CN117500540A - Drug delivery systems, devices and methods - Google Patents
Drug delivery systems, devices and methods Download PDFInfo
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- CN117500540A CN117500540A CN202280042219.0A CN202280042219A CN117500540A CN 117500540 A CN117500540 A CN 117500540A CN 202280042219 A CN202280042219 A CN 202280042219A CN 117500540 A CN117500540 A CN 117500540A
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- Infusion, Injection, And Reservoir Apparatuses (AREA)
Abstract
Examples of the present application disclose a drug delivery device comprising a first piston, a second piston, and a container configured to receive at least a portion of the second piston and the first piston. The container and the second piston define a dilution chamber configured to receive a diluent. The container defines a dilution chamber opening. The first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation. The second piston includes a one-way valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the diluting chamber. The one-way valve is configured to move from a closed position to an open position upon application of a force to an inlet side of the valve that exceeds a valve threshold force. The valve threshold force is less than a sum of the break-out force of the second piston and the break-out force of the first piston.
Description
Technical Field
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
Administration of pharmaceutical formulations (e.g., intravenous drugs) to patients can involve a number of risks. The risk is particularly related to patients with drug hypersensitivity to specific intravenous drugs. Drug hypersensitivity to specific intravenous drugs is often unpredictable, if not impossible. In particular, the specific drug dosage of a drug that may induce drug hypersensitivity in a particular patient is difficult to predict prior to administration of the drug.
To reduce the risk of any patient suffering from a life threatening drug response, one method of administering a particular intravenous drug is to administer a specific dose (referred to as the test dose) that will elicit a sub-maximum adverse response to the patient. The test dose is delivered prior to delivering the therapeutic dose of the drug.
Once any sub-maximal or slight adverse effects in response to the test dose are detected, administration of the intravenous drug may be immediately discontinued to minimize the risk of developing a more severe adverse effect or the final death of the patient.
Nevertheless, the practice of administering test doses is neither routine nor recommended. This is especially because:
the test dose which normally causes the next greatest response is usually about 0.01% to 0.1% of the therapeutic dose to be administered to the patient, and the preparation of this amount of test dose is time consuming and difficult.
The test dose that causes the detectable sub-maximum response varies from patient to patient, possibly between 0.01% and 100% of the therapeutic dose. For example, the detectable next-to-maximum response for a particular patient may occur at any of 0.01%, 1%, 10% or 100% of the therapeutic dose, and this varies from patient to patient.
These and other reasons make it difficult or even impossible for a clinician to select an appropriate test dose to test to confirm whether adverse reactions will occur during administration of a therapeutic dose. In particular, administration of relatively small test doses may not cause adverse reactions in patients; however, administration of relatively large doses (above a specific threshold specific to each patient) may cause life-threatening adverse reactions. This reaction may lead to patient death. Thus, administration of a test dose may result in a life-threatening condition that the test dose is intended to prevent.
Since it is difficult to determine which specific percentage of the therapeutic dose should be administered to a patient is the test dose for that specific patient, current practice is to administer intravenous drugs by constant infusion (brief 'push' or constant infusion over a fixed period of time). This has similar risks as mentioned above. Administering a therapeutic dose of a drug without confirming whether the patient is hypersensitive or allergic to the particular drug may result in administration of a lethal drug dose to the patient or cause serious adverse effects.
Furthermore, any test dose that may be currently administered to a patient must be performed prior to and separate from the infusion of the therapeutic dose required by the particular patient. Preparing individual test doses requires preparing a large number of pharmaceutical formulations for each test dose and therapeutic dose. This procedure is cumbersome and therefore typically does not provide a test dose to the patient. In contrast, in the absence of testing the patient's response to the drug, the patient is provided with a therapeutic dose. This increases the risk that a particular patient (having a drug hypersensitivity to a particular drug) may suffer from a life threatening condition when this particular drug is administered. This is especially because current methods for administering full therapeutic doses ('push' or constant infusion over a fixed period of time) provide relatively large doses at the beginning of the infusion process compared to those required to typically cause serious adverse effects. This leaves the clinician with insufficient time to detect that the patient infused with the drug formulation has an adverse (i.e., negative) reaction to the drug.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this disclosure.
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 groups of steps.
Disclosure of Invention
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 groups of steps.
A first aspect of the present disclosure provides a drug delivery device comprising: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston; wherein: the container and the second piston define a dilution chamber configured to receive a diluent; the container defining a dilution chamber opening; the first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation; and the second piston includes a one-way valve configured to permit flow of the pharmaceutical formulation from the active agent chamber to the diluting chamber and to block flow of fluid from the diluting chamber to the active agent chamber.
A second aspect of the present disclosure provides a drug delivery device comprising: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston; wherein: the container and the second piston define a dilution chamber configured to receive a diluent; the container defining a dilution chamber opening; the first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation; and the second piston includes a one-way valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the diluting chamber; the one-way valve is configured to move from a closed position to an open position upon application of a force to an inlet side of the valve that exceeds a valve threshold force; and the valve threshold force is less than a sum of the break-out force of the second piston and the break-out force of the first piston; wherein the drug delivery device is operable to force a drug formulation from the active agent chamber into the dilution chamber through the one-way valve to mix with the diluent in the dilution chamber and to force the mixed diluent and drug formulation out of the dilution chamber through the dilution chamber opening. Mixing of the pharmaceutical formulation with the diluent in the dilution chamber occurs simultaneously with the diluted pharmaceutical formulation being discharged from the dilution chamber through the dilution chamber opening.
A third aspect of the present disclosure provides a drug delivery device comprising: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston; wherein: the first piston is configured to seal with the container to provide a first seal; the second piston is configured to seal with the container to provide a second seal; the container and the second piston define a dilution chamber configured to receive a diluent; the container defining a dilution chamber opening; the first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation; the second piston includes a one-way valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber; and the break-away force of the second piston is greater than the break-away force of the first piston.
The first, second or third aspect of the present disclosure may have any of the following additional features.
The container may define an active agent chamber opening and an active agent chamber port including an active agent chamber port opening. The active agent chamber port may be positioned on a side of the container between an active chamber opening and the dilution chamber opening. For example, between the initial position of the first piston and the initial position of the second piston.
The valve threshold force may be less than the break-out force of the second piston. The first piston may have a concave surface facing the second piston. The second piston may have a convex surface facing the first piston and a convex surface facing the dilution chamber opening.
The first and second pistons may be shaped such that when the first piston moves into contact with the second piston, an air gap exists between the first and second pistons. The air gap may act as a bubble trap. The second piston may partially conform to the shape of the first piston to minimize loss of the pharmaceutical formulation while also allowing space for any air bubbles to be trapped between the first and second pistons when the first piston is moved into contact with the second piston.
In some embodiments, the distal end of the container defines the dilution chamber opening, the second piston is movable toward the distal end of the container to an end position at which the second piston is unable to move further toward the distal end of the container, and wherein the second piston is shaped such that in the end position there is a gap between at least a portion of the second piston and the distal end of the container to avoid suction attaching the second piston to the distal end of the container. The second piston may have a different shape or profile than the distal end of the container to avoid sucking the second piston to the distal end of the container.
The second piston may partially conform to the distal end of the container to minimize loss of drug formulation and/or diluent when the second piston is moved into contact with the distal end of the container to expel the contents of the dilution chamber. When the second piston moves into contact with the distal end of the container, a gap remains between at least a portion of the second piston and the distal end of the container to avoid suction attaching the second piston to the distal end of the container, as the second piston partially conforms to the distal end of the container.
In some embodiments, a side of the second piston facing the distal end of the container includes a first portion that abuts the distal end of the container in the end position and a second portion that does not abut the distal end of the container in the end position.
The one-way valve may be a duckbill valve.
In some embodiments, the one-way valve is contained within a body of the second piston, the body containing at least one outlet opening, and the body containing at least one internal passage leading from an outlet of the one-way valve to the at least one outlet opening.
In some embodiments, the body of the second piston includes at least two outlet openings.
In some embodiments, the at least two outlet openings are configured to generate a first jet of the pharmaceutical formulation directed at a first corner of the dilution chamber and a second jet of the pharmaceutical formulation directed at a second corner of the dilution chamber when the pharmaceutical formulation is forced from the active agent chamber through the one-way valve.
In some embodiments, the device is configured such that the first jet and the second jet of the pharmaceutical formulation rebound from an inner surface of the dilution chamber, thereby facilitating back mixing of the pharmaceutical formulation with the diluent in the dilution chamber.
In some embodiments, the one-way valve is a duckbill valve having a slit substantially perpendicular to a line joining a first opening and a second opening of the at least two outlet openings.
In some embodiments, the body of the second piston includes three outlet openings.
In some embodiments, a middle opening of the three outlet openings is configured to generate a third jet of the pharmaceutical formulation directed towards the dilution chamber opening.
In some embodiments, the length of the second piston along the longitudinal axis of the container is at least 9mm.
In some embodiments, the first piston includes a piston lumen for delivering a drug formulation through the piston lumen and into the active agent chamber, the piston lumen extending between a first piston lumen opening and a second piston lumen opening.
In some embodiments, a piston lock is further provided to fix the position of the first piston relative to the container such that the first piston may not move further into the container, optionally the piston lock may include a first recess for receiving a projection (e.g., flange) of the first piston and a second recess for receiving a projection (e.g., flange) of the container.
In some embodiments, the container has indicia indicating a starting position of the second piston to be positioned within the container at the beginning of an infusion.
A fourth aspect of the present disclosure provides a drug delivery device according to any one of the preceding claims in combination with a tubing device comprising: a plumbing enclosure, the plumbing enclosure comprising: a first housing port; a second housing port; and a conduit connecting the first housing port and the second housing port; wherein: the first housing port includes a first connector configured for connection with a dilution chamber outlet opening; and the second housing port includes a second connector configured for connection with a tube connected to a patient.
A fifth aspect of the present disclosure provides a method of preparing the drug delivery device of the preceding aspect, the method comprising: a) Filling the dilution chamber with a diluent; and b) filling the active agent chamber with a pharmaceutical formulation.
In some embodiments, the dilution chamber is filled with a diluent prior to filling the active agent chamber with the pharmaceutical formulation.
In some embodiments, the dilution chamber is filled via a dilution chamber opening and the active agent chamber is filled with an active agent port on one side of the container.
In some embodiments, the active agent chamber is filled with an active agent before the dilution chamber is filled with a diluent.
In some embodiments, the active agent chamber is filled with active agent via a piston lumen of the first piston.
In one example, the second piston is positioned at a starting position defining an initial volume of the dilution chamber that the dilution chamber is to have at the beginning of the infusion, prior to filling the dilution chamber. The second piston may be provided to the clinician at an initial position that is the same as or further from the distal end of the container than the initial position.
A sixth aspect of the present disclosure provides a method of preparing a drug delivery device comprising an active agent chamber, a dilution chamber, a one-way valve connecting the active agent chamber and the dilution chamber, and a dilution chamber opening, the method comprising: c) Connecting the drug delivery device to an infusion driver; d) Attaching an elongated tube having a known predetermined volume to the dilution chamber opening of the drug delivery device; and e) priming the drug delivery device by: passing a pharmaceutical formulation from the active agent chamber into the diluting chamber through the one-way valve; mixing with the diluent in the dilution chamber; and then exits through the dilution chamber opening into the elongated tube such that the elongated tube having a known predetermined volume is filled with a diluted drug formulation to form a first portion of an infusion, and wherein a concentration profile of the diluted drug formulation in the elongated tube is according to a desired dose profile of the first portion of the infusion.
In some embodiments, after loading the drug delivery device, the elongate tube is attached to a patient and the infusion driver is used to control the drug delivery device to dilute the drug formulation by mixing the drug formulation with the diluent in the dilution chamber and deliver the diluted drug formulation to the patient according to a predetermined dose profile.
A seventh aspect of the present disclosure provides a drug delivery system comprising: the drug delivery device according to any of the preceding claims; an infusion device; wherein the infusion device comprises: at least one infusion device processor; and an infusion device memory storing program instructions accessible by the at least one infusion device processor and configured to cause the at least one infusion device processor to control the drug delivery apparatus to deliver the drug formulation to the patient according to a predetermined dose profile.
In some embodiments, the infusion device is configured to actuate an infusion device actuator to displace the first piston such that the drug formulation is output by the drug delivery apparatus according to the predetermined dose spectrum; or the infusion device is configured to apply an infusion pressure at the dilution chamber outlet, thereby causing displacement of the first piston such that the drug formulation is output by the drug delivery device.
In some embodiments, the system further comprises an elongated tube of known predetermined volume leading to the drug delivery device, and the processor is configured to perform a priming process prior to the beginning of the infusion, wherein the priming process comprises: the drug delivery device is filled by: passing a pharmaceutical formulation from the active agent chamber into the diluting chamber through the one-way valve; mixing with the diluent in the dilution chamber; and then exits through the dilution chamber opening into the elongated tube such that the elongated tube having a known predetermined volume is filled with a diluted drug formulation to form a first portion of the infusion, and wherein a concentration profile of the diluted drug formulation in the elongated tube is according to a desired dose profile of the first portion of the infusion.
In some embodiments, a drug delivery device is provided. The drug delivery device comprises: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston. The container and the second piston define a dilution chamber configured to receive a diluent. The container defines a dilution chamber opening. The first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation. The second piston includes a valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber. The first piston includes a piston lumen extending between a first piston lumen opening and a second piston lumen opening.
In some embodiments, the active agent chamber is configured to receive the pharmaceutical formulation through the piston lumen.
In some embodiments, the first piston includes a first luer lock connector defining the first piston lumen opening.
In some embodiments, the first piston lumen opening is a piston lumen inlet.
In some embodiments, the second piston lumen opening is a piston lumen outlet.
In some embodiments, the first piston includes a one-way valve configured to control flow of the pharmaceutical formulation from the piston lumen to the active agent chamber.
In some embodiments, the drug delivery device further comprises a first piston cap configured to connect to the first piston to cap the first piston lumen opening.
In some embodiments, the first piston cap includes a second luer lock connector configured to connect with the first luer-lock connector of the first piston.
In some embodiments, the first piston includes an air lumen extending between a first air lumen opening and a second air lumen opening.
In some embodiments, the first piston and the second piston are each configured to be displaced relative to a longitudinal axis of the container.
In some embodiments, the second piston is disposed between the first piston and the dilution chamber opening.
In some embodiments, the container defines a container interior surface, and the first piston includes a first piston sealing surface configured to seal with the container interior surface to inhibit fluid flow between the container interior surface and the first piston sealing surface.
In some embodiments, the first piston comprises a first piston O-ring comprising the first piston sealing surface.
In some embodiments, the container defines a container interior surface, and the second piston includes a second piston sealing surface configured to seal with the container interior surface to inhibit fluid flow between the container interior surface and the second piston sealing surface.
In some embodiments, the second piston comprises a second piston O-ring comprising the second piston sealing surface.
In some embodiments, the valve includes an inlet side and an outlet side.
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.
In some embodiments, the valve is configured to move from the open position to the closed position upon removal of the pressure applied to the inlet side.
In some embodiments, the valve is biased toward the closed position.
In some embodiments, the valve comprises a plurality of petals configured to separate upon application of pressure to the inlet side.
In some embodiments, the drug delivery device further comprises a conduit configured to be fluidly connected to the dilution chamber opening, and the conduit has a predetermined volume.
In some embodiments, the drug delivery device further comprises a dilution chamber port cover configured to connect to the container to cover the dilution chamber opening.
In some embodiments, the first piston is configured to seal with the container to provide a first seal.
In some embodiments, the second piston is configured to seal with the container to provide a second seal.
In some embodiments, the break-away force of the second piston is greater than the break-away force of the first piston.
In some embodiments, a drug delivery device is provided. The drug delivery device comprises: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston. The container and the second piston define a dilution chamber configured to receive a diluent. The container defines a dilution chamber opening. The first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation. The second piston includes a valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber.
In some embodiments, a drug delivery device is provided. The drug delivery device comprises: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston. The container and the second piston define a dilution chamber configured to receive a diluent. The container defines a dilution chamber opening. The first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation. The second piston includes a valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber. The valve is configured to move from a closed position to an open position upon application of a force to an inlet side of the valve that exceeds a valve threshold force. The valve threshold force is less than a sum of the break-out force of the second piston and the break-out force of the first piston.
In some embodiments, the valve threshold force is less than the break-out force of the second piston.
In some embodiments, the valve opening force of the valve is less than the break-out force of the second piston.
In some embodiments, the valve is configured to move from the open position to the closed position upon removal of the force applied to the inlet side of the valve.
In some embodiments, a drug delivery device is provided. The drug delivery device comprises: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston. The first piston is configured to seal with the container to provide a first seal. The second piston is configured to seal with the container to provide a second seal. The container and the second piston define a dilution chamber configured to receive a diluent. The container defines a dilution chamber opening. The first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation. The second piston includes a valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber. The break-off force of the second piston is greater than the break-off force of the first piston.
In some embodiments, the container defines an active agent chamber opening.
