Delivery of infusion using diluent chamber

Abstract

The present disclosure describes a medication delivery apparatus, which according to one example comprises a syringe comprising a first plunger and a first container which together define an active agent chamber for receiving a pharmaceutical preparation and a second container comprising a diluent chamber, which is removably attachable to a distal end of the first container. In some examples, a second plunger is positioned between the first end and second end of the second container and a hollow tube attached to the second plunger extends back from the second plunger into the first container. Also disclosed is a nesting arrangement in which at least a distal portion of a syringe is inserted into and nests within a container which includes a diluent chamber. Also disclosed is a diluent chamber that is split into a plurality of partition chambers by one or more partitions and a diluent chamber in which a foam insert is disposed.

Description

DELIVERY OF INFUSION USING DILUENT CHAMBERBACKGROUND

[0001] While many patients tolerate a therapeutic dose of a drug without significant adverse reaction, some patients may be hypersensitive to the drug. Drug hypersensitivity may present as an immediate hypersensitivity reaction and if the reaction is severe and potentially lifethreatening it is referred to as anaphylaxis. One strategy to prevent anaphylaxis is to administer a partial dose of the drug (referred to as a test dose) to see if a patient is hypersensitive to the drug. The test dose should be small enough to cause a reaction that can be recognised by a clinician, but not severe or life-threatening. If a mild reaction is recognised, the full dose is aborted and anaphylaxis can be prevented. If no adverse reaction is detected then the full therapeutic dose is prepared and administered at a constant dose rate (which is typically much faster than the dose rate of the test dose).

[0002] A significant challenge lies in determining the appropriate size of test dose for each patient. Due to individual variability, the threshold for inducing a mild hypersensitive reaction differs greatly among hypersensitive individuals. The size of dose that will cause severe or lifethreatening anaphylaxis is also different for different individuals. In fact, the life-threatening dose for very sensitive individuals may be smaller than the dose required to cause a mild hypersensitive reaction in less sensitive individuals. Therefore, providing a uniform test dose for all individuals will risk causing severe or life-threatening anaphylaxis in more sensitive individuals, and yet fail to induce a recognisable mild hypersensitivity reaction in less sensitive individuals (who may then suffer a severe life-threatening reaction when the full therapeutic dose is subsequently administered).

[0003] Another difficulty is that administering test doses is time consuming as each partial dose needs to be prepared to the correct size and the speed of administration of the test dose is generally very slow.

[0004] One approach described in WO 2021 / 113925 and WO 2022 / 261708, which are incorporated herein by reference, is to deliver both the test dose and the therapeutic dose as part of the same infusion. The drug can be administered at a dose rate which increases over time, with a first part of the infusion (where the dose rate is lower) acting as a plurality of test doses of gradually increasing size and the infusion as a whole delivering the full therapeutic dose. The dose rate can be increased continuously or in a series of discrete steps. In this way, thetime taken to check for adverse reaction and infuse a therapeutic dose can be shortened and adverse reactions detected for individuals with different levels of hypersensitivity.

[0005] 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 of the appended claims.BRIEF SUMMARY

[0006] According to a first aspect of the present disclosure, there is provided a medication delivery apparatus comprising: (a) a syringe comprising a first plunger and a first container which together define an active agent chamber (for receiving a pharmaceutical preparation); (b) a second container comprising: (i) a first end having a first opening configured to receive at least a distal portion of the syringe, (ii) a second end having an outlet opening for delivering a mixture of diluent and pharmaceutical preparation to a patient, (iii) a second plunger movable within the second container between the first end and the second end, and (iv) a diluent chamber located between the second plunger and the second end; wherein at least a distal end of the syringe is insertable through the first opening of the second container to nest within the second container; and wherein the apparatus has a flow path for allowing flow of fluid from the active agent chamber into the diluent chamber during use, whereby movement of the first plunger is operable to eject pharmaceutical preparation into the diluent chamber to mix with diluent and eject a mixture of pharmaceutical preparation and diluent through the outlet opening.

[0007] According to a second aspect of the present disclosure, there is provided a medication delivery apparatus comprising:

[0008] (a) a syringe comprising a first plunger and a first container which together define an active agent chamber for receiving a pharmaceutical preparation;(b) a second container including a diluent chamber, the second container having a first end with a first opening and a second end with an outlet opening;(c) wherein the second container is removably attachable to the first container to allow fluid communication between the active agent chamber and the diluent chamber during use; and (d) whereby movement of the first plunger in a distal direction is operable to ejectpharmaceutical preparation from the active agent chamber into the diluent chamber to mix with diluent therein and eject a mixture of diluent and pharmaceutical preparation through the outlet opening to a patient,such that a concentration of the pharmaceutical preparation in the diluent chamber increases during an infusion process.

[0009] According to a third aspect of the present disclosure, there is provided a medication delivery apparatus comprising:

[0010] (a) a container forming part of a syringe or configured to be attached to a syringe; (b) a plunger movable within the container;(c) a diluent chamber for containing diluent, the diluent chamber located between the plunger and a distal end of the container;(d) an outlet at the distal end of the container for delivery of fluid to a patient;(e) a flow path configured, during use, to allow pharmaceutical preparation to enter the diluent chamber; and(f) a compressible foam insert disposed in the diluent chamber, wherein the foam insert is positioned in a flow region between the plunger and the outlet.

[0011] According to a fourth aspect of the present disclosure, there is provided a medical device for connection to the outlet of a syringe, the medical device comprising:

[0012] (a) a container extending between a first end having an inlet opening and a second end having an outlet opening;(b) the inlet opening configured to receive at least a distal end of a syringe;(c) a plunger positioned between the first end and the second end of the container, wherein a space between the plunger and the second end of the container defines a diluent chamber for containing diluent; and(d) a hollow tube having a lumen in fluid communication with an aperture of the plunger and extending back from the plunger;the hollow tube being insertable into an outlet of a syringe and providing a conduit through which an active agent may be injected into the diluent chamber to mix with the diluent; and wherein the hollow tube is pushable to move the plunger towards the second end of the second container to force a mixture of diluent and active agent out of the diluent chamber through the outlet opening.

[0013] According to a fifth aspect of the present disclosure, there is provided a dilution device for removable attachment to a syringe to dilute pharmaceutical preparation ejected by the syringe before delivery to a patient, the device comprising:

[0014] (a) a container body having a first end with a first opening configured for removable attachment to the syringe and a second end with an outlet opening for delivering a mixture of diluent and pharmaceutical preparation to a patient;(b) a plunger movable within the container body;(c) a diluent chamber located between the plunger and the second end of the container body; and(d) a flow path configured to allow pharmaceutical preparation from the syringe to enter the diluent chamber during use,whereby a concentration of pharmaceutical preparation in the diluent chamber increases during infusion as pharmaceutical preparation enters and mixes with diluent therein.

[0015] Further features of the present disclosure are provided in the appended claims and the description below.TERMS AND DEFINITIONS

[0016] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0017] The term pharmaceutical preparation refers to a preparation comprising an active ingredient which is to produce a therapeutic effect on a patient. The active ingredient (also referred to as an “active agent” or “drug”) may be dissolved in a solvent or mixed with another solution to form the pharmaceutical preparation.

[0018] The term infusion refers to delivery of the pharmaceutical preparation to a patient via flow of fluid into the patient, e.g. through an intravenous access point.

[0019] The term active agent chamber refers to a chamber for holding the pharmaceutical preparation at the start of the infusion. The active agent chamber may also be referred to as the drug chamber.

[0020] The term diluent chamber (or dilution chamber) refers to a chamber for holding diluent at the start of the infusion which is to be used to dilute the pharmaceutical preparation before delivery to the patient.

[0021] The fluid infused to the patient may be pharmaceutical preparation, diluent or a mixture of pharmaceutical preparation and diluent depending on the type of infusion and stage of the infusion.

[0022] The term infusion rate refers to the rate at which fluid flows into the patient in the infusion. In some cases, the infusion rate may vary over the course of the infusion.

[0023] The term dose refers to a quantity of active ingredient. The term therapeutic dose or full therapeutic dose refers to the quantity of active agent that is to be delivered to the patient.

[0024] For a given volume of pharmaceutical preparation the dose is the concentration of active ingredient in the pharmaceutical preparation multiplied by the volume of the pharmaceutical preparation. The dose may be expressed as a percentage of the therapeutic dose. Unless stated otherwise, 100% of the therapeutic dose is considered to be 100% of pharmaceutical preparation present in the active agent chamber at the start of the infusion.

[0025] The term dose rate refers to the rate at which the active agent is delivered to the patient. The dose rate may be expressed as a percentage of the therapeutic dose per minute. The dose rate may vary over the course of the infusion. The dose rate is distinct from the infusion rate, as the dose rate refers to the amount of active agent delivered (which is based on the volume of pharmaceutical preparation delivered) per unit time, whereas the infusion rate refers to the volume of fluid delivered per unit time. The same infusion rate may deliver different dose rates depending on the concentration of pharmaceutical preparation in the delivered fluid.

[0026] The term cumulative dose refers to the total dose delivered to the patient up to a certain point in the infusion. For instance the cumulative dose at 5 minutes is the total dose delivered 5 minutes into the infusion.

[0027] The term dose profile refers to the way in which the cumulative dose delivered to the patient varies over time.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0028] To easily identify the discussion of any particular element or act, the most significant digit or digits in a reference number refer to the figure number in which that element is first introduced.

[0029] FIG. 1A illustrates an aspect of the subject matter in accordance with one embodiment.

[0030] FIG. IB illustrates an aspect of the subject matter in accordance with one embodiment.

[0031] FIG. 2A illustrates an aspect of the subject matter in accordance with one embodiment.

[0032] FIG. 2B illustrates an aspect of the subject matter in accordance with one embodiment.

[0033] FIG. 2C illustrates an aspect of the subject matter in accordance with one embodiment.

[0034] FIG. 3 illustrates an aspect of the subject matter in accordance with one embodiment.

[0035] FIG. 4 illustrates an aspect of the subject matter in accordance with one embodiment.

[0036] FIG. 5 illustrates an aspect of the subject matter in accordance with one embodiment.

[0037] FIG. 6A illustrates an aspect of the subject matter in accordance with one embodiment.

[0038] FIG. 6B illustrates an aspect of the subject matter in accordance with one embodiment.

[0039] FIG. 6C illustrates an aspect of the subject matter in accordance with one embodiment.

[0040] FIG. 6D illustrates an aspect of the subject matter in accordance with one embodiment.

[0041] FIG. 6E illustrates an aspect of the subject matter in accordance with one embodiment.

[0042] FIG. 6F illustrates an aspect of the subject matter in accordance with one embodiment.

[0043] FIG. 7 illustrates an aspect of the subject matter in accordance with one embodiment.

[0044] FIG. 8 illustrates an aspect of the subject matter in accordance with one embodiment.

[0045] FIG. 9 illustrates an aspect of the subject matter in accordance with one embodiment.

[0046] FIG. 10A illustrates an aspect of the subject matter in accordance with one embodiment.

[0047] FIG. 10B illustrates an aspect of the subject matter in accordance with one embodiment.

[0048] FIG. 10C illustrates an aspect of the subject matter in accordance with one embodiment.

[0049] FIG. 10D illustrates an aspect of the subject matter in accordance with one embodiment.

[0050] FIG. 10E illustrates an aspect of the subject matter in accordance with one embodiment.

[0051] FIG. 11 illustrates an aspect of the subject matter in accordance with one embodiment.

[0052] FIG. 12A illustrates an aspect of the subject matter in accordance with one embodiment.

[0053] FIG. 12B illustrates an aspect of the subject matter in accordance with one embodiment.

[0054] FIG. 12C illustrates an aspect of the subject matter in accordance with one embodiment.

[0055] FIG. 12D illustrates an aspect of the subject matter in accordance with one embodiment.

[0056] FIG. 12E illustrates an aspect of the subject matter in accordance with one embodiment.

[0057] FIG. 12F illustrates an aspect of the subject matter in accordance with one embodiment.

[0058] FIG. 13A illustrates an aspect of the subject matter in accordance with one embodiment.

[0059] FIG. 13B illustrates an aspect of the subject matter in accordance with one embodiment.

[0060] FIG. 13C illustrates an aspect of the subject matter in accordance with one embodiment.

[0061] FIG. 13D illustrates an aspect of the subject matter in accordance with one embodiment.

[0062] FIG. 13E illustrates an aspect of the subject matter in accordance with one embodiment.

[0063] FIG. 13F illustrates an aspect of the subject matter in accordance with one embodiment.

[0064] FIG. 14A illustrates an aspect of the subject matter in accordance with one embodiment.

[0065] FIG. 14B illustrates an aspect of the subject matter in accordance with one embodiment.

[0066] FIG. 15A illustrates an aspect of the subject matter in accordance with one embodiment.

[0067] FIG. 15B illustrates an aspect of the subject matter in accordance with one embodiment.

[0068] FIG. 15C illustrates an aspect of the subject matter in accordance with one embodiment.

[0069] FIG. 15D illustrates an aspect of the subject matter in accordance with one embodiment.

[0070] FIG. 16A illustrates an aspect of the subject matter in accordance with one embodiment.

[0071] FIG. 16B illustrates an aspect of the subject matter in accordance with one embodiment.

[0072] FIG. 16C illustrates an aspect of the subject matter in accordance with one embodiment.

[0073] FIG. 16D illustrates an aspect of the subject matter in accordance with one embodiment.

[0074] FIG. 16E illustrates an aspect of the subject matter in accordance with one embodiment.

[0075] FIG. 16F illustrates an aspect of the subject matter in accordance with one embodiment.

[0076] FIG. 17A illustrates an aspect of the subject matter in accordance with one embodiment.

[0077] FIG. 17B illustrates an aspect of the subject matter in accordance with one embodiment.

[0078] FIG. 17C illustrates an aspect of the subject matter in accordance with one embodiment.

[0079] FIG. 17D illustrates an aspect of the subject matter in accordance with one embodiment.

[0080] FIG. 17E illustrates an aspect of the subject matter in accordance with one embodiment.

[0081] FIG. 17F illustrates an aspect of the subject matter in accordance with one embodiment.

[0082] FIG. 18A illustrates an aspect of the subject matter in accordance with one embodiment.

[0083] FIG. 18B illustrates an aspect of the subject matter in accordance with one embodiment.

[0084] FIG. 18C illustrates an aspect of the subject matter in accordance with one embodiment.

[0085] FIG. 18D illustrates an aspect of the subject matter in accordance with one embodiment.

[0086] FIG. 18E illustrates an aspect of the subject matter in accordance with one embodiment.

[0087] FIG. 18F illustrates an aspect of the subject matter in accordance with one embodiment.

[0088] FIG. 19A illustrates an aspect of the subject matter in accordance with one embodiment.

[0089] FIG. 19B illustrates an aspect of the subject matter in accordance with one embodiment.

[0090] FIG. 19C illustrates an aspect of the subject matter in accordance with one embodiment.

[0091] FIG. 19D illustrates an aspect of the subject matter in accordance with one embodiment.

[0092] FIG. 19E illustrates an aspect of the subject matter in accordance with one embodiment.

[0093] FIG. 19F illustrates an aspect of the subject matter in accordance with one embodiment.

[0094] FIG. 20 illustrates an aspect of the subject matter in accordance with one embodiment.

[0095] FIG. 21 illustrates an aspect of the subject matter in accordance with one embodiment.

[0096] FIG. 22 illustrates an aspect of the subject matter in accordance with one embodiment.

[0097] FIG. 23 illustrates an aspect of the subject matter in accordance with one embodiment.

[0098] FIG. 24 illustrates an aspect of the subject matter in accordance with one embodiment.

[0099] FIG. 25 has been deleted.

[0100] FIG. 26 illustrates an aspect of the subject matter in accordance with one embodiment.

[0101] FIG. 27 illustrates an aspect of the subject matter in accordance with one embodiment.

[0102] FIG. 28 A illustrates an aspect of the subject matter in accordance with one embodiment.

[0103] FIG. 28B illustrates an aspect of the subject matter in accordance with one embodiment.

[0104] FIG. 29A illustrates an aspect of the subject matter in accordance with one embodiment.

[0105] FIG. 29B illustrates an aspect of the subject matter in accordance with one embodiment.

[0106] FIG. 29C illustrates an aspect of the subject matter in accordance with one embodiment.

[0107] FIG. 29D illustrates an aspect of the subject matter in accordance with one embodiment.

[0108] FIG. 29E illustrates an aspect of the subject matter in accordance with one embodiment.

[0109] FIG. 29F illustrates an aspect of the subject matter in accordance with one embodiment.

[0110] FIG. 29G illustrates an aspect of the subject matter in accordance with one embodiment.

