, the distal side of the second plunger facing the distal end of the container may include a first portion that abuts the distal end of the container at an end position and a second portion that does not abut the distal end of the container at an end position. For example, the first portion may be a portion protruding from the second plunger, a valve (if a valve protrudes from the second plunger), or a portion of the distal surface of the second plunger. In some examples, the first portion is a portion of the distal surface of the second plunger, and 5% to 50% of the distal area of ​​the second plunger contacts or abuts the distal end of the container when the second plunger is moved to contact the distal end of the container.

[0318] As previously mentioned, the second plunger has a one-way valve. In some examples, as shown in FIG. 27, the one-way valve 39 can be included inside the main body 14M of the second plunger 14. This helps protect the one-way valve from distortion due to contact with the edge of the container 11. In some examples, the main body 14M of the second plunger 14 includes at least one outlet opening 223 and at least one internal channel 222 leading from the outlet of the one-way valve 39 to the at least one outlet opening 223. In some examples, the one-way valve 39 can be a duckbill valve.

[0319] In Fig. 27 there is one outlet opening 223. In other examples the main body of the second plunger 14 may have two or more outlet openings. Fig. 28 shows a similar arrangement to Fig. 27, where like reference numbers represent like parts, but the main body 14M has two outlet openings 223A and 223B. A first internal channel 219 of the main body leads to the first outlet opening 223A and a second internal channel 221 leads to the second outlet opening 223B. In this case, reference number 217 indicates a portion of the main body separating the first and second channels.

[0320] FIG. 29A is a perspective view from the front (distal end) of the second plunger 14 of FIG. 28 showing the first and second outlet openings 223A, 223B. FIG. 29B is a plan view showing one possible arrangement in which the one-way valve is arranged horizontally relative to the outlet openings. That is, the one-way valve, which may be a duckbill valve, has a slit substantially perpendicular to the line joining the first and second outlet openings 223A, 223B. In other examples, the one-way valve may have a different orientation. For example, as shown in FIG. 29C, the valve may have a vertical orientation with the valve slit parallel to the line joining the first and second outlet openings 223A, 223B.

[0321] In some examples, there may be a dispersion member disposed on the outlet side 47 of the valve 39. The dispersion member may be disposed in a flow path of the fluid flowing through the valve 39. The dispersion member may be configured to disperse the fluid flowing through the valve 39. This may improve mixing of the fluid within the dilution chamber 25. In some examples, the dispersion member may define a first dispersion channel 219 and a second dispersion channel 221. The fluid flowing through the valve 39 is forced through the first dispersion channel 219 and the second dispersion channel 221, increasing the degree of mixing within the dilution chamber 25.

[0322] In some embodiments, the at least two outlet openings 223A, 223B and / or the internal channel (or dispersion channel) are configured to generate a first jet of the pharmaceutical formulation that is directed towards a first corner of the dilution chamber 25 and a second jet of the pharmaceutical formulation that is directed towards a second corner of the dilution chamber 25 when the pharmaceutical formulation is swept out of the active agent chamber through the one-way valve. In some embodiments, the device is configured such that the first and second jets of the pharmaceutical formulation repel each other at an inner surface of the dilution chamber, thereby facilitating back-mixing of the pharmaceutical formulation and the diluent within the dilution chamber.

[0323] In some implementations, the outlet opening and channel may be formed by a dispersion member that extends from an outer portion of the flow path into a central portion of the flow path of the fluid flowing through the valve 39. The dispersion member may define a dispersion channel. The direction of the fluid flowing through the dispersion channel is changed by the dispersion member. This increases the degree to which the fluid mixes in the dilution chamber 25.

[0324] Examples of jetting and mixing are shown in Figures 30A-30F. Although Figures 30A-30F show the priming process, similar jetting and mixing occurs during injection. Figure 30A shows a first time, e.g., 0.25 seconds after starting priming, at which time two jets are generated. Figure 30B shows a second time, e.g., 0.41 seconds later, at which time each of the two jets reaches a respective corner of the dilution chamber. Figure 30C shows a third time, e.g., 1.51 seconds later, at which time the two jets reach the dilution chamber outlet. Figure 30D shows a fourth time, e.g., 1.95 seconds later, at which time back mixing begins to occur. Figure 30E shows a fifth time, e.g., 2.15 seconds later, at which time the pharmaceutical formulation begins to enter a conduit (e.g., an extension tube) attached to the dilution chamber. FIG. 30F shows a sixth time, eg, after 2.90 seconds, at which time good mixing occurs.