In some embodiments, the container defines an active agent chamber port that includes an active agent chamber port opening.
In some embodiments, the first piston includes a first number of O-rings.
In some embodiments, the second piston includes a second number of O-rings.
In some embodiments, the second number is greater than the first number.
In some embodiments, one or more of the first number of O-rings includes a first O-ring having a first diameter and a first O-ring groove having a first groove width.
In some embodiments, one or more of the second number of O-rings includes a second O-ring having a second diameter and a second O-ring groove having a second groove width.
In some embodiments, the second diameter is greater than the first diameter.
In some embodiments, the second piston comprises a valve arrangement configured to control flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber, the valve arrangement comprising a valve.
In some embodiments, the second piston comprises a second valve.
In some embodiments, the valve and the second valve are configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber.
In some embodiments, a drug delivery device is provided. The drug delivery device comprises: a first piston; a second piston; and a container configured to receive at least a portion of the second piston and the first piston; and at least one resistive element configured to resist displacement of the second piston when the first piston is displaced. The container and the second piston define a dilution chamber configured to receive a diluent. The container defines a dilution chamber opening. The first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation. The second piston includes a valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber.
In some embodiments, the container defines an active agent chamber opening.
In some embodiments, the at least one resistive element comprises a second piston O-ring.
In some embodiments, the second piston comprises the second piston O-ring.
In some embodiments, the first piston includes a first number of first piston O-rings.
In some embodiments, one or more of the first number of first piston O-rings includes a first piston O-ring having a first diameter and a first piston O-ring groove having a first groove width.
In some embodiments, one or more of the second number of second piston O-rings includes a second piston O-ring having a second diameter and a second piston O-ring groove having a second groove width.
In some embodiments, the second diameter is greater than the first diameter.
In some embodiments, the second groove width is less than the first groove width.
In some embodiments, the second piston comprises a valve arrangement configured to control flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber, the valve arrangement comprising a valve.
In some embodiments, the second piston comprises a second valve.
In some embodiments, the valve and the second valve are configured to control the flow of the pharmaceutical formulation from the active agent chamber to the dilution chamber.
In some embodiments, the valve is configured to move from the closed position to the open position upon application of a force to the inlet side of the valve that exceeds a valve threshold force.
In some embodiments, the valve threshold force is less than a sum of the break-out force of the second piston and the break-out force of the first piston.
In some embodiments, the break-away force of the second piston is greater than the break-away force of the first piston.
In some embodiments, a plumbing device is provided. The plumbing device includes: a housing, the 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 includes a second connector.
In some embodiments, the conduit is coiled within the housing.
In some embodiments, the conduit has a predetermined volume.
In some embodiments, the housing further comprises a collar extending away from the second connector in a direction parallel to the longitudinal direction of the plumbing fixture.
In some embodiments, the collar is configured to engage with the container.
In some embodiments, the first connector is a third luer lock connector configured to connect to a dilution chamber port defining the dilution chamber opening.
In some embodiments, the second connector is a fourth luer lock connector.
In some embodiments, a drug delivery system is provided. The drug delivery system comprises: any of the above drug delivery device embodiments; and any of the plumbing embodiments described above.
In some embodiments, a drug delivery system is provided. The drug delivery system comprises: any of the above drug delivery devices; an infusion device. The infusion device comprises: at least one infusion device processor; infusion device memory. The infusion device memory stores program instructions accessible by the at least one infusion device processor and configured to cause the at least one infusion device processor to: actuating an infusion device actuator to displace the first piston such that the drug formulation is output by the drug delivery device.
In some embodiments, a drug delivery system is provided. The drug delivery system comprises: any of the above drug delivery device embodiments; an infusion device. The infusion device comprises: at least one infusion device processor; and an infusion device memory storing program instructions accessible by the at least one infusion device processor and configured to cause the at least one infusion device processor to: controlling the infusion device to apply an infusion pressure at the dilution chamber outlet, thereby causing displacement of the first piston such that the drug formulation is output by the drug delivery device.
Drawings
Embodiments of the present disclosure will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
fig. 1A is a perspective view of a drug delivery system according to some embodiments;
FIG. 1B is a block diagram of the drug delivery system shown in FIG. 1, according to some embodiments;
fig. 2 is a side view in cross section of a drug delivery device according to some embodiments;
fig. 3 is a perspective view of the drug delivery device of fig. 2, wherein a portion of the container of the drug delivery device is transparent;
fig. 4 is a perspective view of a drug delivery system according to some embodiments;
fig. 5A-5E illustrate methods of operation of a drug delivery system according to some embodiments;
fig. 6 illustrates a method of operation of the drug delivery device of fig. 1-5E according to some embodiments;
fig. 7 illustrates another method of operation of the drug delivery device of fig. 1-5E according to some embodiments;
fig. 8 illustrates a method for preparing the drug delivery device of fig. 1-5E, according to some embodiments;
fig. 9 illustrates another method for preparing the drug delivery device of fig. 1-5E according to some embodiments;
fig. 10 illustrates a drug delivery device according to some embodiments having a first piston with a concave surface facing the second piston and a second piston with a convex surface facing the first piston and a convex surface facing the distal end of the container;
FIG. 11 illustrates a cover for a primary piston and a support structure for the cover, according to some embodiments;
fig. 12 illustrates a drug delivery device including a piston lumen according to some embodiments;
fig. 13A is a schematic diagram of a cross-section of the drug delivery device of fig. 12, according to some embodiments;
fig. 13B is a schematic diagram of a cross-section of the drug delivery device of fig. 12 when filled with a diluent and a drug formulation, according to some embodiments;
fig. 14 illustrates a method of preparing the drug delivery device of fig. 12-13B, according to some embodiments;
fig. 15 illustrates an embodiment of a drug delivery device comprising an alternative first piston and an alternative second piston, according to some embodiments;
fig. 16 illustrates a method of preparing the drug delivery device of fig. 15, according to some embodiments;
fig. 17 illustrates a method of preparing a drug delivery device according to some embodiments;
fig. 18 illustrates another method of preparing a drug delivery device according to some embodiments;
19A and 19B illustrate side views of a drug delivery device having a piston in different positions according to some embodiments;
FIG. 20A illustrates a side view of a drug delivery device including an O-ring in a first state according to some embodiments;
FIG. 20B illustrates a side view of another drug delivery device including an O-ring in a first state, according to some embodiments;
FIG. 20C illustrates a cross-section of an O-ring according to some embodiments;
fig. 21 illustrates a side view of a drug delivery device in a first state according to some embodiments;
fig. 22 illustrates a side view of a drug delivery device including a protrusion in a first state according to some embodiments;
fig. 23 illustrates a side view, partially in cross-section, of a drug delivery device according to some embodiments;
fig. 24 illustrates a side view, partially in cross-section, of a drug delivery device according to some embodiments;
FIG. 25A illustrates a second piston according to some embodiments;
FIG. 25B illustrates another second piston according to some embodiments;
FIG. 25C illustrates a piston according to some embodiments;
FIG. 25D illustrates a piston according to some embodiments;
FIG. 26 illustrates a drug delivery device having a first piston and a second piston shaped to provide an air trap, according to some embodiments;
FIG. 27 illustrates a second piston having a single outlet, according to some embodiments;
FIG. 28 illustrates a second piston having two outlets according to some embodiments;
FIG. 29A illustrates a second piston having two outlets according to some embodiments;
fig. 29B is a plan view of a second piston having two outlets and a horizontal duckbill valve, according to some embodiments;
fig. 29C is a plan view of a second piston having two outlets and a vertical duckbill valve, according to some embodiments;
30A-30F illustrate a jet of a pharmaceutical formulation that is ejected through two outlets of a second piston into a dilution chamber and mixes the pharmaceutical formulation with a diluent, according to some embodiments;
FIG. 31 is a perspective view of a second piston having three outlets according to some embodiments;
FIG. 32 is a cross-sectional view of a second piston having three outlets according to some embodiments;
33A-33F illustrate jets of a pharmaceutical formulation ejected through three outlets of a second piston into a dilution chamber and mixing the pharmaceutical formulation with a diluent, according to some embodiments;
FIG. 34 illustrates an internal structure of a second piston having multiple passages and outlets according to some embodiments;
fig. 35 illustrates a drug delivery system according to some embodiments;
FIG. 36 illustrates a pump having a primary inlet and a secondary inlet that may be connected to a tubing set or a drug delivery device, according to some embodiments;
FIG. 37 illustrates a perspective view of a portion of a tubing device and a drug delivery device according to some embodiments; and is also provided with
Fig. 38 illustrates a perspective view of the tubing set and drug delivery device of fig. 37, according to some embodiments.
Detailed Description
The present disclosure relates to systems for administering pharmaceutical formulations. In particular, various embodiments of a drug delivery device for administering a pharmaceutical formulation are disclosed.
It will be understood that the term "active agent" as used in this description may correspond to, or also be referred to as "active ingredient" or "drug". That is, throughout the present disclosure, the terms "active ingredient," "active agent," and "drug" have been used to describe an active agent to be administered to a patient. In some embodiments, the pharmaceutical formulation may be delivered to a patient. The pharmaceutical formulation may include an active agent. The pharmaceutical formulation may also include one or more other 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 specific concentration of the active agent. This may be referred to as the active agent concentration. The pharmaceutical formulation may be a solution. It will be appreciated that in some embodiments, the term "drug" as used in this description may correspond to an active agent of the "pharmaceutical formulation".
Drug deliveryDelivery system
Fig. 1A, 1B, 4, and 5A to 5E illustrate 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 output the mixed fluids. In some embodiments, the fluid delivery device 2 is in the form of a drug delivery device 2. Fig. 2, 3, 6 and 7 illustrate a drug delivery device 2 according to some embodiments.
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 drug formulation according to a target flow rate approximating a flow rate delivery function. In some embodiments, the drug delivery system 1 is configured to provide a drug formulation according to a target flow rate as described in international patent application 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 drug formulation according to a target flow rate as described in australian provisional patent application No. 2021901792, the contents of which are incorporated herein by reference in its entirety. The target flow rate may vary over time.
As described in PCT/AU2020/051363 and australian provisional patent application No. 2021901792, an infusion device may be configured to control intravenous delivery of a pharmaceutical formulation by a drug delivery apparatus to a patient, the infusion device comprising a processor and a memory, the memory storing instructions accessible by the processor to cause the drug delivery apparatus to deliver the pharmaceutical formulation to the patient according to a predetermined dose profile; wherein the predetermined dose profile is designed to deliver the therapeutic dose of the pharmaceutical formulation to the patient over a predetermined infusion time in a manner that facilitates a safe detection of adverse effects of the pharmaceutical formulation by the patient or desensitization of the pharmaceutical formulation by the patient during a first phase of administration of the therapeutic dose.
In some examples, the predetermined dose profile is such that the dose rate varies with the predetermined infusion time. In some examples, the cumulative dose delivered to the patient increases exponentially, or at a rate that increases over time, for at least a portion of the predetermined infusion time. In some examples, the dose spectrum is such that there is a first time period between reaching 0.01% and 0.1% of the cumulative dose of the therapeutic dose and a second time period between reaching 0.1% and 1% of the cumulative dose of the therapeutic dose, and the first time period and the second time period are selected from the group consisting of: at least 6 minutes, at least 5 minutes, at least 4 minutes, at least 3 minutes, 2 minutes to 10 minutes, and at least a latency of adverse reactions.
The processor of the infusion device may control the drug delivery device by controlling the infusion device to deliver the drug formulation according to a predetermined profile. For example, the infusion device may drive a pump or be controlled to drive a piston of the drug delivery device such that the drug formulation is delivered according to a predetermined dose profile. For example, the processor may divide the predetermined infusion time into a plurality of infusion steps and determine a target flow rate or target output volume for each infusion step such that a predetermined dose profile is achieved when the actuator is controlled in accordance with the target flow rate or target output volume for each infusion step. The target flow rate or target output volume of the infusion step of the predetermined dose spectrum may be determined by reference to a look-up table stored in memory or by real-time calculation. In any event, the cumulative dose of drug delivered to the patient begins at a very low level and increases during infusion; in some cases, the dose rate increases as the infusion proceeds. Infusion may for example last 20 to 180 minutes. The dose rate may be relatively low and only slowly increase during the first part of the infusion, for example during the first 10 minutes of infusion.
Many infusion drivers may have difficulty accurately delivering low infusion rates. Thus, in some examples, the drug delivery device may include an active agent chamber that discharges the drug formulation into a separate dilution chamber containing the diluent, and then the diluted drug formulation may flow to the patient, for example, through a conduit such as an elongated tube. Since the pharmaceutical formulation can be diluted in large amounts at the beginning of the infusion in this way, a higher infusion rate can be used while still delivering a low dose rate. The concentration of the drug formulation in the dilution chamber and delivered to the patient may vary and may increase during at least part of the infusion. A convenient embodiment is a drug delivery device in the form of a syringe having a pair of pistons defining an active agent chamber and a diluting chamber, as will be described in more detail below.
The drug delivery system 1 comprises an infusion device 3, such as a syringe driver, peristaltic pump, volumetric pump or similar drug infusion pump. The infusion device 3 may comprise or be in the form of an infusion driver 3. The infusion device 3 may comprise or be in the form of a vacuum infusion device 3. Wherein the infusion device 3 comprises or is in the form of a vacuum infusion device 3, the infusion device 3 may apply an infusion pressure (i.e. a vacuum pressure 61) at the dilution chamber opening 53, thereby causing displacement of the first piston 13 such that the drug formulation is output by the drug delivery device 2. The pharmaceutical formulation may be delivered at a target flow rate.
The infusion device 3 comprises a control unit for controlling the flow rate at which the infusion device 3 delivers the drug 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 includes a plurality of instructions for running an algorithm designed to calculate a flow rate as specified by a flow rate delivery function. In some embodiments, the flow rate delivery function is characterized by a flow rate of the drug formulation provided to the patient by the drug delivery device 2. Fig. 1B shows a block diagram of a drug delivery system 1.
The drug delivery device 2 comprises a first piston 13. The first piston 13 may also be referred to as primary piston. The drug delivery device 2 comprises a second piston 14. The second piston 14 may also be referred to as a split piston. The drug delivery device 2 comprises a container 11. Container 11 may also be referred to as a syringe 11. The container 11 is configured to receive a second piston 14. The container 11 is configured to receive at least a portion of the first piston 13. This may be the distal portion of the first piston 13.
The second piston 14, when housed in the container 11, defines two chambers within the container 11. Specifically, the second piston 14 defines a first chamber 15 and a second chamber 25 when housed in the container 11. The first chamber 15 is configured to store a first fluid. The first fluid may be a solution comprising an active agent and a solvent. The active agent may be as described herein. The solvent may be as described herein. The first chamber 15 may be referred to as an active agent 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 diluting chamber 25. Specifically, the container 11 and the second piston 14 together define a dilution chamber 25. The dilution chamber 25 is configured to receive a dilution liquid. The first piston 13, the reservoir 11 and the second piston 14 together define an active agent chamber 15.
The active agent chamber 15 is configured to receive an active agent. In some embodiments, the active agent may be a solid (e.g., in crystalline form or as a powder). In such cases, the active agent chamber 15 may be configured to receive a solvent. The solvent is configured to dissolve the solid active agent. The pharmaceutical formulation thus comprises the active agent dissolved in a solvent. That is, the pharmaceutical formulation includes a solution that includes an active agent and a solvent.
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 an active agent (when dissolved) and a solvent. In these cases, the active agent chamber 15 is configured to receive a pharmaceutical formulation as a solution comprising an active agent and a solvent.
The second piston 14 is configured to enable fluid (e.g., a pharmaceutical formulation) contained in the active agent chamber 15 to flow into the dilution chamber 25. Dilution chamber 25 includes a diluent for mixing with the pharmaceutical formulation (or active agent) flowing from active agent chamber 15.
The second piston 14 includes a valve 39. The valve 39 may also be referred to as a valve device 39. Valve 39 is configured to control the flow of the pharmaceutical formulation from the active agent chamber 15 into the diluting chamber 25. In other words, the second piston 14 comprises a valve 39 configured to control the flow of the pharmaceutical formulation from the active agent chamber 15 to the dilution chamber 25. Dilution chamber 25 is near the distal end of container 11, while active agent chamber 15 is farther from the distal end of the container. As shown in fig. 6, in use, the pharmaceutical formulation may be expelled from the active agent chamber 15 through the valve 39 to the diluting chamber 25 and from the diluting chamber 25 through the diluting chamber opening 51. The dilution chamber opening 51 may be connected to a conduit 23, such as an elongated tube, which leads to the patient. In this way, the pharmaceutical formulation may be mixed with the diluent in the dilution chamber, and the diluted pharmaceutical formulation may be ejected from the device and delivered intravenously to the patient. Since the fluid can be continuously forced through the dilution chamber and out of the dilution chamber opening, mixing of the drug formulation and the diluent in the dilution chamber can occur simultaneously, as the diluted drug formulation is ejected through the dilution chamber opening.