[0111] FIG. 29H illustrates an aspect of the subject matter in accordance with one embodiment.

[0112] FIG. 291 illustrates an aspect of the subject matter in accordance with one embodiment.

[0113] FIG. 30A illustrates an aspect of the subject matter in accordance with one embodiment.

[0114] FIG. 30B illustrates an aspect of the subject matter in accordance with one embodiment.

[0115] FIG. 30C illustrates an aspect of the subject matter in accordance with oneembodiment.

[0116] FIG. 30D illustrates an aspect of the subject matter in accordance with one embodiment.

[0117] FIG. 30E illustrates an aspect of the subject matter in accordance with one embodiment.

[0118] FIG. 3 OF illustrates an aspect of the subject matter in accordance with one embodiment.

[0119] FIG. 31 A illustrates an aspect of the subject matter in accordance with one embodiment.

[0120] FIG. 3 IB illustrates an aspect of the subject matter in accordance with one embodiment.

[0121] FIG. 31C illustrates an aspect of the subject matter in accordance with one embodiment.

[0122] FIG. 3 ID illustrates an aspect of the subject matter in accordance with one embodiment.

[0123] FIG. 3 IE illustrates an aspect of the subject matter in accordance with one embodiment.

[0124] FIG. 3 IF illustrates an aspect of the subject matter in accordance with one embodiment.

[0125] FIG. 32 illustrates an aspect of the subject matter in accordance with one embodiment.

[0126] FIG. 33 illustrates an aspect of the subject matter in accordance with one embodiment.

[0127] FIG. 34A illustrates an aspect of the subject matter in accordance with one embodiment.

[0128] FIG. 34B illustrates an aspect of the subject matter in accordance with one embodiment.

[0129] FIG. 34C illustrates an aspect of the subject matter in accordance with one embodiment.

[0130] FIG. 34D illustrates an aspect of the subject matter in accordance with one embodiment.

[0131] FIG. 34E illustrates an aspect of the subject matter in accordance with oneembodiment.

[0132] FIG. 34F illustrates an aspect of the subject matter in accordance with one embodiment.

[0133] FIG. 35 illustrates an aspect of the subject matter in accordance with one embodiment.

[0134] FIG. 36 illustrates an aspect of the subject matter in accordance with one embodiment.

[0135] FIG. 37 illustrates an aspect of the subject matter in accordance with one embodiment.

[0136] FIG. 38 illustrates an aspect of the subject matter in accordance with one embodiment.

[0137] FIG. 39 illustrates an aspect of the subject matter in accordance with one embodiment.

[0138] FIG. 40 illustrates an aspect of the subject matter in accordance with one embodiment. FIG. 42 illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 43A illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 43B illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 43 C illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 44A illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 44B illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 44C illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 45A illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 45B illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 46 illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 47A illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 47B illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 48 illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 49A illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 49B illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 49C illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 49D illustrates an aspect of the subject matter in accordance with one embodiment.FIG. 50 and 51 illustrates an aspect of the subject matter in accordance with one embodiment. FIG. 52 has been deleted.FIGS 53A to 53C, 54A to 54C, 55, 56A to 56G illustrate aspects of the subject matter in accordance with one embodiment.FIG. 57A illustrates an aspect of the subject matter in accordance with one embodiment relating to plunger and valve design.FIG. 57B illustrates an aspect of the subject matter in accordance with one embodiment relating to plunger and valve design.FIG. 57C illustrates an aspect of the subject matter in accordance with one embodiment relating to plunger and valve design.DETAILED DESCRIPTION

[0139] Examples disclosed herein may provide a convenient system of administering test doses at a dosage which is appropriate for a large number of individuals. The system may deliver the test doses in a convenient and clinically -appropriate time-frame, thereby allowing hypersensitivity to be detected while avoiding severe life-threatening hypersensitivity in a large number of individuals.

[0140] FIG. 1A shows an example of an apparatus which is able to deliver a drug over a period of time using a dose rate which increases in a non-linear fashion. This apparatus includes a dual chambered syringe 100 comprising a container 110 which receives at least part of a first plunger 120 and a second plunger 140. A space between the container walls, the first plunger 120 and the second plunger 140 defines an active agent chamber 130 for receiving pharmaceutical preparation. A space between the second plunger 140 and the distal end of the container 110 defines a diluent chamber 150 for receiving diluent. The second plunger 140 has an opening with a one-way valve 142 for allowing pharmaceutical preparation to flow from the active agent chamber 130 to the diluent chamber 150. The distal end of the container 110 has an outlet opening 152 which may be attached to tubing which leads to the patient.

[0141] The dual chambered syringe 100 is mounted to an infusion driver (not shown) which drives the first plunger 120 towards the second plunger 140. This causes pharmaceutical preparation to flow through the valve 142 into the diluent chamber and mix with diluent while simultaneously ejecting contents of the diluent chamber through the outlet opening 152 to the patient. In this way the concentration of pharmaceutical preparation in the diluent chamber and thus the concentration infused to the patient gradually increases. At some point the first plunger 120 will abut the second plunger 140 (effectively collapsing the active agent chamber) and he first plunger 120 and second plunger will then be moved together towards the distal end of thecontainer 110 to collapse the diluent chamber and evacuate the remaining pharmaceutical preparation to the patient.

[0142] FIG. IB shows the cumulative dose delivered over time for a 30 minute infusion delivered by the apparatus of FIG. 1A according to one example dose profile. It can be seen that the first 15 minutes of the infusion have a very low dose rate and that by 24 minutes only about 10% of the full dose has been delivered. However, in the later part of the infusion the dose rate and cumulative dose delivered increase rapidly. In the example of FIG. IB, not only does the dose rate increase, but also the rate of increase increases over time. This further shortens the time taken to check for an adverse reaction and infuse a therapeutic dose, compared to protocols in which the drug is delivered at a constant rate or in discrete steps with linear increase in dose rate.

[0143] Infusion drivers have low accuracy at low infusion rates and low volumes. However, the device of FIG. 1A to achieve relatively accurate slow dose rates while being driven at a higher infusion rate, because the pharmaceutical preparation is diluted before before delivery to the patient. As the concentration in the diluent chamber increases over the course of the infusion, the dose rate and cumulative dose delivered at each point in the infusion is dependent on a complex interaction between the variable infusion rate of the infusion driver and the concentration of the pharmaceutical preparation (and active agent) in the dilution chamber. WO 2021 / 113925 teaches how to model this interaction for a dual chambered syringe and control the infusion driver to deliver a desired dose profile.

[0144] While the apparatus of FIG. 1A is able to deliver a drug to the patient in a dose profile as shown in FIG. IB, the design of the apparatus poses some challenges.

[0145] Firstly, a specialized dual chambered syringe is needed, which increases costs.Secondly, the preparation process for the dual chambered syringe 100 is relatively time consuming and involves a number of different steps.

[0146] The preparation process involves filling the diluent chamber with the correct volume of diluent, filling the active agent chamber with the correct volume of pharmaceutical preparation and moving the first and second plungers to the correct starting positions (which may be marked on the container). For instance, the preparation may involve filling the diluent chamber 150 first through the outlet opening 152 thereby pushing the second plunger 140 to the desired initial position, and then filling the active agent chamber 130 through the side inlet port 116 thereby pushing the first plunger 120 to the desired initial position. While, the preparationprocess could be simplified by providing the dual chambered syringe 100 with pre -filled diluent and active agent chambers, this would risk the pharmaceutical preparation mixing with the diluent prematurely or prior to administration to the patient. This could result in an inappropriately high initial dose of the drug and potentially cause severe hypersensitivity or life-threatening anaphylaxis.

[0147] Thirdly, in order to achieve certain dose profiles with the dual chambered syringe, it is necessary to use a specialized infusion device capable of multiple infusion steps each with a different infusion rates. For example, the dose profile shown in FIG. IB may be approximated by using a dual chambered syringe together with an infusion driver capable of 12 different infusion steps each with a different rate. If an infusion device capable of only a smaller number of infusion steps and infusion rates, or capable of only a single infusion rate throughout the infusion, is used then while the dose rate will increase (due to increasing concentration in the diluent chamber), the curve will be flatter and it becomes difficult to achieve dose profiles with very large differences between (low) dose rates at the beginning of infusion and (high) dose rates at the end of the infusion.

[0148] The present disclosure proposes a detachable container comprising a dilution chamber, which may be attached to the outlet end of a syringe. This may simplify the preparation process and in some cases may be used with a standard syringe.

[0149] The present disclosure also proposes a dilution chamber having partitions which separate the dilution chamber into a plurality of partition chambers. The partition chambers make it possible to achieve more favorable dose profiles with a single rate infusion driver or an infusion driver which has only a small number of steps / infusion rates. The partitioned dilution chamber may be part of a detachable container as described above, or integrated into a dual chambered syringe or other types of medication delivery apparatus.

[0150] For ease of navigation the following description is divided into 7 sections. Examples of detachable containers are discussed in Section 1. General considerations for dose profiles are discussed in Section 2. The dose profiles produced by a detachable container are discussed in Section 3. Sections 4A provides examples of a container with a hollow tube, and Section 4C describes the dose profiles they produce. Section 4A-2 describes the nested arrangement in which at least a distal end of the syringe is insertable through the first opening of the second container to nest within the second container. Section 5 discusses examples of partitioned dilution chambers and the dose profiles they may produce. Section 6 discloses gaskets andother parts which may be used together with the diluent chamber and / or medication delivery apparatus. Section 7 describes a dilution device in which a compressible foam insert is disposed in the diluent chamber.

[0151] 1 A. DETACHABLE CONTAINER COMPRISING DILUTION CHAMBER

[0152] One aspect of the present disclosure proposes providing a detachable container comprising a dilution chamber, which may be attached to a syringe containing the pharmaceutical preparation immediately prior to administration of the infusion. This container may be used with a standard syringe thereby reducing costs. Furthermore, as the dilution chamber is provided in a separate container, which is attached immediately prior to the infusion, premature mixing of the pharmaceutical preparation with diluent can be prevented. The preparation step is also simplified compared to a dual chambered syringe. For example, the dilution chamber of the separate container may be pre -filled with diluent prior to packaging, in which case the preparation step may simply comprise attaching the container to the syringe. In some cases the diluent chamber may be supplied empty, in which case the preparation steps comprise the clinician filling the diluent chamber with diluent and then attaching the container to the syringe.

[0153] FIG. 2A shows a medication delivery apparatus 200 for delivering a pharmaceutical preparation to a patient according to one example of the present disclosure. The medication delivery apparatus 200 comprises a syringe 210 and a separate container 250, including a diluent chamber 260, which is removably attachable to the syringe.

[0154] The syringe 210 comprises a first plunger 230 and a first container 220 which together define an active agent chamber 240 for receiving a pharmaceutical preparation. The first plunger 230 is received through a proximal opening in the proximal end 222 of the first container and may be attached to a shaft 232 for driving movement of the first plunger. A distal end 226 of the first container may act as the distal end of syringe. The distal end 226 has a distal opening for ejecting fluid from the active agent chamber when the first plunger 230 is pushed in the distal direction.

[0155] The removably attachable container 250 may be referred to as the “second container”. The second container is shown by itself in FIG. 2B. The second container 250 comprises a first end 252 having an inlet opening 254, a second end 256 having an outlet opening 258, and a diluent chamber 260. The first end 252 of the second container 250 is removably attachable to a distal end 226 of the first container 220. For example the first and second containers may beattached such that part of the first container physically contacts and is attached to part of the second container. They maybe attached such that the first container and second container cannot move laterally or axially apart when attached together.

[0156] The second container is attachable to the first container in a manner which puts the first container 220 and second container 250 in fluid communication. For example, pharmaceutical preparation may flow through the distal opening 228 at the distal end of the first container and the inlet opening 254 at the first end 252 of the second container. A one-way valve may be provided between the active agent chamber 240 and the diluent chamber 260 to inhibit backflow of fluid from the diluent chamber into the active agent chamber.

[0157] In some examples the first end 252 of the second container may comprise a connector for mechanically attaching the first end 252 of the second container to the distal end 226 of the first container. The attachment may be such that the first container and second container are coaxial as shown in FIG. 2A. In some examples the distal opening 228 of the first container and the inlet opening 254 of the second container may be bore connectors (e.g. Luer lock or Luer slip connectors) which are attachable to each other.

[0158] The apparatus 200 is configured such that movement of the first plunger 120 in a distal direction is operable to eject pharmaceutical preparation from the active agent chamber 240 into the diluent chamber 260 to mix with the diluent and eject a mixture of pharmaceutical preparation and diluent through the outlet opening 258 of the second container. The diluent may thus be mixed with the pharmaceutical preparation simultaneously with a mixture of pharmaceutical preparation and diluent being ejected through the outlet opening 258. The concentration of pharmaceutical preparation in the diluent chamber 260 may increase in concentration over time during the infusion as more pharmaceutical preparation enters the diluent chamber. The outlet opening 258 may be connected to the patient via flexible tubing and an intravenous access point.

[0159] When the first and second containers are attached together they may functionally act as a single container comprising an active agent chamber and a diluent chamber. However, as the second container 250 is provided separately from and removably attachable to the syringe 210, accidental mixing of diluent and pharmaceutical preparation may substantially reduced or prevented. Preparing the medication delivery apparatus 200 for the infusion is also straightforward and may be as simple as filling the syringe with the desired quantity ofpharmaceutical preparation and attaching a second container which has been pre -filled with diluent.

[0160] The medication delivery apparatus 200 may be provided as a single chamber syringe 210 and a separate container 250 which is attachable to the outlet of the syringe. The syringe may comprise an active agent chamber 240, while the separate container 250 comprises a diluent chamber 260. In some examples the diluent chamber may be prefilled with diluent, while in other examples the container 250 may be provided empty and filled by the clinician prior to attaching to the syringe. In some examples the active agent chamber of the syringe may be pre-filled and in other examples provided empty and filled by the clinician prior to the infusion. Thus one or both of the active agent chamber and the diluent chamber may be pre-filled. Providing a container with a pre-filled diluent chamber filled with a predetermined volume of diluent may be particularly convenient allowing for quick assembly of the apparatus.

[0161] IB. DIVIDER OR PLUNGER

[0162] FIG. 2C shows another example of a second container 250 according to the present disclosure, in which like parts are denoted by the same reference numerals as in FIG. 2B. In the example of FIG. 2C, the second container 250 has a divider 270 positioned between the first end 252 and second end 256 of the second container. The diluent chamber 260 is thus defined by the space between the divider 270 and the second end 256 of the second container.

[0163] The divider 270 is a member which substantially blocks passage of fluid between a first side and a second side of the divider, but has at least one opening or aperture 272 for allowing fluid to pass from the first side to the second side. The divider 270 may for example be a plunger, in which case it may be referred to as the second plunger.

[0164] The space 430 between the divider 270 and the first end 252 of the second container may be empty. The arrangement may be such that fluid does not flow into this empty space 430. In the illustrated example, the walls of the second container define a hollow passage 255 between the inlet opening 254 and the aperture 272 of the divider 270. Fluid may thus flow directly through this hollow passage 255 to the aperture 272 and into the diluent chamber 260. In other examples, there may be no hollow passage 255, in which case the space 430 may effectively form part of the active agent chamber if the space 430 does not contain diluent and the pharmaceutical preparation is able to flow from the first container into the space 430.

[0165] In some examples a one-way valve may be provided in the inlet opening 254, the hollow passage 255 or the aperture 272 to allow fluid to pass from the active agent chamberinto the diluent chamber 260, but inhibit fluid from flowing from the diluent chamber into the active agent chamber.

[0166] In some examples, there may be an arrangement to generate at least two divergent jets of pharmaceutical preparation (or pharmaceutical preparation and diluent) in the diluent chamber 260. This helps to promote mixing of diluent and pharmaceutical preparation in the diluent chamber. The arrangement may comprise at least first and second openings in the divider 270 .

[0167] FIG. 3 shows an example of a divider in the form of a second plunger 310 comprising a first opening 312 and a second opening 314.