[0325] In some embodiments, the main body of the second plunger may comprise three exit openings, where an intermediate opening of the three exit openings and / or an internal channel leading to the third exit opening may be configured to generate a third jet of pharmaceutical formulation that is directed towards the dilution chamber opening.

[0326] FIG. 31 shows an exemplary perspective view of a second plunger 41 having three outlet openings 223A, 223B, and 223C. The three outlets may be arranged in a row. The middle outlet may be smaller than the peripheral outlets. FIG. 32 shows an exemplary cross-sectional view of a second plunger 14 having three outlet openings 223A, 223B, and 223C. Like reference numbers indicate like parts as in FIGS. 27-31.

[0327] Examples of jetting and mixing are shown in Figures 33A-33F. Although Figures 33A-33F show the priming process, similar jetting and mixing occurs during injection. Figure 33A shows a first time, e.g., 0.26 seconds after starting priming, at which time one central jet and two lateral jets are generated. Figure 30B shows a second time, e.g., 0.60 seconds later, at which time the central jet reaches the dilution chamber outlet and each of the two lateral jets reaches the middle sidewall of the dilution chamber. Figure 30C shows a third time, e.g., 0.8 seconds later, at which time the central jet enters a conduit attached to the dilution chamber opening and the two lateral jets reach their respective corners of the dilution chamber. Figure 30D shows a fourth time, e.g., 1.67 seconds later, at which time the lateral jets reach the dilution chamber outlet. Figure 30E shows a fifth time, e.g., 2.6 seconds later, when back-mixing of the side jets begins to occur, and Figure 30F shows a sixth time, e.g., 3.2 seconds later, when the back-moving side jets collide with the forward moving central jet, causing further turbulence and mixing.

[0328] 34 is a cross-sectional view of an example of a second plunger 14 having a main body including a valve 29 therein, the main body having multiple (e.g., three) outlet openings and multiple internal channels, each of which leads to a respective outlet opening. Each channel may extend in a different direction or angle. Thus, there are three outlets and three outlet channels, but because they extend in different directions, only the first channel 219 and first outlet 223A, and a portion of the second outlet channel 221 are visible in the cross-section of FIG.

[0329] 35 illustrates a drug delivery system 1 according to some embodiments. The drug delivery system 1 includes a remote active agent 15A. The remote active agent chamber 15A is in addition to the active agent chamber 15 of the drug delivery device 2. That is, the remote active agent chamber 15A may be disposed remotely from the drug delivery device 2 and fluidly connected to the plunger lumen 93 of the drug delivery device 2 described herein by an active agent chamber conduit 201. The active agent chamber conduit 201 may be configured to connect to the outlet of the remote active agent chamber 15A and the first plunger connector 96.

[0330] An external pump 15A may be used to pump the pharmaceutical formulation from the remote active agent chamber 15A into the active agent chamber 15 of the drug delivery device 2. In this arrangement, the active agent chamber 15 of the drug delivery device 2 is maintained at a constant volume. The flow of the pharmaceutical formulation is driven by an external pump 15B, which may be, for example, a peristaltic pump or other pump. The pump 15B may drive the flow of the pharmaceutical formulation into the active agent chamber 15, through a valve 39 (not shown) in the diluent chamber 25 (not shown), and out through the diluent chamber opening 51.

[0331] To maintain the active agent chamber 15 at a constant volume, the drug delivery system 1 may include a plunger lock 203. The plunger lock 203 locks the first plunger 13 in a particular position. This allows the pharmaceutical formulation to be delivered into the diluent chamber 25 via the valve 39 for mixing with the diluent and out the diluent chamber opening for delivery to the patient. Because the first plunger does not move, the second plunger also remains in a predetermined position and therefore the volume of the diluent chamber is also fixed.

[0332] The plunger lock 203 comprises a body 205. The body 205 comprises a lower surface 207 for resting on a support surface. The body 205 comprises a first groove 209. The body comprises a second groove 211. The first groove 209 is configured to receive a first plunger flange 213 of the first plunger 13. The second groove 211 is configured to receive a vessel flange 215 of the vessel 11. The plunger lock 203 is configured to secure the first plunger 13 in a particular position such that the first plunger 13 rests within the vessel 11.