In fig. 5A-5D and 6, diluting chamber 25 is oriented distally of container 11 and active agent chamber 15 is oriented proximally. This arrangement differs from prior art dual chamber syringes where the diluting chamber is located proximally and the active agent chamber is located distally, as in the examples of the present disclosure the order of the chambers is different. In some examples, the medical delivery device of the present disclosure may have an empty diluting chamber and an active agent chamber to be filled by a clinician. This is in contrast to prior art dual chamber syringes where the syringe has an active agent chamber prefilled with solid drug at the distal end and a diluent chamber prefilled with diluent at the proximal end.
Valve 39 is a one-way valve that allows fluid flow from the active agent chamber 15 to the diluting chamber 25, but prevents fluid flow from the diluting chamber to the active agent chamber. The valve 39 may be configured to control the flow of the pharmaceutical formulation in response to the applied pressure. The pressure may be applied by the first piston 13. Alternatively, the pressure may be applied via the first piston 13. In the particular arrangement shown in at least figures 1 to 8, the valve 39 comprises a duckbill valve 41. The duckbill valve 41 includes a plurality of petals 43 that separate relative to each other when pressure is applied to the first piston 13, thereby opening the duckbill valve 41. After removal of the pressure applied to the first piston 13, the flap 43 returns to its original state, thereby closing the duckbill valve 41 and preventing the back flow of the pharmaceutical formulation to the active agent chamber 15.
The valve 39 (or valve device 39) includes an inlet side 45 and an outlet side 47. The valve 39 (or valve device 39) is configured to move from a closed position to an open position upon application of pressure to the inlet side 45. Pressure may be applied to the inlet side 45 of the valve 39 (or valve device 39) by longitudinally displacing (or actuating) the first piston 13 within 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 upon removal of pressure applied to the inlet side. When the pressure applied to the inlet side 45 exceeds a pressure threshold, the valve 39 (or valve device 39) may be configured to move from a closed position to an open position. When the pressure applied to the inlet side 45 is below a pressure threshold, the valve 39 (or valve device 39) may be configured to move from an open position to a closed position.
The valve 39 (or valve means 39) is biased towards a closed position. The valve 39 (or valve means 39) comprises a plurality of petals 43. The plurality of petals 43 are configured to separate upon application of pressure to the inlet side 45. The first piston 13 is configured to contact the second piston 14 once all or most of the drug formulation in the active agent chamber 15 has been transferred to the dilution chamber 25. Further actuation of the first piston 13 will also result in movement of the second piston 14. Thus, actuation of the first piston 13 causes movement of the second piston 14 and causes the drug formulation in the dilution chamber 25 to be output by the drug delivery device 2.
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 allow the first port 49 to 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 through which the active agent chamber 15 and/or the interior of the container 11 can be accessed. The drug delivery system 1 comprises a first port cap 50. The first port cover 50 is configured to cover the active agent chamber port 49. The first port cover 50 may be referred to as an active agent chamber port cover 50.
The container includes a second port 51. The second port 51 may be referred to as a vessel outlet port 51. The second port 51 may also be referred to as a dilution chamber port 51. Dilution chamber port 51 defines a dilution chamber opening 53. Dilution chamber opening 53 is an opening in container 11 through which dilution chamber 25 and/or the interior of container 11 may be accessed. The drug delivery system 1 comprises a second port cover 52. The second port cover 52 may be referred to as a container outlet port cover 52. The second port cover 52 may be referred to as a dilution chamber port cover 52. The dilution chamber port cover 52 is configured to cover the dilution chamber port 51.
The container filling port 49 is capable of filling the container 11 with a pharmaceutical formulation. Dilution chamber port 51 enables (1) filling dilution chamber 25 with a diluent or (2) allowing a mixture of active agent and diluent (pharmaceutical composition) to exit from container 11 (specifically, from dilution chamber 25) for delivery to a patient.
As previously described, the container 11 includes the active agent chamber opening 17. The active agent chamber opening 17 is configured to receive at least a portion of the first piston 13. Specifically, the active agent chamber 15 includes an active agent chamber opening 17. The active agent chamber port opening 49 may be considered a second active agent chamber opening. In other words, the active agent chamber 15 may be said to comprise a second active agent chamber opening configured to receive a pharmaceutical formulation. An active agent chamber port opening 49 is defined in the wall of the container 11. The active agent chamber 15 may be filled with a pharmaceutical formulation by introducing the pharmaceutical formulation into the active agent chamber 15 via the second active agent chamber port opening 49. The active agent chamber port 49 may thus be referred to as an active agent chamber inlet.
As previously described, the container 11 includes the dilution chamber port 51. Specifically, the dilution chamber 25 includes a dilution chamber port 51. The second port 51 may be referred to as a dilution chamber port 51. Dilution chamber port 51 includes a dilution chamber opening 53. The dilution chamber port 51 may thus be considered as an outlet port 51 of the drug delivery device 2 and/or of the dilution chamber 25.
In the arrangement shown in the figures, the active agent chamber port 49 and the dilution chamber port 51 are shown to include male luer lock connectors (i.e., first luer lock connectors). For example, in an alternative arrangement, the active agent chamber port 49 and/or the dilution chamber port 51 may include a female luer lock connector (i.e., a second luer lock connector).
The active agent chamber port cover 50 may include a luer lock connector that is complementary to the luer lock connector of the active agent chamber port 49. The active agent chamber port cover 50 prevents fluid flow through the active agent chamber port 49 while being connected to the active agent chamber port 49. The dilution chamber port cover 52 may include a luer lock connector that is complementary to the luer lock connector of the dilution chamber port 51. The dilution chamber port cover 52 prevents fluid from flowing through the dilution chamber port 51 while being connected to the dilution chamber port 51.
The first piston 13 and the second piston 14 are each configured to be displaced relative to a longitudinal axis 21 of the container 11. The second piston 14 is disposed between the first piston 13 and the dilution chamber opening 53 (and the dilution chamber port 51). The second piston 14 is disposed between the active agent chamber port 49 (and the active agent chamber port opening) and the dilution chamber opening 53.
The container 11 defines a container inner surface 55. The first piston 13 includes a first piston sealing surface 57. The first piston 13 is configured to seal with the container inner surface 55. Specifically, the first piston 13 is configured to seal with the vessel interior surface 55 to inhibit fluid flow between the vessel interior surface 55 and the first piston sealing surface 57. The first piston 13 is configured to seal with the first piston sealing surface 57.
The second piston 14 includes a second piston sealing surface 59. The second piston 14 is configured to seal with the container inner surface 55. Specifically, the second piston sealing surface 59 is configured to seal with the container inner surface 55 to inhibit fluid flow between the container inner surface 55 and the second piston sealing surface 59. The second piston 14 is configured to seal with a second piston sealing surface 59.
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 inner surface area of the tube 23 are sized such that the tube 23 defines a predetermined volume. Thus, the tubing 23 may hold or store a volume of the diluted pharmaceutical formulation prior to delivery of the diluted pharmaceutical formulation to a patient. The conduit 23 may be referred to as a minimum volume elongate tube. The tubing 23 is configured to retain a first infusion volume to be delivered to a patient. The first infusion volume may be prepared by a priming process at a rate that will result in efficient mixing in the dilution chamber 25. This is possible because during this period no drug formulation is delivered to the patient. Thus, when filling, a different flow rate may be used for the first volume, while the mixed fluid exiting the dilution chamber 25 is driven to the end of the conduit 23. Although the tubing 23 of the drug delivery device 2 is described as having a predetermined volume, it should be understood that tubing having a predetermined volume may be used with any of the drug delivery devices disclosed herein to achieve similar functions and benefits.
The infusion device 3 comprises a computer system 5. The infusion 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 device 2) to a patient in a specific manner, e.g. according to a flow rate delivery function.
The computer system 5 includes at least one processor 27. The computer system 5 includes a memory 29. The memory 29 may be in the form of Random Access Memory (RAM). The computer system 5 includes a data storage device 31. The computer system 5 includes 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 the system bus 39.
The at least one processor 27 is configured to execute infusion device program instructions stored in the memory 29 to cause the infusion device 3 to function as described herein. In other words, the infusion device program instructions are accessible to the at least one processor 27 and are configured to cause the at least one processor 27 to operate as described herein.
In some embodiments, the infusion device program instructions are in the form of program code. At least one processor 27 includes 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.
Memory 29 may include one or more volatile or non-volatile memory types. For example, memory 29 may include one or more of Random Access Memory (RAM), read Only Memory (ROM), electrically Erasable Programmable Read Only Memory (EEPROM), or flash memory. The 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.
Wherein the infusion device 3 comprises or is in the form of a vacuum infusion device 3, the infusion device 3 may apply an infusion pressure (i.e. a vacuum pressure 61) at the dilution chamber opening, thereby causing displacement of the first piston 13 such that the drug formulation is output by the drug delivery device 2 at the target flow rate.
In some embodiments, the infusion device 3 is configured to actuate the first piston 13. The infusion device 3 may be configured to actuate the infusion device actuator to displace the first piston 13 such that the drug formulation is output by the drug delivery device 2. The pharmaceutical formulation may be delivered at a target flow rate.
The computer system 5 may optionally contain a drug library and a database containing the 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 drug exiting the dilution chamber 25 does not exceed the maximum allowable drug administration rate. This may result in an infusion time greater than the expected infusion time, but ensures that the maximum allowable or recommended pharmaceutical administration rate is not exceeded.
During the method of infusing a drug formulation in accordance with the current method of the present disclosure, the drug library may be accessed by the computer system 5 to confirm whether the drug delivery rate exceeds the maximum allowable drug administration rate; and if exceeded, decreasing the infusion rate according to the maximum allowable infusion rate to produce the maximum allowable drug administration rate.
Processor 27 may execute instructions to control drive mechanism 9 of infusion device 3 to deliver a drug according to, for example, a flow rate delivery function. The code executed by processor 27 may be stored in memory 29 of computer system 5 or may be provided from an external source via data storage 31. This software will contain instructions to control the drive mechanism of the infusion device 3 such that the drug formulation leaves the drug delivery device 2 at a specific flow rate to match or approximate the infusion rate of the drug formulation specified by the flow rate delivery function.
Fig. 4 and 5A to 5E show a drug delivery device 2 mounted on an infusion set 3, thereby forming a drug delivery system 1. The infusion device 3 of fig. 4 and 5A to 5E is in the form of a syringe driver 3. Fig. 6 illustrates a first method 600 of operation of the drug delivery device 2 according to some embodiments. The first method 600 of operation of the drug delivery device 2 in fig. 5A to 6 comprises actuating the first piston 13 by applying a force to the first piston in a direction parallel to the longitudinal axis 21 of the drug delivery device 2. A force is applied by the infusion driver 9, which contacts and pushes the first piston 13. Fig. 5A to 6 illustrate a number of steps involving the evacuation of the active agent chamber 15 and the dilution chamber 25 according to a first method 600.
As shown in fig. 5A to 5E, the preparation of the pharmaceutical composition (i.e. the solution output by the drug delivery device 2) comprises the step of pushing the first piston 13 in order to deliver the pharmaceutical formulation contained in the active agent chamber 15 into the dilution chamber 25 to mix (via valve 39) with the diluent contained in the diluent chamber 25. In fig. 6, this step is shown at 602 and 604.
At 602, drug delivery device 2 is in a filled state. In the filled state, the active agent chamber 15 is filled with a pharmaceutical formulation, the dilution chamber 25 is filled with a diluent, and the conduit 23 is filled with the diluent.
In fig. 5A to 5C and at 602 and 604 in fig. 6, the infusion set 3 engages and actuates the first piston 13. The infusion device 3 actuates the first piston 13 in a direction parallel to the longitudinal axis 21 of the drug delivery device 2. In fig. 5A to 5C and 604, the primary piston 13 is pushed by the infusion device 3 such that the drug formulation is delivered into the dilution chamber 25 to provide a specific mixing profile within the dilution chamber 25 together with the valve device 39 to allow proper mixing of the drug formulation with the diluent.
When the pharmaceutical formulation contained in the active agent chamber 15 is delivered into the diluting chamber 25, mixing occurs to produce a pharmaceutical composition (in this case, a diluted pharmaceutical formulation) which is then delivered into the tubing 23 for infusion into the patient. As the pharmaceutical composition is delivered into tubing 23, the concentration of active agent within dilution chamber 25 will increase as active agent is delivered into dilution chamber 25 during infusion.
In fig. 5D and 5E and at 606 to 610 in fig. 6, the active agent chamber 15 has been evacuated. That is, the first piston 13 has contacted the second piston 14. Further actuation of the first piston 13 results in movement of the second piston 14. Movement of the second piston 14 causes fluid (i.e., diluted pharmaceutical formulation or pharmaceutical composition) in the dilution chamber 25 to be displaced through the dilution chamber port 51. The fluid in the dilution chamber 25 is displaced into the conduit 23 to be provided to the patient.
For delivery of the pharmaceutical composition to the patient, the first piston 13 (wherein the second piston 14 abuts the primary piston 13) is pushed in such a way that the pharmaceutical composition is delivered according to a specific spectrum. Specifically, the first piston 13 is driven based on a specific algorithm.
Initially, the infusion device 3 is operated to drive the first piston 13 in such a way that the tubing 23 to be fluidly connected to the patient for delivering the pharmaceutical composition is filled (i.e. filled) before the first piston 13 is driven based on a specific algorithm and the tubing 23 is fluidly connected to the patient.
Alternatively, in some embodiments, the tubing 23 is filled with diluent before the first piston 13 is driven based on a particular algorithm and the tubing 23 is fluidly connected to the patient. The infusion device 3 may then deliver the required volume to displace the volume of diluent in the tubing 23 into the patient and fill the tubing 23 with the diluted drug formulation prior to driving the first piston 13 based on the particular algorithm.
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 comprises actuating the first piston 13 by applying a vacuum pressure 61 to the dilution chamber port 51. The force may be applied by a vacuum pump of the infusion driver 3. The vacuum pressure 61 applies a force to the first piston 13. The force causes the first piston 13 to move towards the second piston 14 in a direction parallel to the longitudinal axis 21 of the drug delivery device 2. Fig. 7 illustrates a number of steps involving the evacuation of the active agent chamber 15 and the dilution chamber 25 according to a second method 700.
At 702, the drug delivery device is in a loaded state. In the filled state, the active agent chamber 15 is filled with a pharmaceutical formulation, the dilution chamber 25 is filled with a diluent, and the conduit 23 is filled with the diluent.
At 704, the infusion device 3 applies vacuum pressure 61 to the dilution chamber port 51. Vacuum pressure 61 may be applied via conduit 23. As described herein, the drug delivery device 2 is configured such that the first piston 13 is moved by the vacuum pressure 61. Initially, the first piston 13 is moved by the vacuum pressure 61, while the second piston 14 is not significantly moved. At 704, the first piston 13 is moved, thereby displacing the pharmaceutical formulation from the active agent chamber 15 into the diluting chamber 25 via the valve 39. Movement of the first piston 13 also displaces the pharmaceutical composition (i.e., the diluted pharmaceutical formulation in the dilution chamber 25) through the dilution chamber port 51. At 704, drug delivery device 2 is shown in a first intermediate state. In the first intermediate state, the first piston 13 is partially evacuating the pharmaceutical formulation from the active agent chamber 15.
At 706, the first piston 13 contacts the second piston 14. The infusion set 3 continues to apply vacuum pressure 61, which results in movement of both the first piston 13 and the second piston 14. Movement of the first piston 13 and the second piston 14 displaces the fluid (pharmaceutical composition) in the dilution chamber 25 through the dilution chamber port 51.
At 708, both the first piston 13 and the second piston 14 are moved by the vacuum pressure 61. At 708, drug delivery device 2 is shown in a second intermediate state. In the second intermediate state, the first piston 13 and the second piston 14 have been partially evacuated from the dilution chamber 25.
At 710, the second piston 14 contacts the container 11. Specifically, the second piston 14 contacts the distal end 63 of the container 11. At this point, both the active agent chamber 15 and the diluting chamber 25 have been emptied.
Method 800 for preparing a drug delivery device 2
Fig. 8 illustrates a method 800 for preparing the drug delivery device 2 of fig. 1-5E, according to some embodiments. At 802, the drug delivery device 2 is in an initial state. In the initial state, the first piston 13 contacts the second piston 14. In addition, the second piston contacts the distal end 63 of the container 11.
The clinician covers the active agent chamber port 49 with an active agent chamber port cover 50. The clinician connects the fill tubing 65 with the dilution chamber port 51 of the drug delivery device 2. The fill tubing 65 may include a luer lock connector that is complementary to the luer lock connector of the dilution chamber port 51. The filling duct 65 may be in the form of a needle.
The clinician inserts the distal end of the fill tube 65 into the diluent container 67. The diluent container 67 includes diluent. The clinician inserts the distal end of the fill tube 65 into the diluent stored in the diluent container 67.
At 804, the clinician moves the first piston 13 away from the dilution chamber port 51. Moving the first piston 13 away from the dilution chamber port 51 draws the second piston 14 away from the dilution chamber port 51 along with the first piston 13 because there is a substantial seal between the first piston 13 and the second piston 14. Moving the first piston 13 away from the dilution chamber port 51 also draws diluent from the diluent container 67 into the drug delivery device 2.