[0168] FIG. 4 shows a cross section of the second plunger 310 of FIG. 3. The second plunger 310 may abut against and seal with walls of the second container to substantially prevent fluid passing from the first side 330 to the second side 340 of the plunger except through the first and second openings 312, 314. The second plunger 310 may comprise a one-way valve. The first opening 312 and the second opening 314 are arranged to generate two divergent jets 322, 324 of fluid when fluid passes through second plunger into the diluent chamber. In some examples, the two jets may be directed to opposite (e.g. top and bottom) corners of the diluent chamber (e.g. top and bottom corners at the second end 256). The two divergent jets promote mixing of the pharmaceutical preparation with the diluent in the diluent chamber. In other examples there may be more than two openings, each opening generating a respective jet of fluid and at least some of the jets being divergent. In this example, where the divider is between the active agent chamber and the entrance to the diluent chamber, the jets are formed from pharmaceutical preparation which is ejected from the active agent chamber into the diluent chamber.[0168A] FIG. 57A illustrates an example valve arrangement associated with a plunger aperture in which flow from the syringe into the diluent chamber is directed substantially axially (e.g., a duckbill-type valve producing a generally straight jet). FIG. 57B illustrates an example valve arrangement associated with a plunger aperture in which flow from the syringe is distributed radially into the diluent chamber (e.g., an umbrella-type valve producing generally radial flow). FIG. 57C illustrates an example valve arrangement associated with a plunger aperture in which flow from the syringe is directed at an angle relative to an axis of the diluent chamber (e.g., a flapper-type valve producing an angled jet), which may assist mixing in the diluent chamber. It is to be understood that these are just examples and other types of valve may be used.

[0169] In other examples, the arrangement with two openings for generating the jets may be provided in the inlet opening of the second container or an outlet of a hollow passage extending from the inlet opening (for instance if there is no divider).

[0170] 1 C. PARTITIONS AND PARTITION CHAMBERS

[0171] The term ‘divider’ refers to a member which forms a first end of the diluent chamber. For example, the divider may separate the diluent chamber from the active agent chamber or may separate the diluent chamber from a passage linking the diluent chamber and the active agent chamber. FIG. 2C and FIG. 4 show examples of dividers 270, 310. In contrast, the term ‘partition’ refers to a member which divides the diluent chamber into a plurality of sub-chambers. FIG. 5 shows a further example of a second container 500 in which the diluent chamber has a number of partitions.

[0172] Referring to FIG. 5, the second container 500 has a first end 502 with an inlet opening 254 and a second end 256 with an outlet opening 508 opposite the first end. The inlet opening 504 may have a one-way valve (not shown) for allowing flow through the inlet opening into the second container but inhibiting flow of fluid out of the inlet opening 504.

[0173] The second container 500 comprises a diluent chamber 560 which is separated into a plurality of partition chambers by one or more partitions. In the illustrated example there are three partitions 512, 522 and 532 which separate the diluent chamber 560 into a first partition chamber 510, a second partition chamber 520, a third partition chamber 530 and a fourth partition chamber 540. Each of the partitions has at least one aperture 514, 524 and 534.

[0174] Each of ‘partitions’ is a member which substantially blocks passage of fluid between adjacent partition chambers, but has at least one channel (e.g. an opening, aperture or passage) for allowing fluid to pass from a partition chamber on a first side of the partition to a partition chamber on the second side of the partition. The at least one channel may have a one-way valve for allowing fluid to flow from the first side to the second side of the partition (i.e. in the distal direction toward the patient), but not in the other direction. The partitions may have a cross section of the same shape and area as the dilution chamber (e.g. circular) and may contact the walls of the partition chamber. In some examples, the partitions 512, 514, 316 may be plungers which seal with the walls of the container. In other examples, some or all of the partitions may contact the walls of the container, but fall short of a complete seal. The partitions may, for example, be inserted into the container by deforming and pushing through the inlet or outlet opening, or by disassembling the container if it has a two-piece design.

[0175] In the example of FIG. 5 there is no divider, but only partitions and the diluent chamber is bounded by the inlet opening 504 of the container 500. In other examples the first partition 512 could instead be a divider forming the distal end of the diluent chamber with the chamber 510 forming an empty space or being part of the active agent chamber.

[0176] In some implementations, one or more of the partitions may have two or more apertures for generating divergent jets of fluid, as described above with respect to FIG. 3 and FIG. 4. The jets of fluid may formed of pharmaceutical preparation, diluent, or a mixture of pharmaceutical preparation and diluent depending on the position of the partition.

[0177] As will be explained later in Section 5 of this application, the partitions allow for a greater variety of dose profiles, even if there is a single constant rate infusion driver or a infusion driver capable of only a small number of infusion steps and infusion rates.

[0178] 2. DOSE PROFILES

[0179] The inventor has carried out research on the dose profiles and observed that hypersensitive individuals who are very sensitive to a drug, and who have a low threshold for inducing a mild hypersensitive reaction, will generally suffer a severe reaction when the cumulative dose is not much greater than their mild reaction threshold. However, individuals who are less sensitive to a drug, who have a higher threshold for inducing a mild hypersensitive reaction, will generally suffer a severe reaction when the cumulative dose is much greater than their mild reaction threshold. The inventor has further observed that the difference between an individual's mild reaction threshold and an individual's severe reaction threshold is generally proportional to the individual's mild reaction threshold. Therefore, in the earlier part of the infusion when the cumulative dose rate is low, a relatively small increase in cumulative dose may risk causing a severe reaction, whereas later in the infusion when the cumulative dose rate is higher, a relatively small increase is unlikely to cause a severe reaction.

[0180] It is useful to consider the possible doses that could be an individual’s threshold for hypersensitivity. This is typically between 0.01% and 100% of the therapeutic dose. For any potential threshold, it is desirable to provide a delay in time between that point and the point that a larger dose is given, so that a reaction can be recognised and the infusion aborted before a larger dose that will cause a severe or life-threatening reaction is given. The latent period of a hypersensitivity reaction (time between a given dose and the reaction manifesting as symptoms or signs) is typically 5 minutes. The present disclosure proposes that a reasonable safety margin is a 10-fold multiple in dose above the threshold dose. Accordingly, certain aspects of thepresent disclosure propose ensuring that all 10 -fold dose-difference intervals are greater than 5 minutes. As the cumulative dose increases over time, the 10-fold dose-difference interval may be referred to as the 10-fold dose increase interval.

[0181] We propose the term Order Magnitude Delay (OMD; measured in minutes) to describe the interval of time taken for the cumulative delivered dose to increase by 10 -fold. Each point in the infusion (up to and including the point at which 10% of the final dose is delivered) has an associated OMD. For example, the OMD at 0.1% cumulative dose refers to the length of time taken for the cumulative dose to reach 1% of the final total; meanwhile the OMD at 1% cumulative dose refers to the length of time taken for the cumulative dose to reach 10% of the total. There is an OMD for all points in the infusion where the dose administered is at least 10 times less than the final dose. The OMD may vary between different points in the infusion and the larger the OMD the more time there is to detect an adverse reaction. The reference or starting point for a OMD can be an infusion time or the cumulative dose reached at the infusion time from which the OMD is measured. If the cumulative dose happens to be an individual’s threshold for hypersensitivity, the OMD represents the time interval before the dose profile will administer 10-times that dose and represents a safety margin.

[0182] In summary it is desirable to have a dose profile which delivers a low dose rate at the start of the infusion and a much higher dose rate towards the end of the infusion and one way of characterizing the dose profile is the Order Magnitude Delay (OMD; measured in minutes). Various factors influence the OMD. For example, the OMD can be increased by increasing the infusion time over which the drug is administered. For the purposes of discussion and illustration below, we will consider a fixed infusion time of 30 minutes, but the duration of the infusion could be shorter or longer than this if desired. In general infusion times for an anesthetic, antibiotics and other pharmaceutical preparations may be between 20 minutes and 60 minutes for practical applications in a clinical setting. While the majority of drugs are delivered by an infusion of an hour or less, for a few drugs the infusion may be delivered over 1-2 hours, up to 3 hours or up to 4 hours.

[0183] 3. DOSE PROFILE OF DETACHABLE CONTAINER WITH DILUENT CHAMBER

[0184] FIG. 6A to FIG. 6F are graphs showing the dose profile and other characteristics of an apparatus with a single fixed volume diluent chamber, for example as shown in FIG. 2A and FIG. 2B. An apparatus which has a detachable, non-partitioned, diluent chamber with a divider or plunger as shown in FIG. 2C, FIG. 3 or FIG. 4 will have a similar dose profile as long as the1diluent chamber volume remains constant during the infusion. The graphs show an example in which the diluent chamber has a volume of 30mL with no partitions, the active agent chamber has a volume of 50mL and there is constant infusion rate delivered over 30 minutes.

[0185] FIG. 6A shows the amount of active agent in the diluent chamber over time as a percentage of the therapeutic dose, FIG. 6B shows the concentration (in percentage of the therapeutic dose per ml) in the diluent chamber over time, FIG. 6C shows the dose (as percentage of the therapeutic dose) delivered to the patient over time, FIG. 6D shows the dose (as percentage of the therapeutic dose) delivered to the patient over time on a logarithmic scale. In the context of these graphs the full therapeutic dose is considered to be the dose initially present in the active agent chamber at the start of the infusion.

[0186] FIG. 6E shows the OMD or 10 fold delay time (in minutes) against cumulative delivered drug as a percentage of the full therapeutic dose on a logarithmic scale (solid line), while the vertical dotted line indicates that the OMD is 5 minutes at the point at which 0.42% of the full therapeutic dose has been delivered. As the latent period of anaphylaxis is typically 5 minutes, all individuals with thresholds greater than 0.42% of the therapeutic dose will be recognized in time to avoid 10-times the threshold from being administered.

[0187] If we consider hypothetical hypersensitivity thresholds of 0.05% or 0.5% of the therapeutic dose, the OMD is 1.61 and 5.51 minutes, respectively at these thresholds. This means that the dose profile may not be suitable for individuals having a hypersensitivity threshold of 0.05%, as this would leave only 1.61 minutes to detect an adverse reaction which may not be sufficient for many types of drug. If we take an OMD of 5 minutes as a safe margin, then the system will be suitable for patients having a hypersensitivity threshold of no more than 0.42% of the therapeutic dose.

[0188] One point to note is that, while the dual syringe apparatus of FIG. 1A has a diluent chamber 150 which reduces in size in the later part of the infusion when the second plunger 140 is pushed by the first plunger 120, this is not the case for the syringe plus detachable diluent chamber system of FIG. 2 A. For the apparatus of FIG. 2 A, the diluent chamber 260 has a fixed volume and is not emptied during in the infusion process shown in FIG. 6A to FIG. 6F. Therefore a portion of the therapeutic dose still remains in the dilution diluent chamber 260 at the end of the infusion after the infusion driver has completed emptying active agent chamber 240 of the syringe 210. As shown in FIG. 6C, for an active agent chamber of 50mL and adiluent chamber of 30mL, more than 48% of the pharmaceutical preparation will be left in the diluent chamber at the end of the infusion.

[0189] Accordingly, with this arrangement, in order to deliver the full dose initially in the active agent chamber to the patient, the clinician may manually empty the diluent chamber at the end of the infusion. For example, by driving a bolus of diluent through the diluent chamber. However, this requires a further step and is inconvenient. Leaving the remaining pharmaceutical preparation unused in the diluent chamber is undesirable as it is wasteful of pharmaceutical preparation and makes it more difficult to accurately calculate the actual dose delivered to the patient.

[0190] 4 A. HOLLOW PUSHER TUBE

[0191] The issue of pharmaceutical preparation remaining in the diluent chamber at the end of the infusion may be addressed by providing the detachable container with a hollow tube (also referred to as a ‘hollow pusher tube’) as described below. The detachable container is referred to as the second container below, or ease of understanding as it may be used together with a syringe comprising a first container, however, it is to be understood that the detachable container may be provided separately.

[0192] FIG. 7 shows an example of a second container 400, in which the second container includes a second plunger 420 positioned between the first end 402 and the second end 406 of the container 400 and a hollow tube 440 extends back from the second plunger 420 through the inlet opening 404 of the second container. The hollow tube 440 has a lumen 442 in fluid communication with an aperture 422 of the second plunger 420 through which a pharmaceutical preparation (including an active agent) may be injected into the diluent chamber 410 to mix with the diluent in the diluent chamber.

[0193] FIG. 8 shows an example of the second container 400 when attached to a syringe 900 of the type shown in FIG. 9 to form a medication delivery apparatus 800. The medication delivery apparatus thus comprises the second container 400 attached to the first container 910 of the syringe. When connected together in this way, the first and second container may be considered as one large container.

[0194] The syringe 900 comprises a first container 910 and a first plunger 930 which together define an active agent chamber 940 for receiving a pharmaceutical preparation. The first container extends between a proximal end 912 and a distal end 916. The proximal end has a proximal opening 914 for receiving the first plunger 930 and the distal end has a distal opening918 through which pharmaceutical preparation may be ejected when the first plunger 930 is moved towards the distal end 916.

[0195] The first end 402 of the second container is removably attachable to the distal end 916 of the first container 910. As shown in FIG. 8, when the second container 400 is attached to the syringe in this way, the hollow tube 440 may extend into the first container. Specifically, the hollow tube 440 may extend back through the inlet opening 404 of the second container and through the distal opening 918 of the first container into the first container. The hollow tube 440 has a lumen 442 in fluid communication with the aperture 422 of the second plunger 420 through which a pharmaceutical preparation (including an active agent) may be injected into the diluent chamber 410 to mix with the diluent.

[0196] In use, the first plunger 930 is movable in the distal direction 820 to eject pharmaceutical preparation from the active agent chamber 940 through the lumen of the hollow tube 440 into the diluent chamber 410 to mix with the diluent and eject a mixture of pharmaceutical preparation and diluent through an outlet opening 408 of the second container. In this way the pharmaceutical preparation may be mixed with the diluent simultaneously with a mixture of pharmaceutical preparation and diluent being ejected through the outlet opening 408 of the diluent chamber. The concentration of pharmaceutical preparation in the diluent chamber may increase over time as the infusion progresses and more pharmaceutical preparation enters the diluent chamber.

[0197] The first second plunger 420 may be moved in the distal direction 820 until it abuts against the hollow tube 440. Thereafter further movement of the first plunger in the distal direction pushes the hollow tube 440 and causes the second plunger 420 to move in the distal direction. The hollow tube may therefore also be referred to as a hollow pusher tube. As the second plunger moves in the distal direction 820 this expels some or all of the remaining pharmaceutical preparation (or mixture of pharmaceutical preparation and diluent) from the diluent chamber 410.

[0198] The hollow tube 440 thus helps to expel more of or all of the pharmaceutical preparation from the medication delivery apparatus 800. In comparison, in the embodiment of FIG. 2C in which there is no hollow tube and the second plunger is stationary, a significant amount of pharmaceutical preparation may be left in the diluent chamber at the end of the infusion.

[0199] The inlet opening and / or the outlet opening of the removably attachable container (which may be referred to as the ‘second container’) may comprise a bore connector. In some examples the bore connector may be a luer slip or luer lock (female or male). The distal outlet of the first container (the outlet of the syringe) may also comprise a bore connector, such as a luer slip or luer lock.

[0200] The connection between the distal end 916 of the first container 910 and the first end 402 of the second container 400 provides a passage between the active agent chamber 940 and the diluent chamber 410. The apparatus may include a valve to control flow of fluid from the active agent chamber 940 to the diluent chamber 410. For example, a one-way valve may be provided to allow flow of fluid from the first container in the second container but inhibit flow of fluid in the opposite direction.

[0201] The second container may include a divider or a second plunger 420. The diluent chamber is defined by the space between the divider or second plunger and the second end 406 of the second container. The diluent chamber may be bordered by the divider or second plunger, the inner surface of the second container body and the outlet opening of the second container. The outlet opening 408 may be connected to a minimum -volume extension tubing, intravenous tubing, or other patient access. The diluent chamber 410 may be pre-filled with diluent.

[0202] In some examples, as shown in FIG. 7 to FIG. 9, the second container may include an internal hollow pusher tube 440 that extends from the second plunger 420, through the inlet opening 404 of the second container, and extends into the interior of the standard syringe 900. The hollow tube 440 may have a lumen 442 extending between a proximal end having a proximal opening 444 and a distal end having a distal opening (not shown). The distal opening may be in fluid communication with the aperture 422 of the second plunger. The hollow tube 440 may have a side opening 446 positioned between the distal end and proximal end and in fluid communication with the lumen. The side opening 446 allows pharmaceutical preparation to enter the lumen 442 and flow into the diluent chamber, even when the first plunger 930 abuts against the distal end of the hollow tube and blocks the hollow tube's distal opening.

[0203] In some examples, the hollow tube or the aperture 422 of the second plunger may comprise a one-way valve to allow passage of pharmaceutical preparation into the diluent chamber, but inhibit or prevent flow of diluent into the diluent chamber. As the first plunger 930 of the syringe advances to empty the pharmaceutical preparation into the diluent chamber410, the first plunger may reach the position of the proximal end of the hollow pusher. As the first plunger continues to advance, it will strike the hollow pusher tube and push the hollow tube 440 and the connected second plunger 420. This will then advance the second plunger 420, reducing the volume of the diluent chamber. Mixing in the diluent chamber will continue as pharmaceutical preparation enters the diluent chamber, but the volume of the diluent chamber in which the pharmaceutical preparation and diluent mix will decrease over time.