[0333] The external pump can be controlled to drive the pharmaceutical formulation according to a particular dose profile. For example, the pharmaceutical formulation can be made to flow at a varying flow rate determined by a function suitable for delivering a desired dose profile when the dilution chamber is at a constant volume. For example, the rate of active agent administration can be governed by a Sadleir function as described in International Patent Application No. PCT / AU2020 / 051363, the contents of which are incorporated by reference in their entirety. In some embodiments, the rate of active agent administration can be governed by an increasing volume Sadleir function as described in International Patent Application No. PCT / AU2020 / 051363. FIG. 36 shows another example where there may be two separate pharmaceutical formulations administered to a patient. In this case, a first pharmaceutical formulation may enter pump 15B through first inlet 201. Pump 15B has a second inlet that may receive a second pharmaceutical formulation delivered by drug delivery device 2, as described in various examples above. Pump 15B may combine the first and second pharmaceutical formulations and deliver them to the patient (e.g., by intravenous administration) through outlet conduit 23. Pump 15B may include an air trap 15C to trap any air bubbles formed in the pharmaceutical formulation. Because the dose profile may be sensitive to the initial portion of the injection where the dose rate should be kept low, the drug delivery device 2 may be attached to the outlet 202 by a conduit arrangement 175, as described below. The conduit device enables a priming process using a high infusion rate to fill the conduit 23 with a diluted pharmaceutical formulation at a desired concentration profile, so that the dose rate can be accurately achieved in the first portion of the infusion, such that the first portion of the infusion consists of the diluted pharmaceutical formulation prepared in the conduit 23 as part of the priming process. Without this approach, it may be difficult to achieve the desired low but increasing dose rate in the initial portion of the infusion.

[0334] Figure 37 shows a perspective view of a conduit device 175 and a portion of a drug delivery device 2, according to some embodiments. The housing 177 and the conduit 11 are both partially transparent in Figure 37. Figure 38 shows a perspective view of a conduit device 175 and a drug delivery device 2, according to some embodiments. The housing 177 and the conduit 11 are both partially transparent in Figure 38.

[0335] The housing comprises a first housing port 179. The first housing port 179 comprises a first housing opening 180. The first housing opening 180 extends through the first housing port 179. The first housing port 179 comprises a first connector. The first connector may be a first housing luer lock connector. The first housing luer lock connector may be a male luer lock connector. Alternatively, the first hosed luer lock connector may be a female luer lock connector. The first housing port 179 is configured to connect to the dilution chamber port 51 of the drug delivery device 2.

[0336] The housing 177 includes a second housing port 181. The second housing port 181 includes a second housing opening 182. The second housing opening 182 extends through the second housing port 181. The second housing port 181 includes a second housing connector. The second housing connector can be a second housing luer lock connector. The second housing connector can be a second housing luer lock connector. The second housing luer lock connector can be a female luer lock connector. Alternatively, the second hosed luer lock connector can be a male luer lock connector. The second housing connector is configured to connect to a tube.

[0337] The conduit 23 connects the first housing port 179 and the second housing port 181. Specifically, the conduit 23 fluidly connects the first housing opening 180 and the second housing opening 182. The conduit 23 is coiled within the housing 175. Specifically, the housing 175 includes a conduit chamber 183. The conduit 23 is coiled within the conduit chamber 183. The conduit chamber 183 extends between a middle wall 185 and a distal end 187 of the housing 175. The conduit 23 has a predetermined volume, as described herein.

[0338] The housing 175 includes a collar 186. The collar 186 extends away from the intermediate wall 185, away from the second housing port 181. In particular, the collar 186 extends away from the second housing port 181 in a direction generally parallel to a longitudinal axis 193 of the conduit device 175. The longitudinal axis 193 of the conduit device 175 may be generally parallel to the longitudinal axis 21 of the drug delivery device 2 when the conduit device 175 is connected to the drug delivery device 2.

[0339] The drug delivery system 1 may include any drug delivery device 2 described herein and a conduit device 175. The collar 186 is configured to engage with the container 11. In particular, the collar 186 may be configured to engage with the container 11 via an interference fit. The interference fit may be between an inner collar surface 189 and an outer container surface 191.

[0340] The conduit 23 and / or conduit arrangement 175 provide several important advantages. When the drug delivery device 2 is initially engaged with the injection device 3, there is an amount of "slack" in the system. This may be due to, for example, a lack of compression between the injection driver of the injection device 3 (e.g., the actuator of the injection device 3) and the drug delivery device, compressibility of the fluids and components of the drug delivery device 2, or other reasons. The conduit 23, which is of a predetermined volume (e.g., a predetermined minimum volume) as described herein, can mitigate this "slack."