Moving the first piston 13 away from the dilution chamber port 51 increases the volume of the dilution chamber 25. The increased volume of the diluting chamber 25 is occupied by the diluent pumped through the second outlet 51. The clinician moves the first piston 13 (and the second piston 14) away from the dilution chamber port 51 to an initial dilution chamber piston position. When the first piston 13 is in the initial dilution chamber piston position, the dilution chamber 25 has an initial dilution chamber volume. The initial dilution chamber volume may relate to the volume of diluent to be provided to the patient during infusion. For example, the initial dilution chamber volume may be greater than the volume of diluent to be provided to the patient during infusion.
At 806, the clinician removes the fill tubing 65 from the dilution chamber port 51. The clinician moves the drug delivery device 2 such that the diluting chamber port 51 faces in an upward direction 69. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to move air bubbles that may be in the diluent within the diluent chamber 25 toward the diluent chamber port 51. The clinician then moves the first piston 13 (and the second piston 14) toward the dilution chamber port 51 to a dilution chamber piston position, thereby forcing excess air out of the dilution chamber port 51. The dilution chamber 25 has a dilution chamber infusion volume when the first piston 13 is in the dilution chamber piston position. The dilution chamber infusion volume may relate to the volume of diluent to be provided to the patient during infusion. For example, the dilution chamber infusion volume may correspond to the volume of diluent to be provided to the patient during infusion.
At 808, the clinician covers the dilution chamber port 51 with the dilution chamber port cover 52. The dilution chamber port cover 52 may include a luer lock connector that is complementary to the luer lock connector of the dilution chamber port 51. The dilution chamber port cover 52 prevents fluid from flowing through the dilution chamber port 51 while being connected to the dilution chamber port 51.
The clinician removes the active agent chamber port cover 50 from the active agent chamber port 49. The clinician connects the outlet of the fill syringe 71 to the active agent chamber port 49. The filling syringe 71 contains a pharmaceutical formulation to be used for infusion in the filling syringe chamber 72.
At 810, the clinician actuates the fill syringe plunger 73 of the fill syringe 71. Actuation of the fill syringe plunger 73 displaces the drug formulation through the outlet of the fill syringe 71 and into the drug delivery device 2. The pharmaceutical formulation applies pressure to the first piston 13 and causes displacement of the first piston 13 within the container 11. The pressure exerted by the pharmaceutical formulation moves the first piston 13 away from the second piston 14.
Alternatively, the clinician may move the first piston 13 away from the second piston 14, thereby 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 and into the active agent chamber 15.
Moving the first piston 13 away from the second piston 14 increases the volume of the active agent chamber 15. The increased volume of active agent chamber 15 is occupied by the pharmaceutical formulation. The first piston 13 is moved to the initial active agent chamber first piston position. The active agent chamber 15 has an initial active agent chamber volume when the first piston 13 is in the initial active agent chamber first piston position. The initial active agent chamber volume may relate to the volume of the pharmaceutical formulation to be provided to the patient during infusion. For example, the initial active agent chamber volume may be greater than the volume of the pharmaceutical formulation to be provided to the patient during infusion.
At 812, the clinician removes the fill syringe 71. The clinician moves the drug delivery device 2 such that the first port 51 faces generally in an upward direction 69. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to move air bubbles that may be in the drug formulation of the active agent chamber 15 toward the active agent chamber port 49. The clinician then moves the first piston 13 toward the active agent chamber port 49 to an active agent chamber piston position thereby forcing air remaining in the active agent chamber 15 out through the active agent chamber port 49. The active agent chamber 15 has an active agent chamber infusion volume when the first piston 13 is in the active agent chamber piston position. The active agent chamber infusion volume may relate to the volume of the pharmaceutical formulation to be provided to the patient during infusion. For example, the active agent chamber infusion volume may correspond to the volume of the pharmaceutical formulation to be provided to the patient during infusion.
At 814, the clinician covers the active agent chamber port 49 with an active agent chamber port cover 50. The drug delivery device 2 limits the number of possible drug delivery devices that can be stored for subsequent infusion or used in infusion.
Method 900 for preparing a drug delivery device 2
Fig. 9 illustrates a method 900 of preparing the drug delivery device 2 of fig. 1-5E according to some embodiments. At 902, drug delivery device 2 is in an initial state. In the initial state, the first piston 13 contacts the second piston 14. In addition, the second piston 14 contacts the distal end 63 of the container 11. In the initial state, the active agent chamber port cover 50 and the dilution chamber port cover 52 are not in contact with the drug delivery device 2.
At 904, the clinician moves the first piston 13 away from the dilution chamber port 51. Moving the first piston 13 away from the dilution chamber port 51 draws the second piston 14 away from the dilution chamber port 51 along with the first piston 13 because there is a substantial seal between the first piston 13 and the second piston 14. The clinician draws the first piston 13 away from the dilution chamber port 51 and through the active agent chamber port 49.
As the first piston 13 moves through the active agent chamber port 49, the primary seal between the first piston 13 and the second piston 14 is broken by the active agent chamber port 49. That is, air can enter the drug delivery device between the first piston 13 and the second piston 14 through the active agent chamber port opening 54. The second piston 14 thus stops moving together with the first piston 13, since the first piston 13 moves farther from the dilution chamber port 51. The second piston 14 remains in the dilution chamber piston position.
At 906 and 908, the clinician uses the first fill syringe 71 to fill the dilution chamber 25 with diluent. The first filling syringe 71 comprises a first filling syringe chamber 72 containing a diluent. The first filling syringe 71 comprises a first filling syringe conduit 75, which may be, for example, a needle. At 906, the clinician inserts the first fill syringe tubing 75 in the dilution chamber port 51.
At 908, the clinician actuates the first fill syringe piston 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 dilution chamber port 51. Thus, air bubbles present in the diluent when displaced to the dilution chamber 25 may flow through the first fill syringe conduit 75 and exit the dilution chamber 25 during filling.
At 910, the clinician covers the second outlet 51 with the dilution chamber port cover 52. The clinician then moves the first piston 13 to the active agent chamber piston position. The active agent chamber piston position corresponds to the desired volume of the pharmaceutical formulation (i.e., the desired capacity of the active agent chamber 15).
At 912, the clinician uses a second fill syringe 71A to fill the active agent chamber 15 with the pharmaceutical formulation. The second filling syringe 71A includes a second filling syringe chamber 72A containing a pharmaceutical formulation. The second filling syringe 71A includes a second filling syringe tube 75A, which may be, for example, a needle. The clinician inserts a second fill syringe tubing 75A in the active agent chamber port 49.
The clinician actuates the second fill syringe plunger 73A to displace the pharmaceutical formulation from the second fill syringe chamber 72A through the second fill syringe tubing 75A and into the active agent chamber 15. The outer diameter of the second fill syringe conduit 75A is smaller than the inner diameter of the active agent chamber port opening 54. Thus, air bubbles present in the pharmaceutical formulation when displaced into the active agent chamber 15 may flow through the second fill syringe conduit 75A and exit the active agent chamber port opening 54 during filling.
At 914, the clinician covers the active agent chamber port 49 with an active agent chamber port cover 50. The drug delivery device 2 is thereby in a stored state and may be stored for subsequent infusion or used in infusion.
Drug delivery device 2 comprising a concave first piston and a biconvex second piston
Fig. 10 shows an example of a drug delivery device 2, wherein the first piston and the second piston have a specific shape. Like reference numerals refer to like parts as in the previous figures. The first piston 13 has a concave surface 13A facing said second piston. The second piston 14 may be described as biconvex, having a convex surface 14A facing the first piston and a convex surface 14B facing the distal end of the container and the dilution chamber opening 51. The dilution chamber opening may be closed by attaching an end cap 52 to avoid fluid flow out of the opening. In this example, the valve 39 protrudes outwardly from the second piston 14. This may help to maintain separation of the second piston from the distal end of the container 11. In other examples, the valve 39 may not be outwardly convex. In still other examples, the valve 39 may be integrally contained within the second piston to avoid deformation of the valve 39 by contact with the container wall or dilution chamber opening 51. The first piston 13 may include a washer portion and a shaft 94 extending from the washer portion back to the proximal end of the container 11. The shaft 94 may have a lumen 93 for allowing fluid to flow through the first piston 13 to the active agent chamber 11. This lumen 93 may be used, for example, to fill the active agent chamber 15 with a pharmaceutical agent or to withdraw air from the active agent chamber 15.
The facing surfaces 13A, 14A of the first and second pistons may at least partially conform to each other. This minimizes wastage of the drug formulation by minimizing or avoiding trapping of the drug formulation between the first and second pistons. Because the surface 14B of the second piston facing the dilution chamber opening 52 is concave, this may help to minimize wastage of the pharmaceutical formulation, particularly if the inner surface of the distal end of the container 11 is convex, because this arrangement allows all or most of the fluid to drain from the dilution chamber when the second piston moves into contact with the distal end of the container. Further examples of concave first and biconvex second pistons are described later in fig. 26.
Fig. 11 shows an example of a cap 107 that may be attached to the distal end of the first piston 13. As shown, the cap 107 is attached to the shaft 94 of the first piston 13. The cap 107 may have a plurality of struts 107A-107C or other support structure to avoid buckling of the cap 107 when the first piston is pushed into the container 11. This helps to improve the accuracy of the device, as bending of the cap 107 may cause inaccuracy and make it difficult to move the first piston to the desired position when filling the device or during infusion. The cap 107 may further include a central portion 107D within the post that may be screwed onto the piston lumen. The cap 107 may have an end plate 107E supported by the struts 107A-107C, which may form a surface against which a syringe drive actuator or clinician may push to move the first piston 13 toward the distal end of the container 11.
Drug delivery device 2 comprising a piston lumen 93
Fig. 12 shows a perspective view of a cross section of another embodiment of a drug delivery device 2 according to some embodiments. Fig. 13A is a schematic view of a cross-section of the drug delivery device 2 of fig. 12 when empty. Fig. 13B is a schematic view of a cross section of the drug delivery device 2 when filled with a diluent and a drug formulation.
Referring to fig. 12, 13A and 13B, the drug delivery device 2 includes a number of features similar to or identical to other embodiments of the drug delivery device 2 described herein. It will be appreciated 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.
The drug delivery device 2 comprises a first piston 13. The drug delivery device 2 comprises a second piston 14. The drug delivery device 2 comprises a container 11. The container 11 is configured to receive a second piston 14. The container 11 is configured to receive at least a portion of the first piston 13. The container 11 and the second piston define a dilution chamber 25 configured to receive a dilution liquid. Dilution chamber 25 may be as described herein with reference to other embodiments of drug delivery device 2. The first piston 13, the reservoir 11 and the second piston 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.
The container 11 includes a dilution chamber port 51. Dilution chamber port 51 defines a dilution chamber opening 53. Dilution chamber port 51 and/or dilution chamber opening 53 are configured to enable fluid flow into and out of dilution chamber 25 and/or container 11. Dilution chamber port 51 and/or dilution chamber opening 53 may be the same as or similar to dilution chamber port 51 and/or dilution chamber opening 53 described herein with reference to other embodiments of drug delivery device 2. The drug delivery device 2 comprises a dilution chamber port cover 52. The dilution chamber port cover 52 may be the same as or similar to the dilution chamber port cover 52 described herein with reference to other embodiments of the drug delivery device 2. The dilution chamber port cover 52 is configured to be connected to the container 11 to cover the dilution chamber opening 53.
The second piston 2 comprises a valve 39. Valve 39 is configured to control the flow of the pharmaceutical formulation from the active agent chamber 15 to the diluting chamber 25. The valve 39 may be the same as or similar to the valve 39 described herein with reference to other embodiments of the drug delivery device 2. For example, valve 39 includes a valve inlet side 45 and a valve outlet side 47. As described herein, the valve 39 is configured to move from a closed position to an open position upon application of pressure to the inlet side 45. As described herein, the valve 39 is configured to move from the open position to the closed position upon removal of the pressure applied to the inlet side 45.
The first piston 13 includes a piston lumen 93. The piston lumen 93 extends between a first piston lumen opening 95 and a second piston lumen opening 97. The piston lumen 93 extends through the shaft 94 of the first piston 13. The shaft 94 may also be referred to as a rod. In use, the piston lumen 93 is substantially parallel to the longitudinal axis 21 of the drug delivery device 2. The active agent chamber 15 is configured to receive a pharmaceutical agent through the piston lumen 93.
The first piston lumen opening 95 is a piston lumen inlet. The first piston lumen opening 95 is configured to receive a pharmaceutical formulation to be provided through the piston lumen 93. The second piston lumen opening 97 is a piston lumen outlet. The second piston lumen opening 97 is configured to enable the pharmaceutical formulation within the piston lumen 93 to flow into the active agent chamber 15.
The first piston 13 includes a first piston connector 96. The first piston connector 96 is in the form of a first luer lock connector. The first piston connector 96 defines a first piston lumen opening 95.
The first piston 13 includes a first piston O-ring 99. The first piston O-ring 99 includes a first piston sealing surface 101. The first piston 13 is configured to seal with the container 11 to provide a first seal. Specifically, the first piston sealing surface 101 is configured to seal with the vessel inner surface 55 to inhibit fluid flow between the vessel inner surface 55 and the first piston sealing surface 101.
Alternatively, in some embodiments, the first piston 13 includes a first piston seal portion. The first piston sealing portion may be an elastic portion. The first piston seal portion may be as described herein. The first piston sealing portion may be configured to seal with the vessel inner surface 55 to inhibit fluid flow between the vessel inner surface 55 and the first piston sealing surface 101. In some embodiments, the first piston seal includes a raised portion. The raised portion may extend around the circumference of the first piston 13. The raised portion may be configured to seal with the vessel inner surface 55 to inhibit fluid flow between the vessel inner surface 55 and the first piston sealing surface 101.
The first piston 13 comprises a one-way valve (not shown). A one-way valve may be disposed at the distal end 64 of the first piston 13. For example, the one-way valve may define a second piston lumen opening 97 when open. Once in the active agent chamber 15, the one-way valve advantageously enables fluid to flow from the first piston lumen opening 95 through the piston lumen 93 to the active agent chamber 15, but not in the opposite direction.
The drug delivery device 2 comprises a first piston cap 107. The first piston cap 107 is configured to be connected to the first piston 13. Specifically, the first piston cap 107 is configured to be connected to the first piston 13 to cap the first piston lumen opening 95. The first piston cap 107 is configured to connect to the first piston connector 96. Thus, the first piston cap 107 may include a connector that is complementary to the connector of the first piston connector 96 (e.g., a complementary luer lock connector). In the illustrated embodiment, the first piston cap 107 includes a second luer lock connector configured to connect with a first luer lock connector of the first piston 13 (i.e., the luer lock connector of the first piston connector 96).
The second piston 14 is disposed between the first piston 13 and the dilution chamber opening 53. The second piston 14 includes a second piston O-ring 103. The second piston O-ring 103 includes a second piston sealing surface 105. The second piston 14 is configured to seal with the container 11 to provide a second seal. Specifically, the second piston sealing surface 105 is configured to seal with the vessel inner surface 55 to inhibit fluid flow between the vessel inner surface 55 and the second piston sealing surface 105.
Alternatively, in some embodiments, the second piston 14 includes a second piston seal portion. The second piston sealing portion may be an elastic portion. The second piston seal portion may be as described herein, for example, with reference to fig. 27A and 27B. The second piston sealing portion may be configured to seal with the vessel inner surface 55 to inhibit fluid flow between the vessel inner surface 55 and the second piston sealing surface 105. In some embodiments, the second piston seal includes a raised portion. The raised portion may extend around the circumference of the second piston 14. The raised portion may be configured to seal with the vessel inner surface 55 to inhibit fluid flow between the vessel inner surface 55 and the second piston sealing surface 105.
The first piston 13 is configured to be displaced within the container 11 relative to a longitudinal axis 21 of the container 11. The second piston 14 is configured to be displaced within the container 11 relative to a longitudinal axis 21 of the container 11.
The break-away force of the second piston 14 is greater than the break-away force of the first piston 13, as described in more detail herein. The valve threshold force of valve 39 is less than the sum of the break-off force of first piston 13 and the break-off force of second piston 14, as described in more detail herein. This method may be used, for example, when the infusion device is a vacuum pump. In some embodiments, the valve threshold force is less than the break-out force of the second piston 14. This method may be used, for example, when the infusion 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 piston, when the valve is opened and fluid flows through the valve, this fluid flow will apply some force to the second piston in the direction of the fluid flow. The force on the second piston caused by fluid flow through the open valve is referred to as the valve opening force. The valve opening force may be proportional to the resistance of the valve opening. The device may be designed such that the valve opening force is less than the break-away force of the second piston 14 even at high flow rates, such that the second piston is not moved by the high flow rate through the valve.