[0204] In a dual chambered syringe 100 as shown in FIG. 1 A, the volume of the diluent chamber 150 does not reduce until the active agent chamber 130 is empty. In contrast, in a medication delivery apparatus 800 as shown in FIG. 8, the active agent chamber 940 and the diluent chamber 410 may reduce in volume simultaneously at least towards the end of the infusion depending on the length of the diluent chamber 410 and the length of the hollow pusher hollow tube 440. This simultaneous reduction in volume of both the active agent chamber and diluent chamber may modify the dose profile by increasing the speed at which the concentration of pharmaceutical preparation increases in the diluent chamber.

[0205] There may be a gasket 450 to seal a space between the hollow tube 440 and the walls of the passage between the distal opening of the first container and the inlet opening of the second container. For example the gasket may be provided in the inlet opening 404 of the second container to seal a space between the hollow tube 440 and the inlet opening 404.

[0206] There may be an opening (not shown) in the second container 400 between the first end 402 of the second container and an initial position of the second plunger 420. For example, the opening may be an aperture in the first end 402 of the second container. This opening may act as a vent to allow air into an empty space 430 between the second first second plunger 420 and the first end 402 of the second container. This helps to prevent a vacuum forming when the second plunger 420 is moved in the distal direction toward the second end of the second container.

[0207] FIG. 10A to FIG. 10E show the medication delivery apparatus of FIG. 8 at different stages of the infusion process according to one example. FIG. 10A shows the start of the infusion, with the first plunger in an initial position which is spaced apart from the distal end of the hollow tube.

[0208] FIG. 10B shows a first stage of the infusion in which the first plunger is being moved in the distal direction toward the distal end of the first container, but has not yet reached the hollow tube. During this first stage the volume of the active agent chamber is being graduallyreduced and pharmaceutical preparation is ejected through the hollow tube and into the diluent chamber where it mixes with the diluent. As the diluent chamber has constant volume in this stage but is receiving pharmaceutical preparation, a mixture of diluent and pharmaceutical preparation are ejected from the diluent chamber through the outlet opening at the second end of the second container. There is thus simultaneous mixing and ejection of diluent and pharmaceutical preparation.

[0209] FIG. 10C shows the end of the first stage and the start of the second stage when the first plunger abuts against the hollow tube.

[0210] FIG. 10D shows a second stage in which the first plunger is being moved toward the distal end of the first container and pushes the hollow tube which moves the second plunger in the distal direction toward the second end of the second container. In this second stage the first plunger and the second plunger move in concert and both the active agent chamber and the diluent chamber are being gradually reduced in volume. Pharmaceutical preparation continues to be ejected from the active agent chamber through hollow tube (e.g. through the side opening) into the diluent chamber and a mixture of diluent and pharmaceutical preparation is ejected through the outlet opening of the diluent chamber.

[0211] This is in contrast to the dual chambered syringe 100 shown in FIG. 1A, in which the active agent chamber and the diluent chamber are reduced in volume sequentially, but not at the same time. That is with the dual chambered syringe 100 of FIG. 1A, the active agent chamber is reduced in volume and fully evacuated in a first stage. Then in a second stage (when the first plunger 120 abuts the second plunger 140) only the diluent chamber is evacuated.

[0212] The simultaneous reduction in volume of the active agent chamber and the diluent chamber during the second stage of the infusion, enables the arrangement of FIG. 8 to generate a dose profile with a more rapid increase in dose rate compared to the apparatus of FIG. 1A.

[0213] FIG. 10E shows an end of the second stage in which the first plunger abuts the distal end of the first container and the second plunger abuts the second end of the second container and the full contents of the active agent chamber have been delivered.4A-2 NESTED SLEEVE: EVACUATION BY RELATIVE SYRINGE MOVEMENT [213A] In another example, instead of the hollow pusher tube mechanism described above, the removable diluent container may be implemented in a nested configuration in which a syringe is received within a proximal portion of the removable container and, in some examples, the removable container is secured to an infusion driver such that the syringe advances relative tothe removable container to evacuate the diluent chamber. An example nested arrangement is shown in FIGs 40A to 40C.[213B] Referring to FIGs 40A to 40C, a medication delivery apparatus 4000 comprises a syringe 4100 and a second container 4200 (removable dilution device). The second container 4200 has a first end 4202 with a first opening 4204 configured to receive at least a distal portion of the syringe 4100 such that the syringe is received at least partially within the second container (nested arrangement). The second container 4200 further has a second end 4206 with an outlet opening 4208 for delivery of a mixture to a patient (e.g., via tubing)[0213C] A second plunger 4300 (also referred to as a diluent-chamber plunger) is movable within the second container 4200 between the first end 4202 and the second end 4206. A diluent chamber 4400 is located between the second plunger 4300 and the second end 4206. In the illustrated example of FIGs 40A to 40C, a foam insert 4450 is shown within the diluent chamber 4400 as an optional flow-conditioning element. However, in other examples the foam insert 4450 may be omitted such that there is no optional flow-conditioning element in the diluent chamber. In still other examples the foam insert 4450 may be replaced by one or more partitions 4460 that separate the diluent chamber 4400 into two or more partition chambers 4462, 4464, 4646 as shown in Fig. 46, or by other flow-conditioning structures.[0213D] A flow path provides fluid communication from an active agent chamber 4110 of the syringe 4100 into the diluent chamber 4400. In some examples, the flow path passes through or past the second plunger 4300, for example via an aperture 4302 in the second plunger. Instead of, or in addition to an aperture, there may be a valve 4304 configured to allow flow from the syringe into the diluent chamber. The valve may be configured to inhibit reverse flow from the diluent chamber into the syringe (e.g. it may be a one-way valve). In some examples, the second plunger 4300 includes a connector 4306 (e.g., a bore connector such as a luer interface) configured to couple to a distal end of the syringe to provide a sealed connection for the flow path. In other examples, the flow path may additionally or alternatively comprise one or more notches, channels, apertures, or side passages formed in or around the second plunger 4300 and / or the connector 4306, to permit flow into the diluent chamber 4400 during use.[0213E] In some examples, the apparatus is provided pre-filled with diluent in the diluent chamber 4400. In such examples, one or more seals may be provided to inhibit leakage prior to use. For example, a seal 4310 (e.g., a pierceable foil), best seen in FIGs 43A, 43B (intact) and 43C (pierced) may be provided at or in association with the connector 4306 and / or aperturesyringe during assembly so as to allow fluid flow into the diluent chamber 4400 during use, while inhibiting leakage prior to assembly. Alternatively, or additionally, a removable seal 4205 may cover the first opening 4204 prior to use. The seal 4205 may be a foil that is configured to be peeled off before use.[0213F] The nested embodiment may be used with an infusion driver (e.g., a syringe driver or syringe pump) in which the second container 4200 is removably secured to the infusion driver (for example at a clamp point 4212 on the second container, as shown in Fig. 41 C), rather than the barrel of the syringe 4100 being clamped in a conventional manner. An example sequence of operation is illustrated schematically in FIGS. 41A to 41F, which show example usage steps including attaching the patient line (FIG. 4 IB), clamping the second container in the infusion driver (FIG. 41C), and commencing an infusion protocol (FIG. 41C).[0213G] In a first phase of operation (see FIGS. 41A and 41D), the infusion driver advances a syringe plunger 4120 of the syringe 4100 to deliver pharmaceutical preparation from the active agent chamber 4110 into the diluent chamber 4400, where it mixes with diluent while a mixture is simultaneously expelled through the outlet opening 4208. During this first phase, the second plunger 4300 (as illustrated in FIG. 4 ID) may remain substantially stationary relative to the second container 4200, such that the volume of the diluent chamber 4400 is substantially constant (or changes only modestly) while pharmaceutical preparation enters and the concentration in the diluent chamber increases.[0213H] In a second phase of operation (see FIGS. 4 IE and 4 IF), after the syringe 4100 is substantially emptied (or after the load increases), the syringe 4100 advances further within the second container 4200 and drives the second plunger 4300 toward the second end 4206 to expel remaining fluid from the diluent chamber 4400 through the outlet opening 4208. This transition is illustrated in FIG. 4 IE (load transfers and the diluent chamber begins evacuation) and FIG.41F (continued evacuation of the diluent chamber).

[2131] In some examples, the apparatus is configured such that an initiation force required to start movement of the second plunger 4300 relative to the second container 4200 is greater than an initiation force required to start movement of the syringe plunger 4120 relative to the syringe 4100. For instance, the friction of the second plunger (diluent chamber plunger) against the second container wall may be greater than the friction of the first plunger (syringe plunger) against the walls of the syringe barrel. For example, the seal geometry, interference, material,and / or surface finish may be selected to increase static friction for the second plunger relative to the container wall. In this way the break-away force of the second plunger may be made greater than the break way force of the first plunger. This can assist in achieving a repeatable transition between the first phase (which may deliver into a substantially fixed-volume diluent chamber), and the second phase (evacuation of the diluent chamber), noting that some overlap of phases may occur depending on tolerances and operating conditions.[0213 J] FIG. 42 illustrates an example infusion driver 4600 (e.g., a syringe pump) suitable for operating the nested sleeve embodiment described above. The infusion driver 4600 comprises a carriage or drive mechanism 4610 configured to advance a syringe plunger (e.g., syringe plunger 4120) and one or more clamp members 4620 configured to restrain a component during operation.[0213K] In conventional use of an infusion device, the clamp members 4620 engage a clamping feature of the syringe, such as a syringe flange. In the nested sleeve embodiment described above, the second container 4200 is instead removably secured to the infusion driver 4600, for example by engagement of the clamp members 4620 with a clamp interface 4212 of the second container 4200. With the second container 4200 restrained in this manner, advancement of the drive mechanism 4610 causes the syringe plunger 4120 to move relative to the syringe 4100, and also allows the syringe 4100 to translate relative to the second container 4200 in a later phase of operation as described above.[0213L] FIGS. 43A to 43C illustrate an example of the second plunger 4300 including a pierceable seal 4310 configured to inhibit leakage of diluent from the diluent chamber 4400 prior to connection of the syringe 4100. In the illustrated example, the second plunger 4300 comprises a connector 4306 (e.g., a bore connector such as a luer interface) and the pierceable seal 4310 is disposed at or adjacent the connector 4306 and / or an aperture 4302 of the second plunger.[0213M] In use, a distal end of the syringe 4100 (for example, an outlet connector of the syringe) is inserted into and / or coupled with the connector 4306 such that the distal end pierces the seal 4310 to establish fluid communication through the flow path into the diluent chamber 4400. Prior to piercing, the seal 4310 inhibits flow of diluent out of the diluent chamber and may also inhibit air ingress into the diluent chamber during transport and storage.[0213N] While FIGS. 43A to 43C show one example arrangement of a pierceable seal, it will be understood that the seal may be implemented in various forms (e.g., foil, film, membrane)and may be positioned at the connector 4306, within the aperture 4302, or otherwise in association with the second plunger 4300 to inhibit leakage prior to assembly while allowing establishment of fluid communication during assembly.

[2130] FIGS. 44A to 44C illustrate an example in which the second container 4200 comprises one or more resilient members 4220 associated with the first opening 4204 and configured to accommodate different syringe barrel diameters received through the first opening. The resilient members 4220 may be integrally formed with the wall of the second container 4200 (for example as resilient tabs, ribs, or leaf-spring portions) or may be provided as separate components.[0213P] In some examples, the resilient members 4220 are configured to deflect when a syringe 4100 is inserted through the first opening 4204 and to apply centring forces that assist in aligning the syringe with the second plunger 4300 and / or with the flow path into the diluent chamber 4400. This may assist in accommodating syringes of different nominal volumes and / or different manufacturers having slightly different barrel diameters.[0213Q] FIG. 44A shows the distal end of a syringe before insertion into the second container, FIG. 44B shows a larger diameter syringe being inserted into the second container, while FIG.44C shows a smaller diameter syringe being inserted into the second container. FIG. 44D illustrates a cross-sectional view of an example arrangement of the resilient members 4220 and an inner wall region 4222 of the second container 4200 adjacent the first opening 4204, showing the resilient members 4220 projecting inwardly to engage and / or centre an inserted syringe 4100. While FIGS. 44A to 44D illustrate one example implementation, it will be understood that other resilient arrangements may be used, including a plurality of circumferentially spaced resilient members 4220, resilient rings, or deformable wall portions etc, while in other implementations the resilient members may not be used, especially in cases where the apparatus is to be used with a specified size or type of syringe.[0213R] In the nested sleeve embodiment, a portion of the second container 4200 between the first opening 4204 and the second plunger 4300 may be referred to as a sleeve portion 4209, and a portion of the second container 4200 between the second plunger 4300 and the second end 4206 comprises the diluent chamber 4400. The sleeve portion 4209 receives at least a distal portion of the syringe 4100 such that the syringe is received at least partially within the second container 4200 during use.[0213S] In some examples, the second container 4200 may comprise one or more anti-rotation features configured to inhibit rotation of the second plunger 4300 relative to the second container 4200. For example these features may inhibit rotation of the second plunger during coupling of a bore connector 4306 to a distal end of the syringe 4100, which may include rotational fit. FIG. 45A illustrates an example in which the second container 4200 comprises one or more longitudinal rails or ribs 4230 disposed on an inner wall region of the second container, and the second plunger 4300 comprises one or more complementary notches or keying features 4312 (e.g. these notches or keying features may be on a plunger frame 4308). Engagement of the rails or ribs 4230 with the notches or keying features 4312 inhibits relative rotation while allowing axial movement of the second plunger 4300 within the second container 4200 during use.[0213T] FIG. 45B illustrates another example anti-rotation arrangement in which the second container 4200 comprises a pressable button 4234 that is movable from a release position to an engaged position. In the engaged position, the button or wall portion 4234 is configured to engage a rib, tab or other protrusion 4316 on the second plunger 4300 (or plunger frame 4308) to limit or prevent rotation of the second plunger 4300 relative to the second container 4200. In still other examples, a wall of the second container 4200 may include a deformable portion 4234, which is adjacent the second plunger 4300 when nested, and which is configured to be compressed (e.g., squeezed) to grip the second plunger 4300 and inhibit rotation during coupling of the syringe 4100 to the connector 4306, after which the grip may be released to allow axial movement of the second plunger 4300 during use.[0213U], It will be noted that in the examples of the second container above, such as FIG. 40B and 45A, the second plunger 4300 is free of a plunger shaft extending from the second plunger toward the first opening 4204. This is different to a standard syringe configuration in which the plunger has a shaft which is pushed to drive the plunger towards the syringe outlet.

[0214] 4B. DOSE PROFILE WITH HOLLOW PUSHER TUBE

[0215] The hollow tube provides both a channel between the active agent chamber and the diluent chamber and a mechanism for reducing the size of the diluent chamber over at least a part of the infusion. As the active agent chamber and diluent chamber reduce in size simultaneously for at least part of the infusion, the dose rate for the arrangement with the hollow tube may increase more rapidly and the dose profile may be more favorable than for adual chambered syringe in which the active agent chamber is completely evacuated before the diluent chamber reduces in size.

[0216] The dose profile depends on several factors. One factor is the initial position of the hollow tube relative to the initial position of the first plunger. FIG. 11 shows an example of a medication delivery apparatus 1100 which is the same as the medication delivery apparatus 800 of FIG. 8, except that the first plunger 930 in its initial position is not spaced apart from the hollow tube, but rather the first plunger 930 abuts against the proximal end of the hollow tube 440. The first plunger 930 and the second plunger 420 therefore move together for the whole of the infusion and the active agent chamber 940 and diluent chamber 410 reduce in volume simultaneously for the whole of the infusion.

[0217] In both FIG. 8 and FIG. 11, the length of the hollow tube 440 may be made at least equal to the distance from the proximal end of the second plunger 420 to the distal end of the first container 910. For example, the apparatus may be arranged so that the hollow tube extends a first distance into the first container which is substantially equal to a second distance between a distal side of the second plunger in the initial position and the outlet opening of the second container. With this arrangement, the active agent chamber and the diluent chamber will be fully evacuated at the same time (as the first plunger will abut the distal end of the first container at the same time as the second plunger abuts the second end of the second container) and substantially all of the pharmaceutical preparation from the active agent chamber may be delivered to the patient.

[0218] The dose profile for the arrangement of FIG. 11 where the hollow tube abuts the first plunger in the initial position will be discussed first. In this case substantially the whole of the pharmaceutical preparation in the active agent chamber may be ejected into the diluent chamber and the whole contents of the diluent chamber may be evacuated by the end of the infusion, thus avoiding pharmaceutical preparation being wasted.