[0341] The drug delivery device 2 can be engaged (i.e. connected) with the injection device 3, which can be operated to drive fluid from the drug delivery device 2 to the end of the conduit 23. The fluid can then be stopped. The flow rate of the fluid is not relevant as no pharmaceutical composition and / or pharmaceutical formulation enters the patient during this period. Therefore, any variation in the flow rate from the predetermined target flow rate is irrelevant. Furthermore, completing this process removes "slack" from the system and therefore does not matter once injection has commenced according to the desired flow rate.

[0342] Furthermore, the pharmaceutical formulation may not always be completely mixed with the diluent as it passes through the valve 39. This is particularly likely when the flow rate is low (e.g., early in the injection) due to the low kinetic energy of the fluid passing through the valve 39. Thus, the rate at which the pharmaceutical formulation is provided to the patient early in the injection is affected. Providing the conduit 23 with a predetermined volume (e.g., a predetermined minimum volume), as described, mitigates this.

[0343] This is because the volume of mixed (i.e. diluted) pharmaceutical formulation delivered during the initial stages of injection may be low and less than the total volume of conduit 23. Because conduit 23 is primed before being connected to the patient, the flow rate during this period may be arbitrarily high. Thus, the clinician may use a flow rate that improves mixing of the pharmaceutical formulation and diluent during priming. Fluid produced during priming is then stored along the length of conduit 23. The diluted pharmaceutical formulation is present at the patient end of conduit 23, and the concentration of the pharmaceutical formulation increases closer to the dilution chamber 25.

[0344] Once the conduit 23 is connected to the patient and the predetermined flow rate program is initiated, the diluted pharmaceutical formulation produced during the priming step is delivered to the patient. The diluted pharmaceutical formulation mixed early in the infusion is delivered to the patient at a much later stage in the infusion, when the flow rate is higher, and therefore has much less impact on the delivery rate of the pharmaceutical formulation.

[0345] In most cases, the conduit arrangement 175 and dual inlet pump of Figure 36 will not be used. In many cases, the drug delivery device 2 will be used as the sole source of pharmaceutical formulation and the dilution chamber outlet may be connected to a conduit 23 (e.g., extension tubing) of known volume such that priming of the conduit 23 can be performed in the same manner as described above before the conduit 23 is attached to the patient and infusion begins.

[0346] Although the fluid delivery system 1 has been described in the context of a pharmaceutical delivery system 1, it will be understood that in some embodiments, the fluid delivery system 1 may be used for purposes other than the delivery of pharmaceutical formulations. For example, in some embodiments, the fluid delivery system 1 is configured to deliver a mixture of fluids as part of an industrial or another process. In these cases, the first fluid stored in the first chamber 15 may be a first industrial fluid and the second fluid stored in the second chamber 25 may be a second industrial fluid. The fluid delivery device 2 may be configured to controllably deliver a mixture of the first and second fluids as part of an industrial or another process. It will be appreciated by those skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.

[0347] For example, the present disclosure describes several embodiments of a drug delivery system 1 and a drug delivery device 2. It will be understood that a particular one of the embodiments of the drug delivery device 2 described herein may include one or more features and / or components of another embodiment of the drug delivery device 2 described herein without departing from the scope of the present disclosure.

Claims

1. 1. A drug delivery device comprising: A first plunger; A second plunger; a container configured to receive the second plunger and at least a portion of the first plunger; the container and the second plunger define a diluent chamber configured to receive a diluent; the container defines a dilution chamber opening; the first plunger, the container, and the second plunger define an active agent chamber configured to receive a pharmaceutical formulation; the second plunger comprises a one-way valve configured to control the flow of pharmaceutical formulation from the active agent chamber to the diluent chamber; The drug delivery device is operable to force a pharmaceutical formulation from the active agent chamber through the one-way valve and into the dilution chamber to mix with the diluent in the dilution chamber, and to push the mixed diluent and pharmaceutical formulation out of the dilution chamber through the dilution chamber opening.

2. The one-way valve is configured to move from a closed position to an open position when a force exceeding a valve threshold force is applied to an inlet side of the valve, 2. The medication delivery device of claim 1, wherein the valve threshold force is less than the sum of the second plunger breakaway force and the first plunger breakaway force.

3. 3. The drug delivery device of claim 1, wherein the first plunger has a concave surface facing the second plunger.

4. 4. The drug delivery device of claim 3, wherein the second plunger has a convex surface facing the first plunger and a convex surface facing the dilution chamber opening.