The drug delivery device 2 comprises a tubing (not shown). The conduit is configured to be fluidly connected to the dilution chamber opening 53. The conduit has a predetermined volume. The tubing of the drug delivery device 2 illustrated with reference to fig. 12 may be similar or identical to the tubing 23 described elsewhere herein.
As shown in fig. 13A and 13B, the first piston 13 includes a distal end 64. The distal end 64 of the first piston 13 is configured to contact the second piston 14. The distal end 64 of the first piston 13 is convex, e.g. conical. The distal end 64 of the first piston 13 includes an apex 66. The distal end 64 of the first piston 13 includes a base 68. In the illustrated configuration, the apex 66 is located at a central portion of the distal end 64 of the first piston 13. Apex 66 is closer to valve 39 of second piston 14 than base 88. Apex 66 is closer to dilution chamber port 51 than base 68.
The second piston 14 includes a proximal end 70. The proximal end 70 of the second piston 14 is configured to contact the first piston 13. The proximal end 70 of the second piston 14 is concave, for example, the proximal end may have an inverted cone shape. That is, the proximal end 70 of the second piston 14 defines a concave, e.g., conical, recess. The proximal end 70 of the second piston 14 is configured to receive the distal end 64 of the first piston 13, which is convex, e.g., conical. In other examples, the distal end 66 of the first piston may be concave and the proximal end 70 of the second piston may be convex, as described in fig. 10 and 26.
Method 1400 for preparing a drug delivery device 2
Fig. 14 illustrates a method 1400 of preparing the drug delivery device 2 described with reference to fig. 12-13B, according to some embodiments. That is, method 1400 is for preparing a drug delivery device 2 comprising a piston lumen 93 as described herein.
At 1402, the drug delivery device 2 is in an initial state. In the initial state, the first piston 13 contacts the second piston 14. In addition, the second piston 14 contacts the distal end 63 of the container 11. In the initial state, the dilution chamber port cover 52 is in contact with the drug delivery device 2.
At 1404, the clinician removes the first piston cap 107. The clinician connects the fill syringe 71 to the first piston connector 96.
At 1406, the clinician uses the first fill syringe 71 to fill the active agent chamber 15 with the pharmaceutical formulation. The first filling syringe 71 comprises a first filling syringe chamber 72 containing a pharmaceutical formulation. The clinician actuates the first fill syringe plunger 73 to displace the pharmaceutical formulation from the first fill syringe chamber 72 into the active agent chamber 15 via the plunger lumen 93.
At 1408, the clinician removes the first fill syringe 71 and moves the drug delivery device 2 such that the dilution 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 air bubbles that may be in the drug formulation of the active agent chamber 15 toward the valve 39 and the diluting chamber port 51. The clinician then moves the first piston 13 toward the dilution chamber port 51. This displaces air bubbles that may be present in the pharmaceutical formulation out of the valve 39 and the second outlet 51.
At 1410, the clinician moves the first piston 13 away from the second outlet 51. This also moves the second piston 14 away from the second outlet 51, creating a volume of the dilution chamber 25.
At 1412, the clinician uses a second fill syringe 71A to fill dilution chamber 25 with diluent. The second filling syringe 71A includes a second filling syringe chamber 72A containing a diluent. The second filling syringe 71A includes a second filling syringe tube 75A, which may be, for example, a needle. The clinician inserts a second fill syringe tube 75A in the dilution chamber port 51.
The clinician actuates the second fill syringe piston 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 dilution chamber opening 53. Thus, air bubbles present in the diluent when displaced to the dilution chamber 25 may flow through the second fill syringe conduit 75A and exit the dilution chamber 25 during filling.
At 1414, the clinician covers the dilution chamber port 51 with a dilution chamber port cover 52. The drug delivery device 2 is thereby in a stored state and may be stored for subsequent infusion or used in infusion.
Alternative first piston 13 and second piston 13 arrangements
As shown in fig. 13A and 13B, the first piston 13 includes a conical distal end 64, and the second piston 14 includes an inverted-conical proximal end 70 configured to receive the conical distal end 64 of the first piston 13. Fig. 15 shows an embodiment of a drug delivery device 2 comprising an alternative first piston 13 and an alternative second piston 14.
The distal end 80 of the first piston 13 of the drug delivery device 2 of fig. 15 is configured to contact the second piston 14. In this case, however, the distal end 70 of the second piston 14 is conical. The distal end 70 of the second piston 14 includes an apex 76. The distal end 70 of the second piston 14 includes a base 78. In the illustrated configuration, the apex 76 is located at a central portion of the proximal end of the second piston 14. The apex 76 is farther from the valve 39 of the second piston 14 than the base 78 in a direction parallel to the longitudinal axis 21. Similarly, the apex 76 is farther from the dilution chamber port 51 than the base 78 in a direction parallel to the longitudinal axis 21.
The first piston 13 includes a proximal end 80. The proximal end 80 of the first piston 13 is configured to contact the second piston 14. The proximal end 80 of the first piston 13 has an inverted cone profile. That is, the proximal end 80 of the first piston 13 defines a conical recess. The proximal end 80 of the first piston 13 is configured to receive the conical distal end 70 of the second piston 14.
Method 1600 for preparing a drug delivery device 2
Fig. 16 illustrates a method 1600 of preparing the drug delivery device 2 described with reference to fig. 15, according to some embodiments. That is, as described herein, the method 1600 is for preparing a drug delivery device 2 comprising a second piston 14 having a conical proximal end 70 and a first piston 13 having an inverted-conical distal end configured to receive the proximal end 70 of the second piston.
At 1602, the drug delivery device 2 is in an initial state. In the initial state, the first piston 13 contacts the second piston 14. In addition, the second piston 14 contacts the distal end 63 of the container 11. In the initial state, the dilution chamber port cover 52 is in contact with the drug delivery device 2.
At 1604, the clinician removes the first piston cap 107. The clinician connects the fill syringe 71 to the first piston connector 96.
At 1606, the clinician uses the first fill syringe 71 to fill the active agent chamber 15 with the pharmaceutical formulation. The first filling syringe 71 comprises a first filling syringe chamber 72 containing a pharmaceutical formulation. The clinician actuates the first fill syringe plunger 73 to displace the pharmaceutical formulation from the first fill syringe chamber 72 into the active agent chamber 15 via the plunger lumen 93.
At 1808, the clinician removes the first fill syringe 71. The clinician moves the drug delivery device 2 (e.g., by tapping the drug delivery device 2) to move air bubbles that may be in the drug formulation of the active agent chamber 15 toward the second piston lumen opening 97 of the first piston 13. Because the distal end 80 of the first piston 13 has an inverted cone shape, air in the drug formulation accumulates at the second piston lumen opening 97 of the first piston 13. The clinician then moves the first piston 13 toward the dilution chamber port 51. This displaces air bubbles that may be present in the pharmaceutical formulation out of the piston lumen 93 and the first piston lumen opening 95 of the first piston 13. Alternatively, the clinician may remove air prior to removing the first fill syringe 71. The clinician may do so by actuating the first fill syringe piston 73 to cause vacuum pressure and drawing air back into the first fill syringe 71.
At 1610, the clinician reconnects the first piston cap 107 to the first piston connector 96. The clinician removes the dilution chamber port cover 52 from the dilution chamber port 51. The clinician moves the first piston 13 away from the second outlet 51. This also moves the second piston 14 away from the second outlet 51, creating a volume of the dilution chamber 25.
At 1612, the clinician uses a second fill syringe 71A to fill dilution chamber 25 with diluent. The second filling syringe 71A includes a second filling syringe chamber 72A containing a diluent. The second filling syringe 71A includes a second filling syringe tube 75A, which may be, for example, a needle. The clinician inserts a second fill syringe tube 75A in the dilution chamber port 51.
The clinician actuates the second fill syringe piston 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 opening of the dilution chamber port 51. Thus, air bubbles present in the diluent when displaced to the dilution chamber 25 may flow through the second fill syringe conduit 75A and exit the dilution chamber 25 during filling.
At 1614, the clinician covers the dilution chamber port 51 with the dilution chamber port cover 52. The drug delivery device 2 is thereby in a stored state and may be stored for subsequent infusion or used in infusion.
Various example methods have been described above in which a drug delivery device is provided to a clinician (e.g., from a factory or storage) and the active agent chamber and dilution chamber are empty, and in which the clinician fills the chamber prior to use. Two additional example methods of filling the active agent chamber and the diluting chamber will now be described with reference to fig. 17 and 18.
In both example methods, before filling the dilution chamber, the second piston 14 (also called 'separation piston') is positioned in a starting position defining an initial volume of the dilution chamber 25 to be present at the beginning of the infusion.
The device may be provided to the clinician (e.g., from a factory or storage) and the second piston 14 is in the same initial position as the initial position or in a starting position further from the distal end of the container than the initial position. If the initial position is different from the starting position, the clinician moves the second piston to the starting position as a first part of the filling process. This movement of the second piston prior to filling the active agent chamber and the dilution chamber ensures that the possible high shrinkage of the separating piston from the wall of the syringe during storage may be broken and also ensures that the clinician has checked that the secondary piston is in the correct starting position before use. If the initial position of the second piston is the same as the starting position, this requires fewer steps to fill the device, but still helps to ensure that the secondary piston is in the correct starting position prior to infusion.
The container 11 may have a marking indicating a starting position of the second piston to be positioned within the container at the start of an infusion. This facilitates the clinician to check the position of the second piston and if the second piston is not in the home position, move the second piston to the home position. The container may also have a marker showing the initial position of the second piston (if the initial position is different from the initial position) and/or the initial position of the first piston to be present at the start of the infusion.
In some examples, the starting position is positioned such that the dilution chamber has a volume of 10mL when the second piston is in the starting position. In some examples, the initial position of the second piston is at a location that provides a dilution chamber volume of 15 mL. In this case, the clinician moves the second piston from the 15mL mark to the 10mL mark.
In the filling method shown in fig. 17, the first piston 13 is retracted and the end cap 52 is removed before the drug formulation is injected into the active agent chamber 15. This allows air to be transported away from the open end of the syringe as the drug formulation is injected.
Referring to fig. 17, at a first step 17-1, a drug delivery device is received by a clinician. The device has an empty diluting chamber and an empty active agent chamber. At this stage the clinician may remove the device from the sterile packaging. At a second step 17-2, the end cap 52 is separated and the first piston 13 is pushed further into the container to push the second piston (by the air pressure in the gap between the first and second pistons) to the starting position. The starting position may be indicated by a marking on the container. In other examples, the device may have a second piston already in the starting position. At block 17-3, the piston lumen cap (also referred to as the 'shaft filling cap') is separated and the first piston is then retracted to its starting position. The starting position of the first piston may be marked on the container 11, for example, or may be found by retracting the first piston until a washer or other portion of the first piston comes into contact with an edge, flange or projection of the container, thereby stopping retraction of the first piston. The first piston may be retracted without moving the second piston because air may enter the active agent chamber 15 between the first and second pistons through the piston lumen.
At step 17-4, the pharmaceutical formulation is injected into the active agent chamber, such as by contacting a pharmaceutical formulation syringe containing the pharmaceutical formulation with the plunger lumen and injecting the pharmaceutical formulation into the active agent chamber through the plunger lumen. In this step, the device is positioned (e.g., held) with the dilution chamber opening facing upward.
At step 17-5, the end cap 52 is placed back over the dilution chamber opening. The device is then counter rotated with the dilution chamber opening facing downward and the drug formulation syringe is used to remove (e.g., extract) any air bubbles formed in the active agent chamber 25.
At step 17-6, the piston lumen cover is replaced over the piston lumen. At step 17-7, the pharmaceutical formulation syringe may be separated from the dilution chamber opening.
At step 17-8, the diluent is injected into the diluent chamber. For example, the end cap 25 may be removed from the dilution chamber opening and a diluent injector used to inject diluent into the dilution chamber through the dilution chamber opening. At step 17-9, the diluent syringe may be removed from the diluent chamber opening, deaeration may be performed, and the end cap 25 may be placed back over the diluent chamber opening.
The filling method shown in fig. 18 is similar to the filling method of fig. 17, but differs mainly in that the end cap 52 is put in place and the first piston 13 is brought into abutment with the second piston 2 before the pharmaceutical formulation is injected or extracted into the active agent chamber. Extraction by moving the piston rod 94 away from the drug chamber (and with the end cap 52 in place on the end of the syringe) helps ensure that positive pressure does not occur in the active agent chamber that could result in accidental injection of the drug formulation into the empty diluent chamber.
At steps 18-1 and 18-2, the end cap 25 is removed and the first piston is moved to move the second piston to the starting position, similar to step 32-2 of fig. 32. At step 18-3, the end cap 25 is placed back over the dilution chamber opening. At step 18-4, the piston lumen cover is removed from the piston lumen. At step 18-5, the device is positioned with the dilution chamber opening pointing upward and the drug formulation injector is used to inject the drug formulation into the active agent chamber via the piston lumen, any residual air in the active agent chamber is drawn down and into the drug formulation injector. At step 18-6, the device is reoriented such that the dilution chamber opening is directed downward and air is drawn out of the activator chamber into the drug formulation injector. At step 18-7, the piston lumen cover is replaced over the piston lumen and the end cap 25 is removed from the dilution chamber opening. At step 18-8, the device is redirected such that the dilution chamber opening is directed upward. The diluent syringe is then connected to the diluent chamber opening. At step 18-9, a diluent injector is used to inject diluent into the diluent chamber and bubbles are drawn out of the diluent chamber. At step 18-10, the end cap 25 may be replaced over the dilution chamber opening.
Alternative configuration of drug delivery device 2
In some embodiments, one or more features of the drug delivery device 2 may be customized to provide certain functional features. Fig. 19A to 24 show a number of alternative configurations of the drug delivery device 2. The embodiment of the drug delivery device 2 illustrated in each of fig. 19A to 24 may be the same or similar in at least some respects to the previously described drug delivery device 2. For example, the embodiment of the drug delivery device 2 illustrated in each of fig. 19A to 24 comprises a first piston 13, a second piston 14, a container 11, a valve 39 (or valve means) and a dilution chamber port 51. At least one or more of the first piston 13, the second piston 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 previously described embodiments), except for any differences mentioned in reference to the relevant disclosure.
As previously described, an alternative configuration of the drug delivery device 2 described with reference to fig. 19A to 24 may comprise a container 11. The container 11 is configured to receive at least a portion of the second piston 14 and the first piston 13. The container 11 and the second piston 14 define a dilution chamber 25. The dilution chamber 25 is configured to receive a dilution liquid. The second port 51 may be referred to as a dilution chamber port 51. The container 11 defines a dilution chamber opening 51. The first piston 13, the container 11 and the second piston 14 define an active agent chamber 15 configured to receive a pharmaceutical formulation. In fig. 19A, the first piston 13 and the second piston 14 are in a pre-infusion state at a start position that the infusion start has. In fig. 19B, the first piston 13 has been moved further into the container 11 so that it contacts the second piston 14.
Although fig. 19A to 24 show a first piston having a convex distal surface facing the second piston and a second piston having a flat proximal surface facing the first piston; the arrangement may be modified such that the first piston has a concave distal surface and the second piston has a convex proximal surface, for example as described elsewhere in this application and shown in fig. 10 or 26. Furthermore, although the apparatus shown in fig. 19A to 24 has the active agent port 49 and the active agent port cover 50 on one side of the container, the arrangement may be modified such that the active agent port 49 and the active agent port cover 50 are not present. The active agent port 49 may be used to fill the active agent chamber, but when the active agent port 49 is not present, the active agent chamber may be filled in other ways, such as through a proximal opening of the container 11 (e.g., if the first piston is removed), through a piston lumen of the first piston, or the device may have a pre-filled active agent chamber.
The first piston 13 is configured to seal with the container 11 to provide a first seal. The first seal may be as described herein. The second piston 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 active agent chamber opening 17, as described herein.
The second piston 14 includes a one-way valve 39. Valve 39 is configured to control the flow of the pharmaceutical formulation from the active agent chamber 15 to the diluting chamber 25, as described herein. The valve 39 is configured to move from a closed position to an open position upon application of a force to the inlet side of the valve 39 that exceeds a valve threshold force. The valve 39 is configured to move from the open position to the closed position upon removal of the force applied to the inlet side of the valve 39.
The break-off force of the plunger in the syringe may be considered the force required to break the static friction of the plunger. In the context of the drug delivery device 2, the break-off force of the first piston 13 may be considered as the force required to break the static friction of the first piston 13 (i.e. the static friction between the first piston 13 and the container 11). That is, the break-off force of the first piston 13 may be regarded as the force required to move the first piston 13 when the first piston 13 is stationary. Break-away forces may be considered when the active agent chamber 15 includes a pharmaceutical formulation and/or the diluting chamber 25 includes a diluent. The break-off force of the first piston 13 may be regarded as a first piston break-off force. The break-off force of the first piston 13 may be regarded as a first break-off force.