[0219] The initial size or volume of the diluent chamber may vary, for example between 5 and 1 OOmL. The initial size or volume of the active agent chamber may also vary, for example between 5 and lOOmL. The initial size of the diluent chamber has an effect on the dose profile and the delay between successive orders of magnitude of cumulative dose (OMD). As the initial size of the diluent chamber relative to the active agent chamber is increased, the mass of drug at any point of time during the infusion is diluted by a larger amount of diluent. The fluid exiting the dilution chamber and entering the patient is therefore of lower concentration and alower mass is transferred early in the infusion time. As the size of the diluent chamber reduces over the period of the infusion, the concentration of drug is lower at each stage of the infusion and the effect on reducing the early dosing rate is greater for a relatively larger initial dilution chamber.

[0220] This can be seen in FIG. 12A to FIG. 12F which are graphs comparing the dose profiles for different sizes of dilution chamber for an apparatus as shown in FIG. 11. The solid line shows the profile for an apparatus with an initial diluent chamber size of 10ml, the dashed lined for an initial diluent chamber size of 30 ml and the dashed and dotted for an initial diluent chamber size of 50ml. In each case the active agent chamber has an initial size of 50ml. The graphs show the profile for an infusion of 30 minutes duration.

[0221] FIG. 12A shows how the percentage of therapeutic dose which is present in the diluent chamber varies over the course of the infusion. FIG. 12B shows how the drug concentration in the diluent chamber (in percentage of therapeutic dose per mL) varies over time. FIG. 12C shows how the cumulative dose delivered to the patient, as a percentage of the full therapeutic dose, varies over time on a linear scale, while FIG. 12D show the same on a logarithmic scale. FIG. 12E shows how the 10-fold delay time (OMD) varies over time on a linear scale, while FIG. 12F shows how the OMD varies against the cumulative dose on a logarithmic scale. The vertical lines in FIG. 12E and FIG. 12F indicate the point at which the OMD reaches 5 minutes for each of the apparatus. It can be seen that as the relative size of the diluent chamber increases, the cumulative dose at which the OMD exceeds 5 minutes decreases. Accordingly, increasing the size of the diluent chamber relative to the active agent chamber may improve the dose profile.

[0222] It is also noted that for an active agent chamber of 50mL and diluent chamber of 30mL the OMD reaches 5 minutes at a cumulative dose of 0.74% of the therapeutic dose. This compares to an OMD of 5 minutes at 0.42% of the therapeutic dose for a similar apparatus but without the hollow tube (e.g. as shown in FIG. 6F). Therefore, while adding the hollow tube helps to deliver all of the contents of the active agent chamber, it can lead to a dose profile which is not quite as good as that without a hollow tube. F or example, the dose profile of FIG.12F (dashed line / 30ml diluent chamber) may risk an adverse reaction that is difficult to spot in time for a patient having a sensitivity threshold of 0.5%, as the OMD only reaches 5 minutes at 0.74% of the therapeutic dose. This is due to the hollow tube moving the second plunger and causing the dose rate to increase more rapidly in the early parts of the infusion.

[0223] 4C. DOSE PROFILE AND SPACING OF HOLLOW PUSHER TUBE FROM PLUNGER

[0224] The initial spacing of the hollow tube from the first plunger affects the dose profile and the manner in which the drug is delivered over the course of the infusion.

[0225] In FIG. 11 and FIG. 12A to FIG. 12F, the apparatus is arranged so that first plunger 930 abuts the hollow tube 440 at the start of the infusion process. Therefore the apparatus simultaneously reduces the active agent chamber volume and the diluent chamber volume for the whole infusion process. That is both the active agent chamber and the diluent chamber reduce in volume from the start of the infusion.

[0226] In contrast, in FIG. 8, the apparatus is configured so that the first plunger is spaced a distance apart from the hollow tube at the start of the infusion process. The initial position of the first plunger 930 and the initial position of second plunger and length of the hollow tube may be such that the proximal end of the hollow tube is spaced apart from the first plunger in the initial positions of the first and second plungers. The result is that the hollow tube does not abut the first plunger in a first portion of the infusion process, but abuts the first plunger in a second portion of the infusion process. The active agent chamber volume and the diluent chamber volume are thus simultaneously reduced for part, but not all, of the infusion process. This may improve the dose profile by increasing the rate of increase of the dose rate in the second portion of the infusion compared to the first portion of the infusion.

[0227] In the arrangement of FIG. 8, the infusion will have a first phase in which the diluent chamber has a constant volume (before the first plunger abuts the hollow tube) and a second phase in which the volume of the diluent chamber begins to reduce (after the first plunger abuts the hollow tube). By choosing a particular spacing distance of the first plunger from the hollow tube in the initial position, the time at which the infusion moves from the first phase to the second phase (also referred to as the ‘start time’ of the second plunger) may be varied. The start time may be measured as a time in minutes (which depends on the spacing distance, infusion rate and infusion profile) or as a percentage of pharmaceutical preparation evacuated from the active agent chamber (which will depend on the spacing distance).

[0228] On the other hand, if the diluent chamber has an initial length which is the same as the hollow tube, but which is short compared to the initial length of the active agent chamber, then proximal end of the hollow pusher will not abut the first plunger until late in the infusion, andso the diluent chamber will remain at constant volume for a first part of the infusion and reduce in volume during a second later part of the infusion.

[0229] Pushing of the second plunger by the hollow tube reduces the volume of the dilution chamber, which increases the rate of drug administration, both by reducing the diluting volume and increasing the fluid flow rate out of the diluent chamber. This can improve the dose profile by providing a steeper curve, or a higher order of magnitude difference (OMD) compared to a dual chambered syringe as shown in FIG. 1 A. Furthermore, as pushing by the hollow tube evacuates the diluent chamber, this makes it possible in some cases for the full contents of the active agent chamber to be substantially fully administered to the patient at the time that the first plunger has completed emptying of the active agent chamber.

[0230] The initial set up of the medication apparatus with the hollow tube may be characterized by the spacing distance between the initial position of first plunger and proximal end of the hollow tube. For a particular infusion, it may also be characterized by the start time of the first plunger abutting the hollow tube and starting to reduce the volume of the diluent chamber. For the arrangement of FIG. 11, in which the first plunger abuts the hollow tube at the start of the infusion, the start time will be 0 seconds. For the arrangement of FIG. 8, in which the first plunger is initially spaced apart from the hollow tube, the start time depends upon the spacing distance, dimensions of the active agent chamber and infusion rate of the infusion driver which moves the first plunger.

[0231] FIG. 13A to FIG. 13F are graphs which compare an infusion for a first medication delivery apparatus in which the first plunger abuts the hollow tube at the start of the infusion ('pusher contact time' 0 minutes shown by the dashed line), and a second medication delivery apparatus in which the first plunger is spaced apart from the hollow tube at the start of the infusion and abuts the hollow tube 15 minutes into the infusion ('pusher contact time' 15 minutes shown by the solid line). In both cases the infusion is 30 minutes long and the initial volume of the active agent chamber is 50 mL.

[0232] FIG. 13A shows how the volume of the diluent chamber changes over the course of the infusion. It can be seen that for the ‘pusher start 15’ apparatus the diluent chamber has a constant volume for the first half (15 minutes) of the infusion and then gradually decreases, while for the ‘pusher start 0’ apparatus the diluent chamber decreases in volume throughout the infusion.

[0233] FIG. 13B shows the change in the amount of active agent (as percentage of the full therapeutic dose) in the diluent chamber over the course of the infusion. For both the first and second apparatus it starts at zero, but has a sharper increase and decrease before and after 15 minutes for the second ('pusher start 15') apparatus.

[0234] FIG. 13C shows the change in concentration of active agent in the diluent chamber (as a percentage of the therapeutic dose per mL) for the first and second apparatus.

[0235] FIG. 13D show the cumulative dose of active agent as a percentage of the full therapeutic dose which has been delivered to the patient over time for the first and second apparatus. This may be referred to as the dose profile.

[0236] FIG. 13E shows how the 10-fold increase interval or OMD varies over time during the infusion for the first apparatus ('pusher start O') and second apparatus ('pusher start 15'). The first vertical dotted line shows that for the second apparatus ('pusher start 15') the OMD reaches 5 minutes at 2.18 minutes, while for the first apparatus ('pusher start O') the OMD reaches 5 minutes slightly later at 2.26 minutes.

[0237] FIG. 13F shows the variation in 10-fold increase interval (OMD) vs percentage dose administered (in logarithmic scale) for the first and second apparatus. The first vertical dotted line shows the percentage of the full therapeutic dose of active agent delivered when the OMD first reaches 5 minutes for the second apparatus ('pusher start 15') is 0.42%, while for the first apparatus ('pusher start O'), the OMD first reaches 5 minutes when the percentage delivered is 0.74%. This illustrates that compared to the first apparatus ('pusher start O'), the second apparatus ('pusher start 15') has a more favorable dose profile which reaches a 5 minute OMD at a lower percentage of the therapeutic dose.

[0238] The active agent chamber and the diluent chamber may be of various different volumes at the start of the infusion. For example, the active agent chamber may have an initial volume of lOOmL, 60mL, 50mL, 45mL, 40mL, 30mL or 20mL, while the diluent chamber may have an initial volume of 50mL, 40mL, 30mL, 20mL or lOmL. Thus various combinations of active agent chamber and the diluent chamber sizes are possible.

[0239] According to some examples, the apparatus is configured such that at the completion of operation of the syringe (when the first plunger has moved from its starting position to the distal end of the first container), the action of the first plunger on the hollow pusher tube has caused the second plunger to move from its starting position through its length of travel to thesecond end of the second container. In this way, when the active agent chamber has emptied completely, the diluent chamber will also have been emptied completely.

[0240] FIG. 14A is a schematic diagram of a medication delivery apparatus according to the present disclose with a hollow pusher tube. The starting position of the tip of the first plunger (drug chamber plunger) is point X. The final position of the first plunger is position Y. The initial position of the tip of the second plunger (dilution chamber plunger) is point P. The final position of the second plunger is point Q.

[0241] FIG. 14B shows the distance between various parts of the apparatus when the first and second plungers are in their initial positions. The distance between points X and Y is length B, and the distance between points P and Q is length A. The hollow tube is of a length A+C. C is the length of the hollow tube between the starting position of the base of the second plunger, and the finish position of the tip of the first plunger. Length A is the length between the point where the tip of the first plunger first contacts the proximal end of the hollow tube, and point Y.

[0242] Length C is determined by the physical characteristics of the first container and the second container when the distal end of the first container is attached to the first end of the second container. If the length B is equal to the length A, then the proximal end of the hollow tube is abutted by the first plunger at the start of the infusion, and the volume of the diluent chamber will decrease throughout the period that the volume of the active agent chamber reduces.

[0243] If the length B is greater than length A, then the tip (distal end) of the hollow pusher tube is not contacted until some point during the infusion when the tip of the first plunger has travelled a distance of B-A. If the infusion is a constant rate infusion, the diluent chamber will not start decreasing in volume until the active agent chamber infusion has been operated for a proportion of the infusion equal to (B-A / B). If the infusion is 30 minutes long, and the length A is half of the length B, then the diluent chamber chamber will start decreasing in volume after 15 minutes. If the infusion is 30 minutes long and the length A is one-third of length B, then the diluent chamber volume will start decreasing after 10 minutes.

[0244] The active agent chamber may be operated by a non-linear infusion, such as at a rate that increases in speed as the infusion continues, for instance similar to the Tansy or Sadleir infusions described in WO 2021 / 113925 and WO 2022 / 261708. The infusion may beprogrammed specifically to give a linearly increasing or exponentially -increasing dose over time when changes in drug concentration leaving the syringe are taken into consideration.

[0245] FIG. 15A to FIG. 15D show the apparatus of FIG. 14A and FIG. 14B at different stages in the infusion process.

[0246] FIG. 15 A shows the apparatus with the first and second plungers in their starting positions and the active agent chamber and the diluent chamber at their initial volumes at the start of the infusion.

[0247] FIG. 15B, shows the apparatus after the infusion has proceeded to the point where the tip of the first plunger has contacted the distal end of the hollow tube. At this point the first plunger has moved through a distance of B-A. If the infusion is a constant rate infusion, this occurs after B-A / B of the infusion duration.

[0248] FIG. 15C, shows the apparatus after the infusion continues further (after the hollow tube has been contacted. In this part of the infusion the first plunger pushes the hollow tube and the second plunger thereby reducing the volume of both the active agent chamber and the diluent chamber.

[0249] FIG. 15D shows the apparatus after the infusion is now complete. The first plunger is at point Y, and the second plunger is at point Q. Both the active agent chamber and the diluent chamber are now substantially empty.

[0250] The relative length of the hollow pusher tube compared to the initial length of the active agent chamber also has an effect on the dose profile.

[0251] The length of the hollow tube determines at what point during the infusion the second plunger starts to move and the diluent chamber volume starts to decrease. If the starting position of the distal end of the hollow tube is at the starting position of the first plunger, both the active agent and diluent chambers will start decreasing in volume at the same time. If the starting position of the distal end of the hollow tube is one -third of the distance between the starting and finishing position of the first plunger, then the first plunger will encounter (abut against) the hollow tube one-third of the period into the drug infusion (for a linear rate infusion). The size of the diluent chamber will therefore reduce during the last two-thirds of the infusion (between 10 and 30 minutes of a 30-minute infusion). If the starting position is five-sixths of the distance from the starting- to end-position of the first plunger, then the diluent chamber will remain of constant volume for the first 25 minutes of a 30-minute infusion, and completely empty during the last 5 minutes.

[0252] These different configurations change the drug profile delivery, and particularly the intervals over which a 10-fold increase in cumulative dose occur.

[0253] This can be seen in FIGs.12A-12F, 13A-13F and 14A-14F to FIG. 16F, which are graphs showing the effect of different lengths hollow pusher tube for a 50mL drug syringe and 30mL dilution chamber.

[0254] For FIG. 16A to FIG. 16F the hollow pusher tube is long enough to contact the first plunger at the start of the infusion, while for FIG. 17A to FIG. 17F the hollow tube that is long enough to contact the first plunger 10 minutes into the infusion, and for FIG. 18A to FIG. 18F 20 minutes into the infusion.

[0255] FIG. 16A shows the volume of the diluent chamber (solid line) and flow rate into (dashed line) and flow rate out of (dash and dot line) the diluent chamber over time. FIG. 16B shows the cumulative volume of fluid infused to the patient (solid line) and the flow rate into the patient (dashed line) over time. FIG. 16C shows the percentage of the full therapeutic dose of the active agent which is present in the diluent chamber (dotted line) and the concentration of active agent in the diluent chamber (dash and dot line) over time (measured in percentage of the therapeutic dose per mL). FIG. 16D shows the percentage of the full dose of active agent which has been delivered to the patient in linear scale (solid line) and logarithmic scale (dashed line) over time. FIG. 16E shows the OMD or interval delay for a lOx cumulative increase in dose over time. FIG. 16F shows the OMD against cumulative percentage of the full therapeutic dose delivered in logarithmic scale. The OMD reaches 5 minutes at 0.74% of the full therapeutic dose.

[0256] FIG. 17A to FIG. 17F correspond to FIG. 16A to FIG. 16F but for an apparatus in which the hollow tube contacts the first plunger 10 minutes into the infusion. In this case the OMD reaches 5 minutes at 0.42% of the therapeutic dose. FIG. 18A to FIG. 18F show the results for a similar apparatus but in which the hollow tube contacts the first plunger 20 minutes into the infusion. In this case, the OMD reaches 5 minutes at 0.42% of the full therapeutic dose.

[0257] The later in the infusion that the diluent chamber starts to reduce in volume (for the same initial volume of diluent chamber), the more linear is the delivery of dose to the patient over time on a semi-logarithmic scale. For a given length of diluent chamber, the start of the diluent chamber reducing in volume can be varied by changing the length of the hollow tube.The shorter the hollow tube, the later in the infusion that the volume of the diluent chamber will start to reduce.

[0258] Note that for a diluent chamber of a given initial length, the volume of the diluent chamber may be increased or decreased by increasing or decreasing the diameter of the chamber body. That is it is possible for apparatus with the same initial length of diluent chamber (and same length of hollow tube) to have different initial volumes of diluent chamber due to differences in the other dimensions (e.g. diameter) of the diluent chamber.