5. the first plunger and the second plunger are shaped such that when the first plunger is moved into contact with the second plunger, an air gap exists between the first plunger and the second plunger; The drug delivery device of claim 3 , wherein the cavity is configured to trap air bubbles.

6. 6. The drug delivery device of claim 4 or 5, wherein a distal end of the container defines the dilution chamber opening, the second plunger is movable toward the distal end of the container to an end position at which the second plunger cannot move further toward the distal end of the container, and the second plunger is shaped such that at the end position there is a gap between at least a portion of the second plunger and the distal end of the container to prevent suction forces attaching the second plunger to the distal end of the container.

7. 7. The drug delivery device of claim 6, wherein a side of the second plunger facing the distal end of the container includes a first portion that abuts the distal end of the container at the end position and a second portion that does not abut the distal end of the container at the end position.

8. 3. The drug delivery device of claim 1, wherein the one-way valve is contained within a main body of the second plunger, the main body including at least one outlet opening, and the main body including at least one internal channel leading from an outlet of the one-way valve to the at least one outlet opening.

9. 9. The medication delivery device of claim 8, wherein the main body of the second plunger comprises at least two exit openings.

10. 10. The drug delivery device of claim 9, wherein the at least two exit openings are configured to generate a first jet of the pharmaceutical formulation directed in a first direction and a second jet of the pharmaceutical formulation directed in a second direction diverging from the first direction.

11. 11. The drug delivery device of claim 10, wherein the device is configured such that the first and second jets of the pharmaceutical formulation repel each other on an inner surface of the dilution chamber, thereby promoting reverse mixing of the pharmaceutical formulation and diluent within the dilution chamber.

12. 12. A drug delivery device according to claim 10 or 11, wherein the main body of the second plunger is provided with three exit orifices.

13. 3. A medication delivery device according to claim 1 or 2, wherein the second plunger has a length along the longitudinal axis of the container of at least 9 mm.

14. A conduit device, the conduit device comprising: A conduit device housing comprising: A first housing port (179), and a conduit device housing including a second housing port (181); a conduit (23) connecting the first housing port and the second housing port; the first housing port (179) comprises a first connector configured to connect to the dilution chamber opening (51); 3. The drug delivery device of claim 1 or 2, wherein the second housing port (181) is combined with a conduit device comprising a second connector configured to connect to a tube connected to a patient.

15. 3. The drug delivery device of claim 1 or 2, wherein the first plunger comprises a plunger lumen extending between a first plunger lumen opening and a second plunger lumen opening for delivering a pharmaceutical formulation into the active agent chamber through the plunger lumen.

16. The first plunger has a concave surface facing the second plunger, the first plunger includes a plunger lumen extending between a first plunger lumen opening and a second plunger lumen opening; 3. The drug delivery device of claim 1 or 2, for delivering a pharmaceutical formulation to the active agent chamber through the plunger lumen of the first plunger and removing air from the active agent chamber.

17. A drug delivery device as described in claim 1 or 2, wherein the device is configured such that the concentration of the pharmaceutical formulation in the dilution chamber and the concentration of the pharmaceutical formulation administered to the patient are increased during at least a portion of the injection.

18. 3. A method for preparing a drug delivery device according to claim 1 or 2, said method comprising: a) filling the dilution chamber with a diluent; b) filling said active agent chamber with a pharmaceutical formulation.

19. The method of claim 18 , wherein the activator chamber is filled with an activator via a plunger lumen of the first plunger.

20. 1. A drug delivery system comprising: A drug delivery device according to claim 1 or 2; an injection device, The injection device comprises: at least one injection device processor; an infusion device memory storing program instructions accessible by the at least one infusion device processor and configured to cause the at least one infusion device processor to control the drug delivery device to deliver the pharmaceutical formulation to a patient according to a predetermined dose profile.

21. The system further comprises an extension tube of known, predetermined volume to the drug delivery device, and the infusion device processor is configured to perform a priming process prior to the start of an infusion, the priming process comprising:

21. The drug delivery system of claim 20, further comprising priming the drug delivery device by passing a pharmaceutical formulation from the active agent chamber through the one-way valve into the dilution chamber, mixing with a diluent in the dilution chamber, and then through the dilution chamber opening and into the extension tube, whereby the known, predetermined volume of the extension tube is filled with the diluted pharmaceutical formulation that will form a first portion of the injection, and wherein a concentration profile of the diluted pharmaceutical formulation in the extension tube follows a desired dose profile for the first portion of the injection.

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