The break-off force of the second piston 14 may be considered as the force required to break the stiction of the second piston 14 (i.e. the stiction between the second piston 14 and the container 11). That is, the break-off force of the second piston 14 may be considered as the force required to move the second piston 14 when the second piston 14 is stationary. Break-away forces may be considered when the active agent chamber 15 includes a pharmaceutical formulation and/or the diluting chamber 25 includes a diluent. The break-away force of the second piston 14 may be considered as a second piston break-away force. The break-off force of the second piston 14 may be regarded as a second break-off force.
The valve threshold force may be less than the sum of the break-out force of the second piston 14 and the break-out force of the first piston
In some embodiments, the valve threshold force is less than the sum of the break-out force of the second piston 14 and the break-out force of the first piston 13. In other words, the valve threshold force is less than the sum of the second break-away force and the first break-away force. This configuration may be advantageous in situations where the infusion device 3 is a vacuum infusion device 3. That is, this configuration may be advantageous in situations where the infusion device 3 applies vacuum pressure 61 to the dilution chamber port 51 of the drug delivery device 2. In this case, where the vacuum pressure 61 applies a force to the valve 39 sufficient to open the valve 39, the second piston 14 is not moved.
As previously described, the infusion device 3 may apply vacuum pressure 61 to the dilution chamber port 51 of the drug delivery device 2. The vacuum pressure 61 applies a vacuum force to the fluid (i.e., diluent) in the dilution chamber 25. As the fluid in the dilution chamber 25 becomes incompressible, a vacuum force is also applied to the second piston 14. If the vacuum force exceeds the valve force threshold, 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 piston 14 (thereby opening the valve 39). As a result of the vacuum force applied to the outlet side 47 of the valve 39, the valve 39 may open and may transfer the vacuum force 61 to the pharmaceutical formulation in the active agent chamber 15. Since the pharmaceutical formulation is fluid, it is also gradually incompressible. Thus, a vacuum force is also applied to the first piston 13.
Whereby a vacuum force sufficient to open the valve 39 will move the first piston 13. Thus, the vacuum pressure 61 will draw the pharmaceutical formulation into the diluting chamber 25. Whereby control of the vacuum pressure 61 enables control of the flow rate of the pharmaceutical formulation into the diluting chamber 25.
The valve threshold force may be less than the break-away force of the second piston 14. This ensures that the second piston 14 remains stationary while the pharmaceutical formulation is pumped from the active agent chamber 15 by the vacuum pressure 61. In some embodiments, the break-out force of the second piston 14 is greater than the break-out force of the first piston 13.
It should be noted that as the fluid in each of dilution chamber 25 and active agent chamber 15 is incompressible, for second piston 14 to be moved by vacuum pressure prior to opening valve 39, the vacuum pressure must overcome the break-away force of first piston 13 and the break-away force of second piston 14 (as both will move). Because the fluid may not be completely incompressible, in some embodiments, the break-away force of the second piston 14 should be greater than the valve threshold force.
When the valve 39 is in the open position, there is a small amount of force (at a low flow rate) on the second piston 14. This force is proportional to the impedance across the valve 39. In some embodiments, when the valve 39 is in the open position, the force on the valve 39 is referred to as the valve opening force. When the valve 39 is in the open position, the first piston 13 will move as long as the infusion device 3 is able to generate a vacuum pressure that is greater than the break-away force of the first piston 13.
When the valve 39 is in the open position, the valve opening force will be greater at high flow rates. That is, the valve opening force is greater at high flow rates. In some embodiments, the break-away force of the second piston 14 is greater than the valve opening force at the maximum flow rate of infusion. This will ensure that the second piston 14 does not move until the first piston 13 contacts the second piston 14. In some embodiments, the break-away force of the second piston is about 450 grams.
In some embodiments, the break-away force of second piston 14 is less than a force alert threshold. The force alarm threshold is the force under which the infusion device 3 will alarm. An alarm of the infusion device 3 will indicate occlusion. In some embodiments, the force alert threshold may be 1,200 grams.
Fig. 20A illustrates a side view of the drug delivery device 2 in a first state according to some embodiments. The first state may be a pre-infusion state. The first state may indicate a first phase of infusion.
Fig. 20B illustrates a side view of another drug delivery device 2 in a first state according to some embodiments. The first state may be a pre-infusion state. The first state may indicate a first phase of infusion.
The drug delivery device 2 illustrated in fig. 20A and 20B comprises a first piston 13 and a second piston 14. In at least some embodiments, the first piston 13 can be as described herein. In at least some embodiments, the second piston 14 can be as described herein. The drug delivery device 2 comprises a container 11. In at least some embodiments, the container 11 can be as described herein. The drug delivery device 2 comprises an active agent chamber 15. In at least some embodiments, the active agent chamber 15 can be as described herein. The drug delivery device 2 comprises a dilution chamber 25. In at least some embodiments, dilution chamber 25 can be as described herein. The drug delivery device 2 comprises an active agent chamber port 49. In at least some embodiments, the active agent chamber port 49 can be as described herein. The drug delivery device 2 comprises a dilution chamber port 51. In at least some embodiments, the dilution chamber port 51 can be as described herein. The drug delivery device 2 comprises a valve 39. In at least some embodiments, the valve 39 can be as described herein.
As illustrated in fig. 20A and 20B, in some embodiments, the first piston 13 includes a first number of O-rings 109. The first number of O-rings 109 includes a first piston O-ring 110. The first number of O-rings 109 is configured to provide a plurality of O-ring joints between the first piston 13 and the container 11. The number of O-ring joints corresponds to the first number of O-rings 109. That is, the number of O-ring joints is the same as the number of O-rings of the first number of O-rings 109.
As also illustrated in fig. 20A and 20B, in some embodiments, the second piston 14 includes a second number of O-rings 111. The second number of O-rings 111 includes a second piston O-ring 112. The second number of O-rings 111 is configured to provide a second number of O-ring joints between the second piston 14 and the container 11. The second number of O-ring joints corresponds to the second number of O-rings 111. That is, the second number of O-ring joints is the same as the number of O-rings of the second number of O-rings 111.
In the embodiment shown in fig. 20A, the first number is one. That is, the first number of O-rings 109 includes one O-ring 110. The second number is greater than one. That is, the second number of O-rings 111 includes more than one O-ring 112, 113. Specifically, the second number is two. 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 first number of O-rings 109 and the second number of O-rings 111 may be the same. That is, the first number of O-rings 109 and the second number of O-rings 111 may have the same size.
In the embodiment shown in fig. 20B, the first number is two. That is, the first number of O-rings 109 includes two O-rings. The second number is greater than two. That is, the second number of O-rings 111 includes more than two O-rings. Specifically, the second number is three. That is, the second number of O-rings 111 includes three O-rings 112, 113. The second number is greater than the first number. The first number of O-rings 109 and the second number of O-rings 111 may be the same. That is, the first number of O-rings 109 and the second number of O-rings 111 may have the same size.
In the embodiment shown in fig. 20A and 20B, the O-rings are of comparable size. That is, the strength of the O-ring joint provided by each O-ring is substantially similar.
Fig. 20C illustrates a cross section of an O-ring 113 according to some embodiments. The O-ring 113 may exhibit 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 the O-ring groove 115. The first piston 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 similar to the groove shown in fig. 20C. Similarly, the second piston 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 similar to the groove shown in fig. 20C.
The O-ring 113 is sized with an O-ring diameter 117. The O-ring groove 115 includes a groove width 119. The O-ring diameter 117 may be less 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 greater 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 the second diameter. In some embodiments, the groove disposed within one of the first number of O-rings 109 is referred to as a first groove. The first groove may have a first groove width. Similarly, the groove disposed within one of the second number of O-rings 111 is referred to as a second groove. The second groove may have a second groove width.
In some embodiments, the second diameter is greater than the first diameter. That is, the diameter of one or more of the second number of O-rings 111 is greater than the diameter of one or more of the first number of O-rings 109. This increases the break-out force associated with the O-ring joints of the associated one of the second number of O-rings 111 when compared to the break-out force associated with the O-ring joints of the associated one of the first number of O-rings 109.
Thus, the drug delivery device 2 is provided such that the valve threshold force is smaller than the sum of the break-off force of the first piston 13 and the break-off force of the second piston 14 may be accomplished in various ways. Similarly, the drug delivery device 2 is provided such that by tailoring the characteristics of the first number of O-rings 109 and the second number of O-rings 111, the break-away force of the second piston 14 is greater than the break-away force of the first piston 13 can be accomplished in various ways. Similarly, the drug delivery device 2 is provided such that the valve opening force is less than the break-off force of the second piston 14 may be accomplished in various ways.
In some embodiments, the break-away force of each of the first piston 13 and the second piston 14 may be controlled by controlling the first amount or the second amount. In this case, the dimensions associated with each O-ring may be comparable. That is, the diameter of the O-rings of the first number of O-rings 109 may be similar or identical to the diameter of the O-rings of the second number of O-rings 111. Thus, in the case where the second number is larger than the first number, the break-off force of the second piston 14 is larger than the break-off force of the first piston 13. The first amount may be selected such that the valve threshold force is greater than the break-away force of the first piston 13.
In some embodiments, the break-away force of each of the first piston 13 and the second piston 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 grooves of the second number of O-rings 111 may be sized to be smaller than the groove width of the grooves of the first number of O-rings 109. In this case, the O-ring joint provided by the second number of O-rings 111 will require more force to overcome, thereby increasing the break-away force of the second piston 14. In this case, these dimensions may be controlled such that the break-out force of the second piston 14 is greater than the break-out force of the first piston 13. Similarly, these dimensions may be controlled such that the valve threshold force is less than the sum of the break-out force of the first piston 13 and the break-out force of the second piston 14. Similarly, these dimensions may be controlled such that the valve threshold force is less than the break-away force of the second piston 14. Similarly, these dimensions may be controlled such that the valve opening force is less than the break-away force of the second piston 14.
In some embodiments, the at least one resistive 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 one of the at least one resistive element 121.
Fig. 21 illustrates a side view of another drug delivery device 2 in a first state according to some embodiments. The first state may be a pre-infusion state. The first state may indicate a first phase of infusion.
The drug delivery device 2 shown in fig. 21 comprises a first piston 13 and a second piston 14. In at least some embodiments, the first piston 13 can be as described herein. In at least some embodiments, the second piston 14 can be as described herein. The drug delivery device 2 comprises a container 11. In at least some embodiments, the container 11 can be as described herein. The drug delivery device 2 comprises an active agent chamber 15. In at least some embodiments, the active agent chamber 15 can be as described herein. The drug delivery device 2 comprises a dilution chamber 25. In at least some embodiments, dilution chamber 25 can be as described herein. The drug delivery device 2 comprises an active agent chamber port 49. In at least some embodiments, the active agent chamber port 49 can be as described herein. The drug delivery device 2 comprises a dilution chamber port 51. In at least some embodiments, the dilution chamber port 51 can be as described herein.
As described herein, the second piston 14 includes a valve 39. In some embodiments, the second piston 14 includes a valve arrangement 149. The valve arrangement 149 is configured to control the flow of the pharmaceutical formulation from the active agent chamber 15 to the dilution chamber 25. The valve arrangement 149 may include a valve 39. Valve 39 may be a duckbill valve 41, as described herein. The valve 39 may include a plurality of petals 43.
In some embodiments, the valve arrangement 149 includes a plurality of valves 39. One or more of the plurality of valves may be a duckbill valve 41. One or more of the plurality of valves 39 may include a plurality of petals 43. For example, the valve arrangement 149 may include 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 active agent chamber 15 to the diluting chamber 25.
The drug delivery device 2 is provided such that the valve threshold force is smaller than the sum of the break-out force of the first piston 13 and the break-out force of the second piston 14 may be done in various ways. The drug delivery device 2 is provided such that the valve threshold force being less than the break-off force of the second piston 14 may be accomplished in various ways. Similarly, the drug delivery device 2 is provided such that the break-out force of the second piston 14 is greater than the break-out force of the first piston 13 may be accomplished in various ways. Similarly, the drug delivery device 2 is provided such that the valve opening force is less than the break-off force of the second piston 14 may be accomplished in various ways.
In some embodiments, the break-out force of the second piston 14 may be controlled by controlling aspects of the valve 39 and/or the valve arrangement 149. Similarly, the valve opening force may 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 made may affect the force required to open the valve 39 as well as the valve opening force (i.e., the force on the valve 39 when the valve 39 is in the open position). Similarly, the size of the petals 43 can affect the force required to open the valve 39 and also the valve opening force. The number of valves in the valve arrangement 149 may also affect the force required to open the valve 39 and also the valve opening force. Since the valve opening force is proportional to the impedance of each valve 39 in the valve arrangement 149, increasing more valves 39 or changing the impedance of the valves 39 (e.g., changing the cross-sectional area of the respective valve 39 when open by modifying valve material, geometry, durometer, flap configuration, opening size, etc.) can reduce the impedance across the valve arrangement 149, thereby reducing the valve opening force.
The valve threshold force, break-off force of the first piston 13, and break-off force of the second piston 14 may be controlled as described herein to ensure that the valve threshold force is less than the sum of the break-off force of the first piston 13 and the break-off force of the second piston 14 and/or less than the break-off force of the second piston 14. The valve arrangement 149 may also be controlled such that the valve threshold force is less than the break-away force of the second piston 14. For example, the material from which the valve 39 in the valve arrangement 149 is made may be modified to reduce the valve threshold force. Similarly, the valve opening force and the break-away force of the second piston 14 may be controlled as described herein to ensure that the valve opening force is less than the break-away force of the second piston 14. For example, the valve opening force may be reduced by increasing the number of valves 39 in the valve arrangement 149 or increasing the size of the openings of the valves 39 when opening the valves 39 in the valve arrangement 149.
Fig. 22 illustrates a side view of the drug delivery device 2 in a first state according to some embodiments. The first state may be a pre-infusion state. The first state may indicate a first phase of infusion.
The drug delivery device 2 shown in fig. 22 comprises a first piston 13 and a second piston 14. In at least some embodiments, the first piston 13 can be as described herein. In at least some embodiments, the second piston 14 can be as described herein. The drug delivery device 2 comprises a container 11. In at least some embodiments, the container 11 can be as described herein. The drug delivery device 2 comprises an active agent chamber 15. In at least some embodiments, the active agent chamber 15 can be as described herein. The drug delivery device 2 comprises a dilution chamber 25. In at least some embodiments, dilution chamber 25 can be as described herein. The drug delivery device 2 comprises an active agent chamber port 49. In at least some embodiments, the active agent chamber port 49 can be as described herein. The drug delivery device 2 comprises a dilution chamber port 51. In at least some embodiments, the dilution chamber port 51 can be as described herein. The drug delivery device 2 comprises a valve 39. In at least some embodiments, the valve 39 can be as described herein.
In the embodiment shown in fig. 22, the drug delivery device 2 comprises a protrusion 147. The protrusion 147 is configured to prevent displacement of the second piston 14. Specifically, the protrusion 147 is configured to prevent displacement of the second piston 14 toward the dilution chamber port 51. The container 11 includes a protrusion 147. The protrusions 147 are inwardly protruded. The protrusion 147 is an annular protrusion. The protrusion 147 extends around the interior of the container 11. The boss 147 is between the active agent chamber port 49 and the diluting chamber port 51. The protrusions 147 may be used to increase the break-away force of the second piston 14.
The drug delivery device 2 is provided such that the valve threshold force is smaller than the sum of the break-out force of the first piston 13 and the break-out force of the second piston 14 may be done in various ways. Similarly, the drug delivery device 2 is provided such that the break-out force of the second piston 14 is greater than the break-out force of the first piston 13 may be accomplished in various ways. Similarly, the drug delivery device 2 is provided such that the valve opening force is less than the break-off force of the second piston 14 may be accomplished in various ways. In some embodiments, one or more of these is at least partially accomplished by appropriately sizing the protrusions 147.
In some embodiments, the break-away force of the second piston 14 may be controlled by controlling aspects of the protrusion. For example, the extent to which the protrusions 147 protrude into the container 11 may be controlled. The extent to which the protrusions 147 extend into the container 11 from the interior surface 55 of the container 11 may be the protrusion size. This may also be referred to as radial protrusion size. The thickness of the protrusions 147 in a direction parallel to the longitudinal axis 21 may be the longitudinal protrusion dimension. The lobe dimension and the longitudinal lobe dimension may also be controlled to control the break-away force of the second piston 14.
Increasing the extent to which the protrusion 147 protrudes into the receptacle 11 may increase the break-away force of the second piston 14, as the resistance applied to the second piston 14 by the protrusion 147 must be overcome. Similarly, increasing the longitudinal lobe size may also increase the break-away force of the second piston 14. Accordingly, the break-away force of the second piston 14 may be greater than the break-away force of the first piston 13, at least in part, due to the resistance provided by the protrusions 147 against movement of the second piston 14. The size of the protrusion 147 (e.g., protrusion size) may be controlled as described herein to ensure that the valve threshold force is less than the sum of the break-away force of the first piston 13 and the break-away force of the second piston 14. Similarly, the size of the protrusions 147 may be controlled as described herein to ensure that the valve threshold force is less than the break-away force of the second piston 14.
In some embodiments, resistive element 121 includes protrusions 147.