[0259] FIG. 19A to FIG. 19F show the same variables as FIG. 16A to FIG. 16F, but for an apparatus with an initial active agent chamber volume of 50ml, an infusion time of 30 minutes with the first plunger striking the hollow tube at 20 minutes, and an initial diluent chamber volume of 10ml (solid line), 30ml (dashed line) or 50ml (dash and dot line). The OMD reaches 5 minutes at 0.94%, 0.42% and 0.27% of the therapeutic dose for the 10ml, 30ml and 50ml diluent chamber volumes respectively. Thus, as previously discussed, increasing the relative initial size of the diluent chamber may improve the dose profile.

[0260] 5 A. PARTITIONED DILUENT CHAMBER

[0261] Examples of medication delivery apparatus of the present disclosure use a diluent chamber in series with a source of pharmaceutical preparation to deliver a mix of pharmaceutical preparation and diluent to the patient. The dose profile depends upon the infusion rate and the concentration of active agent in the diluent chamber over the course of the infusion.

[0262] The dual chambered syringe 100 of FIG. 1A is able to generate a dose profile shown in FIG. IB, in which the dose rate increases at a rate which increases over time and increases particularly quickly in the last 20% of the infusion by time. However, in order to generate the dose profile shown in FIG. IB, the dual chambered syringe 100 is driven by an infusion driver that is capable of multiple infusion steps at different fluid-injection rates. For example, an infusion driver capable of 12 steps at different fluid infusion rates may be used. However, this type of multi-speed infusion driver is expensive and may not be readily available.

[0263] It would be desirable to be able to use either a constant rate infusion driver, or an infusion driver capable only a small number of different infusion rates, to achieve a dose profile in which the dose rate increases at a rate which increases over time and / or in which the dose rate increases rapidly in the later part of the infusion. This would make it possible to use a wider range of less expensive infusion drivers.

[0264] Using a single constant rate of infusion could also improve accuracy and reliability, as if both the infusion rate and the concentration in the diluent chamber change over time (as is the case for a dual chambered syringe and a multi-speed infusion driver) then the infusion rate needs to be synchronized to the current concentration in the diluent chamber to ensure a reproducible dose profile. However, if the infusion rate is constant, there is no longer a unique infusion rate corresponding to a particular concentration and so the system is much more error tolerant. Thus where a constant rate infusion driver is used, the infusion will be simpler to control and less error prone.

[0265] The inventor has found that the use of partitions in the diluent chamber makes it possible to use a constant rate infusion driver, or an infusion driver with only a small number of infusion steps of different rates, to achieve certain dose profiles.

[0266] Accordingly, some examples of the present disclosure provide a diluent chamber which includes one or more partitions which separate the diluent chamber into a plurality of partition chambers. The partition chambers may also be referred to as ‘separation chambers’ or 'compartments'. The partitions effectively divide the dilution chamber into multiple dilution chambers. The partitions make it possible to vary the dose profile and in some examples may provide a more gradual increase in cumulative dose during the early parts of the infusion and / or a more rapid increase in dose rate in later parts of the infusion.

[0267] Each partition may include one or more partition openings for allowing fluid communication between the partition chambers on either side of the partition. The partition openings may also be referred to as partition apertures or partition orifices. Each partition opening may comprise a respective partition valve. The partition valve may be a one-way valve configured to allow fluid to flow from a proximal side of the partition to a distal side of the partition but inhibit or prevent fluid from flowing in the opposite direction.

[0268] In one example, the partitioned diluent chamber may be provided as a detachable container that is configured for attachment to the distal end of a syringe. For example, the diluent chamber 260 of FIG. 2A, FIG. 2B and FIG. 2C, the diluent chamber 410 of FIG. 7 and FIG. 8, or a diluent chamber of any of the above examples, may be made into a partitioned diluent chamber by adding one or more partitions. FIG. 23 shows an example of a medication delivery apparatus comprising a syringe 900 and a container 400 with a partitioned diluent chamber 400 which is detachably attached to a distal end of the syringe 900.

[0269] In another example, the partitioned diluent chamber may be provided as part of a dual chambered syringe 2400 as shown in FIG. 24. In yet another example, the partitioned diluent chamber may be provided as a separate element 2510 which is connectable to a source of pharmaceutical preparation 2502 by a length of flexible tubing 2506 or otherwise, as shown in FIG. 25.

[0270] FIG. 20 shows an example of a diluent chamber 2000 for diluting a pharmaceutical preparation prior to administration to a patient, which is similar to the container shown in FIG.5. The diluent chamber 2000 comprises an inlet end 2002 including an inlet opening 504 for receiving pharmaceutical preparation and an outlet end 2006 including an outlet opening 508 for ejecting diluted pharmaceutical preparation. A container body 2004, which may be a glass cylinder, extends at least between the inlet end and the outlet end of the diluent chamber. One or more partitions 512, 522, 532 are inserted into the container body, and split the diluent chamber into a plurality of partition chambers 510, 520, 530, 540. Each partition has a partition opening 514, 524, 534 for allowing fluid communication between the partition chambers on either side of the partition. The diluent chamber 2000 may be attached to the outlet end of a syringe having an active agent chamber in order to create a medication delivery apparatus similar to the one shown in FIG. 23, but without the plunger and hollow tube. In some examples the inlet opening may be larger and able to receive at least a distal end of a syringe, as is discussed in the nesting embodiments later in the description.

[0271] FIG. 21 and FIG. 22 shows examples of a partitioned diluent chamber having a movable plunger and a hollow tube. This is similar to the arrangement discussed in FIG. 7 and FIG. 8 above, except that the diluent chamber is partitioned. The partitioned diluent chambers of FIG. 21 and FIG. 22 may be attached to the distal end of a syringe to form a medication delivery apparatus as shown in FIG. 23.

[0272] In FIG. 21 like reference numerals indicate like parts as in FIG. 7. The container 2100 of FIG. 21 is removably attachable to the distal end of a syringe to form the medication delivery apparatus shown in FIG. 23. The container 2100 has a first end 402 with an inlet opening 404 and a second end 406 with an outlet opening 408. A movable plunger 420 is disposed between the first end 402 and second end 406 of the container 2100. The movable plunger 420 may be referred to as the ‘second plunger’ when it is attached to a syringe (with the syringe plunger being the first plunger).

[0273] A plunger aperture 422 (which may have a one-way valve) acts as an opening through which pharmaceutical preparation can be ejected into the diluent chamber. A hollow tube 440 is attached to and extends back from the movable plunger 420 and through the first end of the container body. A lumen 442 of the hollow tube is in fluid communication with the opening or aperture 442 of the movable plunger. A gasket 450 may be provided for the plunger as described for FIG. 7. The inlet and outlet openings of the container 2100 may be bore openings such as Luer locks or Luer slip connectors. The first end 402 of the container 2100 may be attached to the distal end of a first container / syringe as described above for FIG. 7 and may have any of the features described in the embodiments above.

[0274] A diluent chamber 410 is defined by the plunger 420, the inner walls of the container 2100 and the second end 406 of the container 2100. The inlet end of the diluent chamber is formed by the movable plunger 420. There may be an empty space 430 between the inlet opening 404 and the initial position (or a later position) of the plunger 420. In order to prevent a vacuum from forming there may be an air vent opening (not shown) in a wall of the container 2100 between the initial position of the plunger 420 and the first end 402 of the container. In some examples, the air vent opening may be in a wall of the first end of the container.

[0275] A partition 460 having a partition opening 462 separates the diluent chamber into a first partition chamber 410A and a second partition chamber 410B. The partition 460 is a member which substantially blocks passage of fluid between adjacent partition chambers 410A, 410B and may have any of the features described in section 1C of this application. The partition 460 may be a plunger, in which case it may be referred to as a movable separation plunger. The partition opening may comprise a valve, which may be a one-way valve for allowing flow of fluid in the distal direction while inhibiting flow of fluid in the proximal direction.

[0276] FIG. 22 shows a further example of a detachable container 2200 comprising a diluent chamber in which like reference numerals denote like parts as in FIG. 21. The container 2200 may be referred to as a ‘second container’ as it may be attached to a first container of a syringe. The container 2200 differs from the container 2100 of FIG. 21 in that there are two partitions 460, 470 each having at least one opening 462, 472, which separate the diluent chamber 410 into three sub-chambers or partition chambers 410A, 410B, 410C. In both FIG. 21 and FIG. 22 the inlet end of the diluent chamber is formed by the movable plunger 420 and the inlet opening of the diluent chamber is formed by the aperture 422 in the movable plunger.

[0277] In other examples there may be even more partitions and partition chambers. For example, there may be 1,2, 3, 4, 5, 6, 7 or 8 or more partitions to create 2, 3, 4, 5, 6, 7, 8 or 9 or more partition chambers. The partitions may be as described in section 3 of this application. In some examples, the partitions may be plungers, in which case they may be referred to as movable separation plungers.

[0278] In operation, the partitions may be struck by the advancing plunger 420, when the plunger 420 is pushed by the hollow tube. Once the first partition 460 is struck with and abuts the diluent chamber plunger 420, the first partition 460 will move with the plunger 420. The first partition 460 then advances until it strikes and abuts against the second end 406 of the container (in the example of FIG. 21) or the second partition 470 (in the example of FIG. 22). The second partition 470 then advances together with the plunger 420 and the first partition 460 etc. In this way, the volumes of the multiple partition chambers 410A, 410B, 410C may be reduced in sequence by the movement of the plunger 420 and the partition(s).

[0279] The partition chambers are thus collapsible in sequential order by pushing of the plunger 420 by the hollow tube 440 in the distal direction towards the second end 406 of the container. Each partition has at least one opening. Each opening may have a partition valve as described above. The partition valve may be located in a recess of the partition. This allows the plunger or adjacent partitions to abut against the partition without the valve sticking our or getting in the way.

[0280] Each partition chamber has a respective initial length at the start of the infusion. The initial length of a partition chamber depends on the initial positions of the partitions, second plunger and / or second end of the container which border the partition chamber. In some examples each partition chamber may have the same initial length. In other examples at least one of the partition chambers may have a different length to at least one other partition chamber.

[0281] In some examples, a proximal side of each partition may conform to a shape of a distal side of the adjacent (i.e. next) partition in the distal direction. This helps to minimize any dead area in which fluid may be trapped when adjacent partitions abut against each other. In some examples, one or more of the partitions may have two or more openings configured to generate two divergent jets of fluid as described above with respect to FIG. 3 and FIG. 4.

[0282] In the example of FIG. 20, the inlet end 2002 of the diluent chamber is formed by the first end of the container body 2004 and the outlet end 2004 of the diluent chamber is formedby a second end of the container body. In other examples the container body may extend beyond the inlet and / or outlet ends of the diluent chamber and encompass other chambers as well. For example, in FIG. 21 and FIG. 22 the container is divided into an empty space 430 and a diluent chamber 410 by a movable plunger 420; in these cases the inlet end and inlet opening of the diluent chamber are formed by the movable plunger 420 and the plunger aperture 422 and are distinct from the container inlet end 316 and inlet opening 404. Likewise, in the dual chambered syringe 2400 of FIG. 24, the inlet end and inlet opening of the partitioned diluent chamber are provided by the second plunger 140 and the plunger aperture 142.

[0283] In FIG. 20, FIG. 21 and FIG. 22 the partitioned diluent chamber may be used as an add-on component which may be detachably attached to the outlet end of a syringe. An example of this is shown in FIG. 23 which depicts a medication delivery apparatus compris ing a syringe 900 and a detachable container 400 with a partitioned diluent chamber attached to the outlet of the syringe.

[0284] In other examples, a partitioned diluent chamber may be provided as part of a syringe. For example, the dual chambered syringe 100 as shown in FIG. 1A could be modified to have a partitioned diluent chamber by adding one or more partitions to the diluent chamber 150. FIG.24 shows an example of a medication delivery apparatus comprising a dual chambered syringe 2400 which includes an active agent chamber 940 and a partitioned diluent chamber and in which like reference numerals indicate like parts as in FIG. 1 A. Unlike FIG. 1 A, the apparatus of FIG. 24 has a diluent chamber with a number of partitions 1, 2 between the second plunger 140 and the outlet opening 152. A first partition chamber A is defined between the second plunger 140 and the first partition 1, a second partition chamber B between the first partition 1 and the second partition 2, and a third partition chamber C between the second partition 2 and the second end 406 of the container 110.

[0285] .

[0286] The apparatus of each of FIG. 23 and FIG. 24 may have any of the features discussed above in relation to FIG. 20 to FIG. 22 or discussed in the description below.

[0287] The effect of partitioning the diluent chamber upon the dose profile and dose rate will now be discussed.

[0288] 5B. EFFECT OF PARTITION(S) ON DOSE PROFILE (NO HOLLOW TUBE)

[0289] When a non-partitioned diluent chamber is in series with an active agent chamber, the concentration of active agent in the diluent chamber (which is delivered to the patient)increases over time with an exponential approach to equilibrium. This can be seen in FIG. 26, which shows the concentration of active agent (in percentage of the therapeutic dose per mL) in the diluent chamber against time over the course of the infusion. It can be seen that the rate at which the concentration increases decreases over time. The concentration of active agent in the diluent chamber is shown on the y-axis of Fig. 26 and refers to the concentration of active agent in the fluid in the dilution chamber; this is measured in percentage (%) of the therapeutic dose per mL. The concentration of active agent in the active agent chamber is 2% per mL if the volume is initially 50mL. The concentration of active agent in the dilution chamber will start at 0% per mL and increase over time as the infusion progresses, e.g. shown in Fig. 26. It will be understood that the concentration of active agent in the diluent chamber is proportional to the amount of pharmaceutical preparation in the diluent chamber.

[0290] The concentration of active agent over time for a non-partitioned diluent chamber, which receives inflow of pharmaceutical preparation from an active agent chamber, assuming instantaneous mixing, is given by:

[0291]

[0292] Where Ci is the concentration of active agent in the diluent chamber (% / mL), Cin is the concentration of active agent entering the diluent chamber, Q is the flow rate (mL / min), V is the dilution chamber volume (mL), and t is the infusion time.

[0293] However, the dose profile can be improved by use of partitions as described above, which separate the diluent chamber into two or more partition chambers. The partition chambers act as compartments in series and modify the concentration profile of drug delivered. The concentration of active agent delivered to the patient is the concentration of the final (distal most) partition chamber next to the outlet opening. The series of partition chambers acts to decrease the early rate of rise in concentration in the final partition chamber, compared to a non-partitioned diluent chamber.

[0294] In some cases, this may make it possible to use a constant infusion rate syringe driver rather than a multi-rate multi-step infusion syringe driver, while still achieving a dose rate which increases at a rate which increases over time (e.g. approximating an exponential, logarithmic or non-linear fashion).

[0295] At the start of the infusion each of the partition chambers is filled with diluent. As the infusion progresses, pharmaceutical preparation enters the first partition chamber where it mixes with the diluent. A mixture of pharmaceutical preparation and diluent then passes through the one or more openings in the first partition into the second partition chamber and so on. The concentration of pharmaceutical preparation (and thus active agent) in the second partition chamber thus differs to that of the first partition chamber and is initially more dilute.

[0296] Considering a system which consists of two partition chambers in series with equal volumes, the second partition chamber will receive the mixture of pharmaceutical preparation and diluent leaving the first partition chamber. The concentration of active agent in the second partition chamber (C2) is given by the following formula:

[0297]

[0298] If we add a third partition chamber with the same volume as the other two partition chambers, and which receives fluid from the second partition chamber, the concentration of active agent in the third partition chamber (C3) is given by:

[0299]

[0300] The general formula for the concentration in the nth partition chamber (Cn) of a system of n partition chambers of equal volume is given by:

[0301]

[0302] The concentration of active agent in the nth partition chamber of a series of n chambers (i.e. the final partition chamber) is the concentration of active agent that will be infused into the patient.

[0303] The effect of splitting the diluent chamber into a plurality of partition chambers is to change the concentration profile of pharmaceutical preparation leaving the system and therefore also the concentration profile of the active agent (drug) leaving the system. The partitions delay the rise in concentration of the drug entering the patient. Specifically the concentration profile changes in such a way that the initial concentration of drug leaving the final (distal most) partition chamber and infused to the patient is lower and the concentration of the drug increases less rapidly. This effect is increased by adding further partition chambers.

[0304] This effect can be understood by considering the situation where the dilution chamber has a single partition and two partition chambers. The pharmaceutical preparation will first pass into the first partition chamber, where it is diluted. The diluted pharmaceutical preparation will then pass into the second partition chamber where it is then diluted further. The concentration of pharmaceutical preparation in the first partition chamber as a percentage of the volume in the first partition chamber (and therefore the concentration of active agent in the first partition chamber) will be greater than the concentration in the second partition chamber. Therefore, the initial concentration of drug entering the patient is initially lower than it would have been if the drug was simply diluted throughout the whole of a non-partitioned dilution chamber.

[0305] This delay in the rise of concentration can be especially helpful when using a constant rate infusion pump or an infusion pump with only a small number of steps, as it makes it possible to obtain a desirable dose profile without a specialized multi-step capable infusion pump. In some implementations it becomes possible for the dose profile to approach or mimic the dose profile of a Sadleir infusion or Tansy infusion as shown in FIG. IB, but with aconstant rate infusion pump or an infusion pump capable of only a small number of different infusion steps.

[0306] The difference made by adding partition chambers can be seen in FIG. 27, which is a graph showing the change in concentration of active agent (measured as percentage of the total therapeutic dose per ml) over time in the final partition chamber of the diluent chamber. The graph shows data for systems with an active agent chamber having an initial volume of 50 mL, a diluent chamber having a fixed volume of 30 mL and 1-5 partition chambers in series. The infusion is delivered over 30 minutes and the concentration of active agent in the active agent chamber is 2.0% / ml.

[0307] The solid line shows the concentration profile when there is only one chamber (i.e. a diluent chamber with no partitions), the dashed line shows the concentration profile in the final partition chamber when there are two partition chambers of equal volume, the dash and dot line when there are three partition chambers of equal volume, the dotted line where there are four partition chambers of equal volume and the dash and two dot line when there are 5 partition chambers of equal volume.

[0308] The volume of diluent is the same regardless the number of partitions (in this case a 30mL diluting system for a 50mL infusion of 2% / ml drug solution delivered over 30 minutes). However, it can be seen that addition of partition chambers in series converts the concentration profile from an exponential approach to a limit (as shown by the solid line), to a sigmoid curve (as shown by the dotted and dashed lines). Furthermore, the greater the number of partition chambers the steeper the gradient of the sigmoid curve.

[0309] The exponential approach to a limit curve for the non -partitioned diluent chamber (solid line) has a maximum rate of change of concentration at the start of the infusion period. In contrast, the sigmoid curve (for the partitioned diluent chambers) has a maximum rate of change later in the infusion period. Adding each additional partition chamber pushes back the maximum rate of change of the dose rate to later in the infusion. The later in the infusion that the maximum rate of change occurs, the lower the dose rate and the smaller the delivered dose will be earlier in the infusion which reduces the risk of triggering an adverse reaction in hypersensitive patients.

[0310] While partition chambers of equal size are discussed above, it is also possible to multiple partition chambers which have different volumes in order to further vary theconcentration profile. The corresponding concentration curves can be calculated by numerical methods.

[0311] FIG. 28A shows the cumulative dose delivered to the patient (as a percentage of the initial dose in the active agent chamber) against time for an apparatus of the type shown in FIG.2A (syringe and non-partitioned diluent chamber) which may be referred to as the 1 compartment model. FIG. 28B shows the cumulative dose delivered to the patient (as a percentage of the initial dose in the active agent chamber) against time for an apparatus similar to FIG. 2A, but where the diluent chamber is partitioned into 5 partition chambers of equal volume (e.g. as shown in FIG. 5 or FIG. 20 but with 5 partition chambers), which may be referred to as the 5 compartment model. In both cases the initial volume of the active agent chamber is 50mL and the volume of the diluent chamber (which remains fixed throughout the infusion) is 30mL.

[0312] It can be seen that the cumulative dose delivered for the 5 compartment model rises more slowly than for the 1 compartment model in the early stages (e.g. first half) of the infusion, but more steeply in the later stages (e.g. second half) of the infusion. This gives more time to spot an adverse reaction a low cumulative doses where there is greater risk of triggering an adverse reaction in hypersensitive individuals. This is because for a dilution chamber with 5 compartments, the concentration in the distal compartments rise with a delayed profile compared to the proximal compartments, and so the drug is delivered to the patient more slowly. For example, cumulative doses of 0.05%, 0.5% and 5% are delivered at 0.7 minutes, 2.4 minutes and 7.9 minutes into the infusion for the single compartment diluent chamber compared to at 5.1 minutes, 8.2 minutes and 14.5 minutes respectively for the 5 compartment diluent chamber.

[0313] Referring to FIG. 28A the cumulative dose delivered to the patient over time by the 1 compartment model is shown by the curved dotted line. The vertical lines indicate the point at which 0.05%, 0.5% and 5% of the dose from the active agent chamber has been delivered to the patient and the horizontal arrows point to corresponding vertical lines indicating the point in time 5 minutes later. The text box indicates the cumulative dose for each time point indicated by the vertical lines. So for the 1 -compartment model a dose of 2.8% is given 5 minutes after 0.05%, a multiple of 55x; a dose of 4.4% is given 5 minutes after 0.5%, a multiple of 8.8x; and a dose of 12.3% is given 5 minutes after 5%, a multiple of 2.5x.

[0314] Referring to FIG. 28B for the 5 compartment model, the solid curved line indicates the cumulative dose delivered to the patient over time. From the vertical lines and text box, it can be seen that for the 5-compartment model a dose of 1.2% is given 5 minutes after 0.05%, a multiple of 55x; a dose of 4.4% is given 5 minutes after 0.5%, a multiple of 8.8x1 and a dose of 12.3% is given 5 minutes after 5%, a multiple of 2.5x. This is relevant in so far as 5 minutes is the latent period of hypersensitive reaction and thus time within which an adverse reaction can be spotted for many types of pharmaceutical preparation. So from these graphs we can see that for an individual whose threshold of hypersensitivity is 0.05% or 0.5%, the 5 compartment model will have delivered less additional drug over the threshold than the 1 compartment model before the adverse reaction is detected (24.4x vs 55x; or 7.2x vs 8.8x). However, for an individual whose threshold is 5%, the 1 compartment model will have delivered less additional drug over the threshold before the adverse reaction is detected compared to the 5 compartment model (2.5x vs 2.7x).

[0315] Another approach is to consider the OMD of the dose profiles at different points. If we consider the hypothetical hypersensitivity thresholds of 0.05% or 0.5% of the therapeutic dose, the OMD for the 5 compartment model is 3.14 and 6.23 minutes, respectively at these thresholds. The OMD reaches 5 minutes at 0.26% of the therapeutic dose. As the latent period of intravenous anaphylaxis is typically 5 minutes, individuals with thresholds greater than 0.26% of the therapeutic dose will be recognized in time to avoid 10-times the threshold from being administered. This is an improvement on the single -compartment model which has an OMD at dose thresholds of 0.05% or 0.5% of 1.63 and 5.51 minutes, respectively and which the OMD reaches 5 minutes at 0.42% of the therapeutic dose.

[0316] However, while the multiple compartment model provides more time to spot the adverse reaction at low cumulative doses, less pharmaceutical preparation is delivered to the patient over the course of the infusion up to the point where all of the pharmaceutical preparation is ejected from the syringe into the diluent chamber. As shown in Fig.28A, for a single compartment diluent chamber, at 30 minutes the active agent chamber is completely evacuated and 52% of the pharmaceutical preparation (and thus 52% of the active agent therapeutic dose) has been infused to the patient (with the remainder still in the diluent chamber). In contrast, for the 5 compartment diluent chamber, as shown in FIG. 28B, at the end of the infusion less than 42% of the pharmaceutical preparation (and thus 42% of the activeagent) from the active agent chamber has been delivered to the patient and more than 58% remains in the diluent chamber.

[0317] This means that, if nothing further is done, the remaining pharmaceutical preparation needs to be infused to the patient in a separate step, such as by infusing a bolus of diluent to flush out the diluent chamber, or the remaining pharmaceutical preparation has to be discarded which is wasteful.

[0318] 5C. EFFECT OF PARTITION(S) ON DOSE PROFILE (WITH HOLLOW TUBE)

[0319] Accordingly, the medication delivery apparatus may be provided with a mechanism to empty the dilution chamber. For example to empty the dilution chamber as the active agent chamber empties. In one example, the diluent chamber may have a movable plunger and hollow tube as described above for FIG. 21 to FIG. 23, so that in use the hollow tube pushes the movable plunger to reduce the volume of the diluent chamber and sequentially collapses the partition chambers.

[0320] Reducing volume of the dilution chamber increases the rate of drug administration, both by reducing the diluting volume and increasing the fluid flow rate out of the dilution chamber. When the active agent chamber plunger and hollow tube are initially spaced apart, the drug delivery has 2 phases, before and after the dilution chamber begins to empty. If the dilution chamber is partitioned and comprises a plurality of partition chambers in series, the partition chambers are emptied sequentially. This can improve the OMD.

[0321] Furthermore, reducing the diluent chamber volume increases the proportion of pharmaceutical preparation from the active agent chamber delivered to the patient. The arrangement may be such that substantially 100% of the pharmaceutical preparation initially in the active agent chamber is administered to the patient. For example, this may be achieved by providing a medication delivery apparatus with a length of hollow tube and initial positions of the first plunger and second plunger such that the active agent chamber is substantially completely emptied at the same at the time that the diluent chamber is substantially completely emptied.

[0322] Depending on whether the active agent chamber plunger and the proximal end of the hollow tube abut or are spaced apart in their initial positions, the diluent chamber may start to reduce in volume from the start of the infusion (time 0) or part way through the infusion (time X). The time at which the diluent chamber starts to reduce in volume may be referred to as the ‘start time’ of the diluent chamber or second plunger.

[0323] FIG. 29A to FIG. 291 illustrate data for a 30 minute constant rate infusion from a medication delivery apparatus having an active agent chamber with an initial volume of 50mL, a diluent chamber having an initial volume of 15mL split into 2 equally sized partition chambers, and configured to have a start time of 15 minutes for reduction in volume of the diluent chamber. As all of the pharmaceutical preparation in the active agent chamber is delivered to the patient by the end of the infusion the initial dose in the active agent chamber is equal to the therapeutic dose. The start time may be set to half way through the infusion (in this example 15 minutes) for a constant rate infusion by positioning the second plunger and hollow tube such that the proximal end of the hollow tube extends half way though the active agent chamber (and so will be struck by the first plunger half way through the infusion).

[0324] FIG. 29A shows the volume of the first partition chamber (solid line), and flow rate of fluid into (dashed line) and out of (dashed and dotted line) of the first partition chamber over time. FIG. 29B shows the same as for FIG. 29B but for the second partition chamber. FIG. 29C shows the volume of fluid delivered to the patient (solid line) and the flow rate of fluid to the patient (dashed line) over time. FIG. 29D shows the percentage of the therapeutic dose which is present in the first partition chamber (solid line) and the concentration of active agent in the first partition chamber (measured in % of the therapeutic dose per mL and shown by the dotted line) over time. FIG. 29E shows the same as FIG. 29D, but for the second partition chamber. FIG. 29F shows the cumulative dose delivered to the patient as a percentage of the therapeutic dose over time. FIG. 29G shows the same as FIG. 29F, but with a logarithmic scale for the cumulative dose. FIG. 29H shows how the OMD varies over time.

[0325] Fig 291 shows how the OMD varies against cumulative dose delivered to the patient over the course of the infusion for the 2 compartment diluent chamber with hollow tube. As shown by the vertical line in FIG. 291, the OMD increases throughout the infusion and first reaches an interval of 5 minutes at a cumulative dose of 0.29%. This is comparable to the scenario for a 5 compartment diluent chamber but no hollow tube (OMD reaches 5 minutes at 0.26% cumulative dose as discussed above for FIG. 28B).

[0326] However, due to the hollow tube, substantially 100% of the pharmaceutical preparation initially in the active agent chamber is delivered to the patient (as shown in FIG. 29F), compared to only 42% for the arrangement without hollow tube shown in FIG. 28B. This makes the arrangement with the hollow tube significantly more convenient to use.

[0327] The dose profile for the 2 compartment diluent chamber with hollow tube (OMD reaches 5 minutes at a cumulative dose of 0.29%) is also better than a similar arrangement with a 1 compartment diluent chamber and hollow tube (OMD reaches 5 minutes at a cumulative dose of 0.42%).

[0328] FIG. 30A to FIG. 3 OF show data for a 30 minute constant rate infusion by a medication delivery apparatus with a diluent chamber which is split into 5 partition chambers and has a hollow pusher tube. The active agent chamber has an initial volume of 50mL and the diluent chamber an initial volume of 30mL. The partition chambers are of equal volume (6mL each) and the hollow tube contacts the plunger of the active agent chamber from the beginning of the infusion (time 0).

[0329] FIG. 30A shows the volume of the first, second, third, fourth and fifth partition chambers over time. FIG. 30B shows the amount of active agent (as percentage of the full therapeutic dose) in each of the partition chambers over time. FIG. 30C shows the concentration of active agent (as % per mL) in each of the partition chambers over time. FIG.30D shows the rate of fluid flow in and out of each of the partition chambers over time. FIG.30E shows the OMD over time during the course of the infusion. FIG. 3 OF shows the OMD over the course of the infusion against cumulative dose delivered to the patient (logarithmic scale).

[0330] The OMD increases throughout the infusion and reaches 5 minutes 6.31 minutes into the infusion. The OMD reaches 5 minutes at a cumulative dose of 1% of the therapeutic dose.

[0331] FIG. 31 A to FIG. 3 IF show data for a 30 minute constant rate infusion by a medication delivery apparatus with a diluent chamber which is split into 3 partition chambers and with a hollow tube. The active agent chamber has an initial volume of 50mL and the diluent chamber an initial volume of 30mL. The partition chambers are of equal volume (lOmL each) and the hollow tube contacts the plunger of the active agent chamber half way through the infusion (time 15 minutes).

[0332] FIG. 31 A corresponds to the type of data shown in FIG. 30A discussed above, FIG. 3 IB corresponds to the type of data shown in FIG. 30B discussed above etc. The OMD increases throughout the infusion and reaches 5 minutes 5.04 minutes into the infusion. The OMD reaches 5 minutes at a cumulative dose of 0.25% of the therapeutic dose. Accordingly for the same size of diluent chamber the dose profile for 3 partition chambers with a hollow tubestart time of 15 minutes is more favorable than the dose profile for 5 partition chambers with a hollow tube start time of 0 minutes, as the OMD reaches 5 minutes at a lower cumulative dose.

[0333] 5D. BYPASS CONDUIT

[0334] The dose profile may be further modified by providing a bypass conduit between a first one of the plurality of partition chambers (referred to as the source chamber) and a second one of the plurality of partition chambers (referred to as the destination chamber). The bypass conduit may be between non-adjacent partition chambers. The passage may be inside the main body of the container, outside the main body, or inside a wall of the main body.

[0335] An example of a container 3200 including a diluent chamber with a bypass conduit is shown in FIG. 32, in which the same reference numerals indicate like parts as in FIG. 22. The diluent chamber is split into first, second and third partition chambers 410A, 410B, 410C by first and second partitions 460, 470. A first end of the diluent chamber is formed by the movable plunger 420 and pharmaceutical preparation can flow into the first partition chamber 410A of the diluent chamber via the plunger aperture 422 and the hollow tube 440.

[0336] The first partition chamber 410A is connected to the third partition chamber 410C by bypass conduit 3220. The bypass conduit 3220 extends between a bypass conduit inlet 3222 in the first partition chamber 410A and a bypass conduit outlet 3226 in the third partition chamber 410C. There is a second bypass conduit 3230, extends between a bypass conduit inlet 3232 in the first partition chamber 410A and a bypass conduit outlet 3236 in the third partition chamber 410C. In other examples there may be only one bypass conduit, or more than two bypass conduits. In some examples the bypass conduit could be an annular passage surrounding the diluent chamber.

[0337] The bypass conduit allows fluid (e.g. pharmaceutical preparation, diluent, or a mixture of pharmaceutical preparation and diluent) to flow directly between the source partition chamber (in this example chamber 410A) and a destination partition chamber (in this example third chamber 410C). The bypass conduit may have one or more valves for regulating flow of fluid through the bypass conduit. The valve(s) may be a one-way valve which allows fluid to flow in the distal direction from the source chamber to the destination chamber, but inhibits fluid flowing in the opposite direction.

[0338] In some examples there may be a bypass conduit between non-adjacent chambers and an opening in a partition between adjacent chambers. This allows a first portion of the fluid to flow from the source chamber and a non-adjacent destination chamber, while a second portionof the fluid flows from the source chamber to the adjacent chamber via an opening in the partition.

[0339] In the example of FIG. 32, when the plunger 420 is moved in the distal direction towards the second end 324 of the container body, some of the fluid in the first partition chamber 410A will enter the second partition chamber 41 OB via the first partition opening 462 and some of the fluid in the first partition chamber 410A will enter the third partition chamber 410C via the bypass conduits 3220, 3230. The bypass conduit thus has the effect of increasing the concentration in the destination (in this case third) partition chamber early in the infusion. This may improve the dose profile and / or OMD. For example, it may result in a desired OMD being achieved earlier in the infusion.