The break-off force of each of the first piston 13 and the second piston 14 may be controlled by controlling the number of O-rings associated with each piston and the size of the O-rings as described above. However, other ways of controlling the break-away force are possible. In some examples, break-away force may be controlled by the number of valves as shown in fig. 21 or by providing a protrusion 147 that resists movement of the second piston as shown in fig. 22. In still other examples, there may be a stopping system 131 that includes an actuating element 133 that is movable to an engaged position in which it engages a groove 139 of the second piston to prevent movement of the second piston (as shown in fig. 19A), and to a disengaged position (as shown in fig. 19B) in which the actuating element 133 does not engage the groove 139 of the second piston and does not prevent movement of the second piston. In still other examples (not shown), a first portion of the container interior surface proximate the distal end of the container and the starting position of the second piston may have a surface that is rougher than a second portion of the container interior surface toward the proximal end of the container such that the rougher first portion of the surface resists movement of the second piston through the starting position toward the distal end of the container. In still other examples, the break-away force may be controlled by a spring between the distal end of the container and the distal surface of the second piston or by providing an engagement member on the proximal surface of the second piston to prevent movement of the second piston.
Second piston 14
Fig. 24 illustrates a side view, partially in cross-section, of a drug delivery device 2 according to some embodiments. An embodiment of the second piston 14 is shown in fig. 23. The second piston 14 of fig. 23 includes a second piston seal portion 151. The second piston 14 includes a second piston seal support portion 153. The second piston seal support portion 153 is configured to be connected to the second piston seal portion 151. The second piston seal support portion 153 is configured to support the second piston seal portion 151. In some embodiments, the second piston sealing portion 151 comprises an elastomeric material. In some embodiments, seal support portion 153 comprises a non-elastic or relatively rigid material (more rigid than the material of seal portion 151). The second piston seal support portion 153 helps the second piston seal portion 151 maintain its shape. The second piston seal support portion 153 may be connected to the first piston seal portion 151 in a tact connection. That is, the second piston seal support portion 153 may be received by a groove in the second piston seal portion 151. The second piston comprises a valve 39. Valve 39 may be as described herein. The second piston 14 includes a valve connector portion 155. The valve connector portion 155 is configured to securely connect the valve 39 to the second piston seal support portion 153.
Fig. 23 illustrates a side view, partially in cross-section, of a drug delivery device 2 according to some embodiments. The second piston 14 includes a second piston recess 157. The second piston recess 157 is a conical recess. The second piston recess 157 is configured to receive the first piston 13.
The valve 39 extends the apex 159 of the second piston 14 shown in fig. 23 and 24. The outer dimension of the valve 39 may be larger than the outer dimension of the passage of the dilution chamber port 51. The valve 39 may thus contact the inner surface of the container 11 as the second piston 14 moves towards the distal end 63 of the container. The valve 39 may therefore avoid or minimize the extent to which the second piston contacts the distal end 63 of the container 11. This may reduce the extent to which the second piston 14 is attached to the distal end 63 of the container 11, thereby improving the ease with which the second piston 14 may be removed from the distal end 63 of the container 11, e.g., to reset for a second infusion.
Furthermore, the described valve 39 design improves the ease with which the drug delivery device 2 can be filled. If the second piston 14 is shaped to correspond to the shape of the distal end 63 of the container 11, the second piston 14 may be sucked to the distal end 63 of the container 11 prior to filling, which may increase the difficulty of filling the dilution chamber 25. Providing a second piston 14 as described overcomes this problem.
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 and toward the dilution chamber port 51). This protrusion may be used to contact the container 11 to minimize the extent to which the second piston 14 is sucked into the container 11. In some embodiments, rather than valve 39 extending beyond apex 159 of second piston 14, valve 39 may be contained within second piston 14.
In some embodiments, valve 39 is sized such that it does not contact container 11. Specifically, valve 39 does not contact dilution chamber port 51. This reduces the deformation of the valve 39 that may occur due to contact.
Fig. 25A illustrates the second piston 14 according to some embodiments. The second piston 14 of fig. 25A includes a front portion 161. The second piston 14 of fig. 27A includes a rear portion 163. The front portion 161 is conical. Front portion 161 extends away from rear portion 163 through front portion depth 165. Rear portion 163 extends away from front portion 161 through rear portion depth 167. The anterior portion depth 165 is greater than the posterior portion depth 167. In some embodiments, the anterior portion depth 165 is less than the posterior portion depth 167.
Rear portion 163 includes a rear portion recess 168. The rear portion recess 168 includes a first angled edge 169 and a second angled edge 171. The angle between the second angled edge 171 and the longitudinal axis 173 of the second piston 14 is greater than the angle between the first angled edge 169 and the longitudinal axis 173 of the second piston 14.
Fig. 25B illustrates the second piston 14 according to some embodiments. The second piston 14 of fig. 25B includes a front portion 161. The second piston 14 of fig. 25B includes a rear portion 163. In some embodiments, the front portion 161 is conical. In some embodiments, anterior portion 161 is semi-spherical. Front portion 161 extends away from rear portion 163 through front portion depth 165. Rear portion 163 extends away from front portion 161 through rear portion depth 167. The anterior portion depth 165 is less than the posterior portion depth 167. In some embodiments, the anterior portion depth 165 is greater than the posterior portion depth 167.
Rear portion 163 includes a rear portion recess 168. The rear portion recess 168 includes 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 piston 14 is the same as the angle between the first angled edge 169 and the longitudinal axis 173 of the second piston 14. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis 173 of the second piston 14 is greater than the angle between the first angled edge 169 and the longitudinal axis 173 of the second piston 14. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis 173 of the second piston 14 is less than the angle between the first angled edge 169 and the longitudinal axis 173 of the second piston 14.
Various features may be provided to prevent or avoid overturning or rotational misalignment of the second piston 14 within the container 11. In some embodiments, the length of the second piston along the longitudinal axis of the container is at least 9mm. This helps to avoid misalignment of the second piston. This length of at least 9mm may for example be the length between the distal side of the second piston facing the dilution chamber opening and the proximal side of the second piston facing the first piston. In some examples, the length 167 of the portion of the second piston in contact with the container wall may be at least 9mm. In some examples, the length is 9mm-11mm.
In some examples, rear portion depth 167 is greater than front portion depth 165, which may help to keep the second piston peripheral edge in contact with the inner wall of container 11 and avoid second piston 14 tipping within the container.
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. Such lubrication may reduce the likelihood of the second piston 14 tipping or rotating out of alignment. This may be achieved by increasing the degree to which the second piston 14 is slidable. In some embodiments, the height of the second piston 14 (i.e., the dimension of the second piston 14 in a direction parallel to the longitudinal axis 21 g) may be increased to reduce the likelihood of the second piston 14 tipping or rotating out of alignment. In some embodiments, the dimensions of the second piston 14 are controlled such that the compression of the second piston 14 is substantially constant about its circumference. For example, the second piston 14 may be sized such that lateral compression at the leading edge of the second piston 14 is substantially the same as lateral compression at the trailing edge of the second piston 14. This may help prevent the second piston from tipping out of alignment.
In some embodiments, the distal end 63 of the container 11 may be considered to define a concave shape, such as a conical recess. The second piston 14 is described as moving to contact the container 11, as described herein. In some embodiments, the distal end (e.g., first portion 161) of second piston 14 may be convex, e.g., conical, as described herein. However, the height of the second piston 14 may be such that the convex distal surface of the second piston 14 (i.e., the curved surface of the front portion 161 of the second piston 14) is not directly aligned, does not conform, or only partially conforms to 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 piston 14 and the concave (e.g., conical) recess of the distal end 63 of the container 11 may have different profiles. This may advantageously reduce the extent to which the second piston 14 may be sucked into the container 11. This arrangement may also advantageously enable the curved surface of the front portion 161 of the second piston 14 to seal the dilution chamber port 51. Thus, fluid exiting valve 39 may be directed through dilution chamber port 51 without entering dilution chamber 25. This may be useful when filling the drug delivery device 2.
Fig. 25C and 25D illustrate the first piston 13 according to some embodiments. The first piston 13 of fig. 25C and 25D includes a front portion 161. The first piston 13 of fig. 25C and 25D includes a rear portion 163. The front portion 161 of the first piston 13 is configured to contact the second piston 14. The front portion 161 has a concave (e.g., inverted conical) profile. That is, the front portion 161 of the first piston 13 defines a concave (e.g., conical) recess 193. The concave (e.g., conical) groove 193 may have a profile corresponding to a truncated cone.
Front portion 161 extends away from rear portion 163 through front portion depth 165. Rear portion 163 extends away from front portion 161 through rear portion depth 167. The anterior portion depth 165 is greater than the posterior portion depth 167. In some embodiments, the anterior portion depth 165 is less than the posterior portion depth 167.
The first piston 13 includes a first piston recess 168. The first piston recess 168 includes 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 piston 13 is the same as the angle between the first angled edge 169 and the longitudinal axis of the first piston 143. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis of the first piston 13 is greater than the angle between the first angled edge 169 and the longitudinal axis of the first piston 13. In some embodiments, the angle between the second angled edge 171 and the longitudinal axis of the first piston 13 is less than the angle between the first angled edge 169 and the longitudinal axis of the first piston 13.
Fig. 26 illustrates an embodiment of a drug delivery device 2 according to some embodiments.
In the embodiment of fig. 26, the first piston 13 has a concave (distal) surface 195 facing the second piston 14. For example, the distal face of the first piston 13 may define a concave recess. The concave recess may have a conical profile. The second piston 14 has a convex (distal) surface 197 facing the first piston. For example, the proximal face of the second piston may include a frustoconical portion 197. Although not shown in fig. 26, the second piston may contain a valve, as previously described in other embodiments.
When the first piston 13 contacts the second piston 14, an air gap 199 is defined between the first piston 13 and the second piston 14. The air gap 199 enables air to accumulate within the drug delivery device 2, thereby preventing or minimizing the extent to which air is injected into the dilution chamber 25 and/or the patient. The air gap may thus act as a bubble trap. In some embodiments, the air gap 199 may be defined by a concave (e.g., conical) groove 195 of the first piston 13 and a frustoconical portion 197 of the second piston 14. Although the air gap 199 in fig. 26 is formed between the central portions of the pistons, in other examples, the air gap may have a peripheral position away from one side.
In general, the first and second pistons may be shaped such that when the first piston moves into contact with the second piston, an air gap exists between the first and second pistons. The second piston may partially conform to the shape of the first piston to minimize loss of the pharmaceutical formulation and there is an air gap that allows space for air bubbles to be trapped between the first piston and the second piston when the first piston is moved into contact with the second piston.
The second piston 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 defining the dilution chamber opening 51. The second piston 14 is movable towards the distal end 11A of the container up to an end position where it cannot move further towards the distal end of the container. For example, the end position of the second piston may be the position where the second piston 14 abuts the distal end 11A of the container. The distal side 198 of the second piston 14 is shaped such that in the end position, there is a gap between at least a portion of the second piston and the distal end of the container. The gap helps prevent the second piston from adhering to the distal end of the container (due to suction or other reasons). For example, the distal face of the second piston may have a different shape or profile than the distal end of the container to avoid sucking or adhering the second piston to the distal end of the container.
The distal side or face 198 of the second piston may partially conform to the distal end of the container 11A to minimize loss of the pharmaceutical formulation and/or diluent as the second piston 14 moves into contact with the distal end of the container to expel the contents of the diluent chamber 25 through the diluent chamber opening 51. When the second piston 14 is moved into contact with the distal end 11A of the container, there is still a gap between at least part of the second piston and the distal end of the container, as the second piston only partially conforms to the distal end of the container. This gap helps to prevent suction that would attach the second piston to the distal end of the container. This may be achieved, for example, by the distal end of the second piston and the distal end of the container having different profiles.
To achieve this clearance, the distal side of the second piston facing the distal end of the container may comprise a first portion that abuts the distal end of the container in the end position and a second portion that does not abut the distal end of the container in the end position. For example, the first portion may be a portion protruding from the second piston, a valve (if the valve protrudes from the second piston), or a portion of the distal surface of the second piston. In some examples, the first portion is a portion of a distal surface of the second piston, and 5% -50% of the distal surface area of the second piston contacts or abuts the distal end of the container when the second piston is moved into contact with the distal end of the container.
As previously discussed, the second piston has a one-way valve. In some examples, as shown in fig. 27, a one-way valve 39 may be contained within the body 14M of the second piston 14. This helps to prevent the one-way valve from deforming by contact with the rim of the container 11. In some examples, the body 14M of the second piston 14 includes at least one outlet opening 223 and at least one internal passage 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 may be a duckbill valve.
In fig. 27, there is one outlet opening 223. In other examples, the body of the second piston 14 has two or more outlet openings. Fig. 28 shows an arrangement similar to that of fig. 27, wherein like reference numerals denote like parts, but wherein the body 14M has two outlet openings 223A and 223B. The first interior passage 219 of the body opens into a first outlet opening 223A and the second interior passage 221 opens into a second outlet opening 223B. In this case, reference numeral 217 denotes a portion of the main body that separates the first passage and the second passage.
Fig. 29A is a perspective view from the front (distal end) of the second piston 14 of fig. 28, showing the first outlet opening 223A and the second outlet opening 223B. Fig. 29B is a plan view showing one possible arrangement in which the one-way valve is arranged horizontally with respect to the outlet opening. That is, the one-way valve, which may be a duckbill valve, has a slit that is 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 direction. For example, as shown in fig. 29C, the valve may have a vertical direction, and the valve slit is parallel to a line joining the first outlet opening 223A and the second outlet opening 223B.
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 the 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 the mixing of the fluids in the dilution chamber 25. In some examples, the dispersion member can define a first dispersion channel 219 and a second dispersion channel 221. The fluid flowing through the valve 39 is forced through the first and second dispersion channels 219, 221, thereby increasing the degree to which it mixes within the dilution chamber 25.
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 directed at a first corner of the diluting chamber 25 and a second jet of the pharmaceutical formulation directed at a second corner of the diluting chamber 25 when the pharmaceutical formulation is forced from the active agent chamber through the one-way valve. In some embodiments, the device is configured such that the first jet and the second jet of the pharmaceutical formulation rebound from an inner surface of the dilution chamber, thereby facilitating back mixing of the pharmaceutical formulation with the diluent in the dilution chamber.
In some embodiments, the outlet opening and the 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 fluids mix within dilution chamber 25.
Examples of spraying and mixing are shown in fig. 30A to 30F. Fig. 30A to 30F illustrate the priming process, but similar spraying and mixing will occur during infusion. Fig. 30A shows a first time, for example 0.25 seconds after the start of filling, when two jets are generated. Fig. 30B shows a second time, for example after 0.41 seconds, in which each of the two jets has reached the corresponding angle of the dilution chamber. Fig. 30C shows a third time, for example after 1.51 seconds, in which both jets have reached the dilution chamber outlet. Fig. 30D shows a fourth time, for example after 1.95 seconds, at which time back mixing begins to occur. Fig. 30E shows a fifth time, e.g., after 2.15 seconds, when the drug formulation begins to enter the tubing (e.g., an elongated tube) attached to the diluting compartment. Fig. 30F shows a sixth time, for example after 2.90 seconds, when good mixing has occurred.
In some embodiments, the body of the second piston may include three outlet openings. In this case, the middle opening of the three outlet openings and/or the internal channel leading to the third outlet opening may be configured to generate a third jet of the pharmaceutical formulation directed towards the dilution chamber opening.
Fig. 31 shows an example perspective view of a second piston 41 with three outlet openings 223A, 223B and 223C. The three outlets may be arranged in rows. The intermediate outlet may be smaller than the peripheral outlet. Fig. 32 shows an example cross section of the second piston 14 with three outlet openings 223A, 223B and 223C. Like reference numerals denote like parts as in fig. 27 to 31.
Examples of spraying and mixing are shown in fig. 33A to 33F. Fig. 33A to 33F illustrate the priming process, but similar spraying and mixing will occur during infusion. Fig. 33A shows a first time, for example 0.26 seconds after the start of filling, when one central jet and two side jets are generated. Fig. 30B shows a second time, e.g. after 0.60 seconds, in which the central jet has reached the dilution chamber outlet and each of the two side jets has reached the middle of the side wall of the dilution chamber. Fig. 30C shows a third time, for example after 0.8 seconds, in which the central jet has entered the duct attached to the opening of the dilution chamber and the two side jets have reached the respective corners of the dilution chamber. Fig. 30D shows a fourth time, for example after 1.67 seconds, in which the side jet has reached the dilution chamber outlet. Fig. 30E shows a fifth time, for example after 2.6 seconds, at which time back mixing of the side jets begins to occur. Fig. 30F shows a sixth time, e.g., after 3.2 seconds, when the counter-movement of the side jet collides with the forward movement of the center jet, resulting in further turbulence and mixing.
Fig. 34 is a schematic cross-sectional view of an example of the second piston 14 having a body containing a valve 29 inside the body, and wherein the body has a plurality (e.g., three) of outlet openings and a plurality of internal passages, each of which opens into a respective outlet opening. Each channel may extend in a different direction or angle. Thus, although there are three outlets and three outlet channels, only a portion of the first channel 219 and the first outlet 223A and the second outlet channel 221 can be seen in the cross section of fig. 34 as they extend in different directions.
Fig. 35 illustrates a drug delivery system 1 according to some embodiments. The drug delivery system 1 includes a far active agent 15A. The far active agent chamber 15A is in addition to the active agent chamber 15 of the drug delivery device 2. That is, the distal active agent chamber 15A is disposed remotely from the drug delivery device 2 and may be fluidly connected to the piston 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 to the first piston connector 96.
The external pump 15A may be used to pump the pharmaceutical formulation from the remote agent chamber 15A into the 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 fixed 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. Pump 15B may drive the flow of the pharmaceutical formulation into active agent chamber 15 and out through valve 39 (not shown) in dilution chamber 25 (not shown) and through dilution chamber opening 51.
To maintain the active agent chamber 15 at a fixed volume, the drug delivery system 1 may include a piston lock 203. The piston lock 203 fixes the first piston 13 at a specific position. This enables the drug formulation to be delivered into the dilution chamber 25 via valve 39 to mix with the diluent and flow out of the dilution chamber opening for delivery to the patient. Since the first piston does not move, the second piston will also remain in place and thus the volume of the dilution chamber is also fixed.
The piston lock 203 includes a body 205. The body 205 includes a lower surface 207 for resting on a support surface. The body 205 includes a first recess 209. The body includes a second recess 211. The first recess 209 is configured to receive a first piston flange 213 of the first piston 13. The second recess 211 is configured to receive a container flange 215 of the container 11. The piston lock 203 is configured to secure the first piston 13 in a particular position such that the first piston 13 is stationary within the container 11.
The external pump may be controlled to drive the pharmaceutical formulation according to a specific dose profile. For example, the pharmaceutical formulation may be flowed at a varying flow rate determined by a function suitable for delivering a desired dose profile when the diluting chamber has a fixed volume. For example, the rate of active agent administration may be controlled by the saldel 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 may be controlled by increasing the volume of the sagley function, as described in international patent application No. PCT/AU 2020/051363.
Fig. 36 shows another example in which two separate pharmaceutical formulations may be administered to a patient. In this case, the primary drug formulation may enter the pump 15B through the first inlet 201. The pump 15B has a second inlet that can receive a second pharmaceutical formulation output by the drug delivery device 2, as described in the various examples above. The pump 15B may combine the first and second pharmaceutical formulations and output them to the patient through the outlet conduit 23 (e.g., by intravenous administration). The pump 15B may contain an air trap 15C for trapping any air bubbles formed in the pharmaceutical formulation.
Since the dose spectrum may be sensitive to the initial part of the infusion, where the dose rate should be kept low, the drug delivery device 2 may be attached to the outlet 202 through the tubing device 175, as described below.
The tubing arrangement allows a filling process that uses a high infusion rate to fill the tubing 23 with a diluted drug formulation in a desired concentration profile, such that a dose rate can be accurately achieved in the first part of the infusion, as the first part of the infusion consists of the diluted drug formulation that has been prepared in the tubing 23 as part of the filling process. Without this approach, it is difficult to achieve the desired low but increasing dose rate in the first part of the infusion.
Fig. 37 illustrates a perspective view of a portion of the tubing device 175 and the drug delivery device 2 according to some embodiments. In fig. 37, both the housing 177 and the tube 11 are partially transparent. Fig. 38 illustrates a perspective view of tubing device 175 and drug delivery device 2 according to some embodiments. In fig. 38, both the housing 177 and the tube 11 are partially transparent.
The housing includes a first housing port 179. The first housing port 179 includes a first housing opening 180. The first housing opening 180 extends through the first housing port 179. The first housing port 179 includes 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 housing 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.
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 may be a second housing luer lock connector. The second housing connector may be a second housing luer-lock connector. The second housing luer lock connector may be a female luer-lock connector. Alternatively, the second housing luer lock connector may be a male luer-lock connector. The second housing connector is configured to connect to a tube.
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 duct 23 is coiled within the duct chamber 183. A conduit chamber 183 extends between an intermediate wall 185 and a distal end 187 of the housing 175. The conduit 23 has a predetermined volume, as described herein.
The housing 175 includes a collar 186. The collar 186 extends away from the intermediate wall 185, away from the second housing port 181. Specifically, the collar 186 extends away from the second housing port 181 in a direction generally parallel to the longitudinal axis 193 of the plumbing 175. When tubing 175 is connected to drug delivery device 2, longitudinal axis 193 of tubing 175 may be substantially parallel to longitudinal axis 21 of drug delivery device 2.
Drug delivery system 1 may include any of drug delivery device 2 and tubing device 175 described herein. The collar 186 is configured to engage with the container 11. Specifically, the collar 186 may be configured to engage with the container 11 via an interference fit. An interference fit may be between the collar inner surface 189 and the container outer surface 191.
The conduit 23 and/or the conduit device 175 provide a number of significant advantages. When the drug delivery device 2 is initially engaged with the infusion set 3, there is a certain amount of "slack" in the system. This is because, for example, the compressibility between the infusion driver of the infusion device 3 (e.g., the actuator of the infusion device 3) and the drug delivery device, the compressibility of the components of the fluid and drug delivery device 2 may be lacking or for other reasons. As described herein, a conduit 23 having a predetermined volume (e.g., a predetermined minimum volume) may mitigate such "slackening.
The drug delivery device 2 may be engaged with (i.e. connected to) the infusion means 3 and the infusion means 3 may be operated to drive fluid from the drug delivery device 2 to the end of the tubing 23. The fluid may then be stopped. Since the pharmaceutical composition and/or pharmaceutical formulation does not enter the patient during this period, the flow rate of the fluid is not relevant. Thus, any change in flow rate relative to the predetermined target flow rate is uncorrelated. Furthermore, completing this process eliminates "slack" in the system, and thus is no longer a problem once infusion is initiated at the desired flow rate.
Furthermore, the pharmaceutical formulation may not always be perfectly mixed with the diluent when passing through the valve 39. This may be especially the case where the flow rate is low, due to the low kinetic energy of the fluid passing through the valve 39 (e.g. during the initial phase of infusion). Thus, the rate at which the drug formulation is provided to the patient during the early stages of infusion is affected. Providing the conduit 23 with a predetermined volume as described (e.g. a predetermined minimum volume) alleviates this situation.
This is because the volume of the mixed (i.e. diluted) drug formulation delivered during the initial phase of infusion is low and may be less than the total volume of tubing 23. Since the tubing 23 is filled prior to connection to the patient, the flow rate during this time may be arbitrarily high. Thus, the clinician may use a flow rate that will improve the mixing of the pharmaceutical formulation with the diluent during loading. The fluid produced during filling will then be stored along the length of the pipe 23. The diluted drug formulation will be present at the patient end of the tubing 23 and the concentration of the drug formulation will increase closer to the dilution chamber 25.
When the tubing 23 is connected to the patient and a predetermined flow rate procedure is initiated, the diluted drug formulation produced in the loading step is delivered to the patient. The diluted drug formulation mixed early in the infusion will be delivered to the patient at a later stage of the infusion, where the flow rate is higher and therefore has a much smaller impact on the delivery rate of the drug formulation.
In most cases, tubing 175 and dual inlet pump shown in FIG. 36 will not be used. In many cases, the drug delivery device 2 is used as the sole source of the drug formulation and the dilution chamber outlet may be connected to a tube 23 (e.g. an elongate tube) of known volume, so that the filling of the tube 23 may be completed in the same manner as described above, and then the tube 23 is attached to the patient to begin infusion.
It will be appreciated that although the fluid delivery system 1 has been described in the context of a drug delivery system 1, in some embodiments the fluid delivery system 1 may be used for purposes other than drug formulation delivery. For example, in some embodiments, the fluid delivery system 1 is configured to deliver a mixed fluid as part of an industrial process 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 drug delivery device 2 may be configured to controllably deliver a mixture of the first fluid and the second fluid as part of an industrial process or another process. Those skilled in the art will appreciate that many 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.
For example, the present disclosure describes many embodiments of the drug delivery system 1 and the drug delivery device 2. It is understood that a particular one of the embodiments of the drug delivery device 2 described herein may incorporate one or more features and/or components of another embodiment of the drug delivery device 2 described herein without departing from the scope of this disclosure.
Claims (31)
1. A drug delivery device, comprising:
a first piston;
a second piston; and
a container configured to receive at least a portion of the second piston and the first piston;
wherein:
the container and the second piston define a dilution chamber configured to receive a diluent;
the container defining a dilution chamber opening;
the first piston, the container, and the second piston define an active agent chamber configured to receive a pharmaceutical formulation;
the second piston comprising a one-way valve configured to control the flow of the pharmaceutical formulation from the active agent chamber to the diluting chamber,
the one-way valve is configured to move from a closed position to an open position upon application of a force to an inlet side of the valve that exceeds a valve threshold force; and is also provided with
The valve threshold force is less than a sum of the break-out force of the second piston and the break-out force of the first piston;
wherein the drug delivery device is operable to force a drug formulation from the active agent chamber into the dilution chamber through the one-way valve to mix with the diluent in the dilution chamber and to force the mixed diluent and drug formulation out of the dilution chamber through the dilution chamber opening.
2. The drug delivery device of claim 1, wherein the valve threshold force is less than the break-loose force of the second piston.
3. The drug delivery device of claim 1 or 2, wherein the first piston has a concave surface facing the second piston.
4. A drug delivery device as in claim 3, wherein the second piston has a convex surface facing the first piston and a convex surface facing the dilution chamber opening.
5. A drug delivery device according to any of the preceding claims, wherein the first and second pistons are shaped such that when the first piston is moved into contact with the second piston, an air gap exists between the first and second pistons.
6. The drug delivery device of any one of the preceding claims, wherein a distal end of the container defines the dilution chamber opening, the second piston being movable towards the distal end of the container up to an end position at which the second piston is not movable further towards the distal end of the container, and wherein the second piston is shaped such that in the end position there is a gap between at least part of the second piston and the distal end of the container to avoid suction attaching the second piston to the distal end of the container.
7. The drug delivery device of claim 6, wherein a side of the second piston facing the distal end of the container comprises a first portion that abuts the distal end of the container in the end position and a second portion that does not abut the distal end of the container in the end position.
8. The drug delivery device of any one of the preceding claims, wherein the one-way valve is a duckbill valve.
9. The drug delivery device of any one of the preceding claims, wherein the one-way valve is contained within a body of the second piston, the body containing at least one outlet opening, and the body containing at least one internal passage leading from an outlet of the one-way valve to the at least one outlet opening.
10. The drug delivery device of claim 9, wherein the body of the second piston comprises at least two outlet openings.
11. The drug delivery device of claim 12, wherein the at least two outlet openings are configured to generate a first jet of the drug formulation directed toward a first corner of the diluting chamber and a second jet of the drug formulation directed toward a second corner of the diluting chamber when the drug formulation is forced from the active agent chamber through the one-way valve.
12. The drug delivery device of claim 11, wherein the device is configured such that the first jet and the second jet of a drug formulation rebound from an inner surface of the diluting chamber, thereby facilitating back mixing of the drug formulation with a diluent in the diluting chamber.
13. The drug delivery device of any one of claims 10 to 12, wherein the one-way valve is a duckbill valve having a slit substantially perpendicular to a line joining a first opening and a second opening of the at least two outlet openings.
14. The drug delivery device of any of claims 9 to 13, wherein the body of the second piston comprises three outlet openings.
15. The drug delivery device of claim 14, wherein a middle opening of the three outlet openings is configured to generate a third jet of drug formulation directed toward the dilution chamber opening.
16. A drug delivery device according to any of the preceding claims, wherein the length of the second piston along the longitudinal axis of the container is at least 9mm.
17. The drug delivery device according to any of the preceding claims, in combination with a tubing device comprising:
a plumbing enclosure, the plumbing enclosure comprising:
a first housing port (179); and
a second housing port (181); and
-a conduit (23) connecting the first housing port and the second housing port;
wherein:
the first housing port (179) comprises a first connector configured for connection with a dilution chamber outlet opening (51); and is also provided with
The second housing port (181) includes a second connector configured for connection with a tube connected to a patient.
18. The drug delivery device of any one of the preceding claims, wherein the first piston comprises a piston lumen for delivering a drug formulation through the piston lumen and into the active agent chamber, the piston lumen extending between a first piston lumen opening and a second piston lumen opening.
19. A drug delivery device according to any of the preceding claims, comprising a piston lock to fix the position of the first piston relative to the container such that the first piston cannot be moved further into the container, optionally the piston lock can comprise a first recess for receiving a protrusion (e.g. flange) of the first piston and a second recess for receiving a protrusion (e.g. flange) of the container.
20. A drug delivery device according to any of the preceding claims, wherein the container has indicia indicating a starting position of the second piston to be positioned within the container at the start of infusion.
21. A method of preparing a drug delivery device according to any one of claims 1 to 20, the method comprising:
a) Filling the dilution chamber with a diluent; and
b) The active agent chamber is filled with a pharmaceutical formulation.
22. The method of claim 21, wherein the diluting chamber is filled with a diluent prior to filling the active agent chamber with a pharmaceutical formulation.
23. The method of claim 21, wherein the active agent chamber is filled with active agent prior to filling the dilution chamber with diluent.
24. The method of claim 21 or 23, wherein the active agent chamber is filled with active agent via a piston lumen of the first piston.
25. The method of any one of claims 21 to 24, wherein the second piston is positioned at a starting position defining an initial volume of the dilution chamber to be present at the beginning of the infusion, prior to filling the dilution chamber.
26. A method of preparing a drug delivery device comprising an active agent chamber, a dilution chamber, a one-way valve connecting the active agent chamber and the dilution chamber, and a dilution chamber opening, the method comprising:
c) Connecting the drug delivery device to an infusion driver;
d) Attaching an elongated tube having a known predetermined volume to the dilution chamber opening of the drug delivery device; and
e) The drug delivery device is filled by: passing a pharmaceutical formulation from the active agent chamber into the diluting chamber through the one-way valve; mixing with the diluent in the dilution chamber; and then exits through the dilution chamber opening into the elongated tube such that the elongated tube having a known predetermined volume is filled with a diluted drug formulation to form a first portion of an infusion, and wherein a concentration profile of the diluted drug formulation in the elongated tube is according to a desired dose profile of the first portion of the infusion.
27. The method as recited in claim 26, further comprising: after loading the drug delivery device, the elongate tube is attached to a patient and the infusion driver is used to control the drug delivery device to dilute the drug formulation by mixing the drug formulation with the diluent in the dilution chamber and deliver the diluted drug formulation to the patient according to a predetermined dose profile.
28. A method, comprising: the preparation method according to any one of claims 21 to 25, preparing a drug delivery device according to any one of claims 1 to 20; and loading the drug delivery device according to the method of claim 26 or 27.
29. A drug delivery system, comprising:
the drug delivery device of any one of claims 1 to 20; and
an infusion device;
wherein the infusion device comprises:
at least one infusion device processor; and
an infusion device memory storing program instructions accessible by the at least one infusion device processor and configured to cause the at least one infusion device processor to control the drug delivery apparatus to deliver the drug formulation to a patient according to a predetermined dose profile.
30. The drug delivery system of claim 29, wherein:
the infusion device is configured to actuate an infusion device actuator to displace the first piston such that the drug formulation is output by the drug delivery apparatus according to the predetermined dose spectrum; or (b)
Wherein the infusion device is configured to apply an infusion pressure at the dilution chamber outlet, thereby causing displacement of the first piston such that the drug formulation is output by the drug delivery apparatus.
31. The drug delivery system of claim 29 or 30, wherein the system further comprises an elongated tube of known predetermined volume leading to the drug delivery device, and the processor is configured to perform a priming process prior to the beginning of the infusion, wherein the priming process comprises:
the drug delivery device is filled by: passing a pharmaceutical formulation from the active agent chamber into the diluting chamber through the one-way valve; mixing with the diluent in the dilution chamber; and then exits through the dilution chamber opening into the elongated tube such that the elongated tube having a known predetermined volume is filled with a diluted drug formulation to form a first portion of the infusion, and wherein a concentration profile of the diluted drug formulation in the elongated tube is according to a desired dose profile of the first portion of the infusion.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2021901794A AU2021901794A0 (en) | 2021-06-15 | Medication Delivery Systems, Apparatuses and Methods | |
| AU2021901792 | 2021-06-15 | ||
| AU2021901794 | 2021-06-15 | ||
| PCT/AU2022/050593 WO2022261707A1 (en) | 2021-06-15 | 2022-06-15 | Medication delivery systems, apparatuses and methods |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117500540A true CN117500540A (en) | 2024-02-02 |
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ID=89680508
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202280042219.0A Pending CN117500540A (en) | 2021-06-15 | 2022-06-15 | Drug delivery systems, devices and methods |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117500540A (en) |
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2022
- 2022-06-15 CN CN202280042219.0A patent/CN117500540A/en active Pending
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