[0340] While in FIG. 32 the bypass conduit extends between and allows fluid communication between the first and third partition chambers, in other examples the bypass conduit may extend and allow fluid communication between other non-adjacent pairs of partition chambers. For instance in a a diluent chamber having five partitions, a bypass conduit could extend between the first partition chamber and the fifth partition chamber, the second partition chamber and the fifth partition chamber, the third partition chamber and the fifth partition chamber, the second partition chamber and the fourth partition chamber or the third partition chamber and the fifth partition chamber. There may be multiple bypasses between different partition chambers of the same diluent chamber.

[0341] The apparatus may be configured so that fluid substantially ceases to flow though a bypass conduit after a predetermined point in the infusion. For example the apparatus may be configured so that flow through the bypass conduit substantially ceases after the plunger 420 has passed an inlet point (e.g. 3222) of the bypass conduit. In some examples, advancement of the plunger 420 may obstruct or close the bypass conduit inlet, or compress and obstruct the bypass conduit lumen, as the plunger advances past a pre-determined point such as the bypass conduit inlet. This helps to ensuring that fluid only passes via the bypass conduit for the early part of the infusion and may improve the dose profile and / or OMD.

[0342] If the bypass conduit inlet is adjacent the initial position of the plunger 420, this will result in fluid passing through the bypass conduit in a first phase of the infusion prior to movement of the plunger 420, but not in a second phase of the infusion after the plunger 420 has started to move. If the bypass conduit inlet is half way between the initial position of the plunger 420 and the first partition 460, then fluid may stop flowing through the bypass conduitafter half of the first partition chamber 410A has been emptied. The partitions may be moved as the partition chambers are collapsed by the plungers, and so the same principle applies in relation to the positioning and movement of a partition (e.g. first partition 460) and a bypass conduit inlet on the distal side of the partition (e.g. an inlet in second partition chamber 41 OB).

[0343] In some examples the bypass conduit extends between a proximal most partition chamber and a distal most partition chamber, i.e. between the first and last partition chamber. In that case, while the first partition chamber still has a volume, diluted pharmaceutical preparation will pass directly from the first partition chamber to the last partition chamber, resulting in a higher early concentration of active agent passing to the patient. However, once the first partition chamber is no longer in communication with the inlet of the bypass conduit or the bypass conduit is otherwise closed, the flow of fluid via the bypass conduit will cease, and the concentration of active agent in the last partition chamber will no longer rise rapidly, and may even fall as lower concentration fluid enters from an intermediate partition chamber. This has the effect of ‘flattening’ the rise in the intermediate part of the dosing curve.

[0344] It is possible to alter the volumes of the individual partition chambers by setting the partitions at different distances along the diluent chamber. That is the partition chambers may have different initial volumes. It is also possible to control the point in the infusion at which the bypass conduit(s) are utilized by setting the inlet(s) of the bypass conduit(s) at different points along the wall of the container. These variations may further modify the dose profile and / or OMD.

[0345] 5E. MOVING PARTITIONS TO INITIAL POSITION

[0346] There are various ways in which the diluent chamber plunger and / or partitions may be moved to the desired initial positions to give the desired initial volumes for the diluent chamber and / or each of the partition chambers.

[0347] In some examples, the container body may include a plurality of parts which have a dis-assembled state in which the parts are separate and an assembled state in which the parts fit together to form the container body. In this way the position of the one or more partitions may adjusted when the container body is in the dis -assembled state. For example, the container body may be disassembled to insert the plunger and / or partitions and then re -assembled once the plunger and / or partitions are in the correct position.

[0348] In some examples, as shown in FIG. 33 (in which like reference numerals indicate like parts as in FIG. 32), each partition 460, 470, 480 may be connected to an adjacent partition by arespective flexible connector flexible connector 3330 such as a tie or a cable. The flexible connector flexible connector 3330 may be compressible, but resistant to extension beyond a predetermined length. The proximal most (i.e. first) partition 470 may be attached to the diluent chamber plunger 420 by a similar flexible connector. The flexible connectors flexible connector 3330 provide the system with slack -tension behavior so that the system is non-resistant under compression but tens ion -resistant under extension. This allows the partitions 460, 470, 480 to be correctly positioned based on the distance between each partition by moving the diluent chamber plunger 420. For example, on first use or re-use of the diluent chamber, the plunger 420 may be moved to push or pull the last (distal most) partition to the desired starting position. The plunger may then be moved in the distal direction to its starting position. This will cause the flexible connectors flexible connector 3330 to become taught (when the predetermined length is reached) and move the partitions to their correct starting positions.

[0349] In some examples, the container 3300 which houses the diluent chamber may further include a rod 3320 for moving the plunger 420 or one of the partitions 460, 470, 480 to the desired initial position. The rod 3320 may be less fragile than the hollow tube 440 and / or able to move the plunger and / or partition more easily. The rod 3320 may extend into the container 3300 through a rod opening 3310, whereby a position of one or more of the partitions 460, 470, 480 (or the plunger 420) is adjustable by movement of the rod. A rod may also be used in diluent chambers without a hollow tube such as those shown in FIG. 5, in which case the rod may be attached directly to one of the partitions (e.g. the first partition).

[0350] The rod 3320 may be referred to as a pusher rod or a pulling rod. On first use, or before re-use of the container, the rod 3320 may be withdrawn or pushed (advanced) into the container 3300 to set the desired starting position of the partition or plunger to which the rod is attached. The rod may be used in combination with flexible connectors flexible connector 3330 as described above, to position the plunger and / or partitions in their initial starting positions.

[0351] FIG. 33 also shows a vent hole vent 401 in the wall of the container adjacent the empty space 430 to enable the plunger 420 to be moved without creating a vacuum. The vent hole vent 401 may be positioned in the first end 402 of the container.

[0352] 5F. EXAMPLE OF DOSE PROFILES WITH BYPASS CONDUIT

[0353] FIG. 34A to FIG. 34F compare the dose profile for an example dilution chamber with 5 partition chambers separated by 4 partitions with a bypass conduit between the first and fifth partition chamber to a similar arrangement without a bypass conduit.

[0354] In this example, the diluent chamber is configured to allow 10% of the flow entering the first partition to pass to the fifth partition via the bypass conduit and 90% of the flow entering the first partition to pass to the second partition. The active agent chamber has a volume of 50mL and is emptied over an infusion lasting 30 minutes. The dilution chamber has an initial total volume of 30mL, with each partition initially holding 6mL of diluent. The apparatus is configured so that the plunger of the active agent chamber strikes the hollow pusher tube 15 minutes into the infusion, and then collapses each partition chamber in turn over a period of approximately 3 minutes each. The diluent chamber is configured so that the bypass conduit is obstructed once the first partition chamber starts to decrease in size (15 minutes into the infusion).

[0355] Fig 34A shows the percentage of the total therapeutic dose in the first partition chamber for the apparatus with the bypass conduit (solid line) and the apparatus without the bypass conduit (dashed line). FIG. 34B is the same as FIG. 34A, but for the fifth partition chamber. Fig 34C shows the cumulative dose as a percentage of the therapeutic dose delivered to the patient over time (logarithmic scale). FIG. 34D shows the concentration of active agent (% / mL) in the infusion delivered to the patient over time. FIG. 34E shows the OMD over time, while FIG. 34F shows the OMD against cumulative dose delivered as percentage of the therapeutic dose (logarithmic scale). In each graph the solid represents the apparatus with the bypass conduit and the dashed line represents the apparatus without the bypass conduit.

[0356] It can be seen from FIG. 34B (drug content in the 5thchamber) and FIG. 34D (concentration administered to patient) that prior to the bypass conduit being closed (prior to 15 minutes), the concentration of active agent (solid line) entering the patient is greater than would be the case for a similar configuration without the bypass (dashed line). This is because the bypass conduit diverts a portion of the drug present in the first chamber is diverted directly to the fifth chamber. After the bypass conduit is closed (after 15 minutes), the concentration of drug entering the patient is lower than would be the case for a similar configuration without the bypass. This is because after the bypass conduit is closed drug enters the fifth chamber from the fourth chamber only, and the fourth chamber will have a lower concentration of drug compared to a system without the bypass conduit.

[0357] Thus a bypass conduit between the first and last partition chamber and active for the first but not second half of the infusion, provides a dose profile in which the dose rate is higher in the first half of the infusion, but slower in the second half of the infusion compared to the situation with no bypass. This can be seen from FIG. 34C in which the bypass (solid line) has a steeper curve in the first few minutes indicating the cumulative dose increasing more rapidly, but then a flatter curve after the first few minutes.

[0358] In general, a bypass conduit speeds up delivery of the dose in the early parts of the infusion, but this is okay as while the cumulative dose is very low (e.g. less than 0.05%) and an adverse reaction is unlikely. Referring to FIG. 34F the bypass conduit causes the OMD to reach 5 minutes earlier (at 0.06% instead of 0.07% cumulative dose) which is good as it enables an adverse reaction to be detected at a lower cumulative dose. Another effect of the bypass conduit, in this example, is that it prevents the OMD from falling below 5 minutes once it has reached the 5 minute level (whereas with no bypass the OMD drops below 5 minutes between about 1% and 2% cumulative dose). Where the OMD drops back below 5 minutes at 1% to 2% cumulative dose, there is a risk that a patient with a hypersensitivity threshold of 1 -2% may receive a 10-fold triggering dose within 5 minutes of their threshold dose and so a more severe reaction may occur then if a system with a bypass was used. In general it is desirable for the OMD to reach 5 minutes by 0.1% (or even better 0.05%), but not drop back below 5 minutes before reaching 5% or 10% of cumulative dose. A bypass conduit may help to achieve this.

[0359] In summary, the bypass conduit increases the dose delivered in the early infusion compared to no bypass. This is advantageous as long as the cumulative dose at this stage is still low enough that it is unlikely to cause an allergic reaction. Later in the infusion, particularly when the source (e.g. first) partition chamber is empty, the rate of increase in dose for the apparatus with a bypass conduit will be less than for the case with no bypass. This may have the effect of reducing the cumulative dose at which the OMD is first over 5 minutes. In this example, a 10% bypass was found to work well. However, a 50% bypass (50% through the bypass, 50% through the partition aperture) was found to be less beneficial (as in that case the OMD first reached 5 minutes at a cumulative dose that was higher than for the 10% bypass).

[0360] FIG. 35 shows an example dose profile for an apparatus which has a plurality of partition chambers of different initial sizes and a bypass conduit. Providing partition chambers with different initial sizes can further adjust and fine tune the dose profile and may be particularly useful when an infusion driver having a constant infusion rate is used.

[0361] Specifically, FIG. 35 compares the dose administered over time (as percentage of the therapeutic dose) for an apparatus having a single compartment (non -partitioned) diluent chamber (dashed line) with the dose delivered by a 5 compartment diluent chamber with bypass conduit (solid curved line). The 5 -compartment diluent chamber comprising 5 partition chambers of volumes 9, 4, 4, 4 and 9mL respectively (total 30mL), and a bypass conduit that extends between the first and fifth partition chamber. The arrangement is configured to transfer 10% of the mixed fluid entering the first compartment from the first to the fifth compartment via the bypass, with 95% of the mixed fluid passing to the second compartment. The infusion has a constant infusion rate. The hollow pusher tube has a start time of 16 minutes. Therefore, over the infusion time of 30 minutes, the diluent chamber compartments start to reduce in volume sequentially from the 16thminute of the infusion.

[0362] The vertical lines show the points in time at which a cumulative dose of 0.1% and 1% of the therapeutic dose are reached and the corresponding points in time 5 minutes later as indicated by the horizontal arrows. It can be seen that for the single compartment arrangement the cumulative dose increases by a factor of 20.9x in the 5 minutes after reaching 0.1% and a factor of 4.4x in the 5 minutes after reaching 1%. In contrast in the 5 -compartment arrangement with the bypass the cumulative dose increases by a factor of 7. Ox in the 5 minutes after reaching 0.1% and a factor of 4.5x in the 5 minutes after reaching 1%. Thus it can be seen that the increase in cumulative dose in the 5 minutes after 0.1% is lower for the 5 compartment and bypass arrangement compared to the 1 compartment arrangement and similar for the 5 minutes after 0.5% level cumulative dose.

[0363] For an apparatus similar to the one discussed above, but in which the bypass is configured to transfer 5% of the fluid entering the first compartment to the last compartment (rather than 10%), it was found that the OMD at 0.05% and 0.1% of the therapeutic dose was 3.43 and 7.38 minutes respectively. The OMD reached 5 minutes at a cumulative dose of 0.15%, meaning that individuals with hypersensitivity thresholds greater than 0.15% of the therapeutic dose should be recognized in time to avoid 10 -times the threshold from being administered.

[0364] It was found that an apparatus with a diluent chamber without partitions of initial volume 30mL and an active agent chamber of initial volume 30mL, when the infusion is delivered at a constant infusion rate over 30 minutes and the active agent chamber plungerstriking the hollow pusher tube at 15 minutes, will deliver a dose profile having the following characteristics.Cumulative dosedelivered (as % of Time (minutes) OMD (minutes) therapeutic dose)0.05% 0.96 2.100.5% 3.06 6.965% 10.0 13.350% 23.3 N / ANon-partitioned diluent chamber (30mL), drug chamber (30mL), 30 minute constant rate infusion, second plunger start time 15 minutes)

[0365] For this non-partitioned arrangement, it was found that for all cumulative doses after 0.09% of the therapeutic dose, the OMD was at least 5 minutes. Accordingly, an adverse reaction could be detected in time for an individual having a hypersensitivity threshold of greater than 0.09% of the therapeutic dose.

[0366] It was found that an apparatus with an active agent chamber of initial volume 30mL and a diluent chamber of initial volume 30mL split into 5 partition chambers of volumes of 9ml, 4ml, 4ml, 4ml and 9ml respectively for the first to fifth partition chamber, and a bypass conduit from the first to the fifth partition chamber configured to transfer 10% of the volume entering the first chamber into the fifth chamber, when the infusion is delivered at a constant infusion rate over 30 minutes and the active agent chamber plunger arranged to strike the hollow tube at 16 minutes, will deliver a dose profile having the following characteristics / Cumulative dosedelivered (as % of Time (minutes) OMD (minutes) therapeutic dose)0.05% 4.45 5.110.5% 9.56 7.515% 17.07 7.6150% 24.68 N / ADiluent chamber with 5 compartments (9ml, 4mL, 4mL, 4mL, 9mL, total 30 mL), 1-510% bypass, drug chamber (30mL), 30 minute constant rate infusion, second plunger start time 15 minutes

[0367] For this arrangement it was found that for all cumulative doses after 0.05% of the therapeutic dose, the OMD was at least 5 minutes. Accordingly, an adverse reaction could be detected in time for an individual having a hypersensitivity threshold of greater than 0.05% of the therapeutic dose.

[0368] From the above, it can be seen that the combination of partition chambers and bypass conduit flattens the dose profile so that OMD is higher earlier in the infusion but lower later in the infusion compared to the non-partitioned diluent chamber. As a result the OMD reaches 5 minutes at a lower cumulative dose and remains at or above 5 minutes for the rest of the infusion.

[0369] In general, it is desirable to achieve a profile in which for all doses after 0.1% but more preferably all doses after 0.05% of the therapeutic dose, the OMD is at least 5 minutes for an infusion of duration 60 minutes or less and more preferably 30 minutes or less. By using a partitioned diluent chamber and if needed one or more bypass conduits it is possible to achieve this with a constant rate infusion of duration 30 minutes or less.

[0370] The inventor has found that a diluent chamber with three or more partition chambers and a bypass conduit from the first partition chamber to the last partition chamber is particularly suitable for achieving this type of dose profile.

[0371] 6. GASKET, END CAP, PARTITION SHAPE AND OTHER FEATURES

[0372] Any of the above described containers or medication delivery apparatus may include a gasket which seals a space between the hollow tube and the inlet opening of the container. FIG.36 and FIG. 37 show examples in which like reference numerals indicate like parts as in FIG. 7 to FIG. 9 and FIG. 32 to FIG. 33 and reference numeral 450 denotes the gasket.

[0373] The gasket 450 seals with the hollow tube 440 and thus helps to prevent flow of fluid from the active agent chamber around the hollow tube 440 and into the empty space 430 bounded by the body of the second container 3300 and the second plunger 420. The second container and the second plunger may also be referred to as the diluent chamber container and the diluent chamber plunger.

[0374] FIG. 36 shows an example in which the gasket 450 is fixed to the inlet opening 404 of the second container 3300 and the hollow tube 440 is movable relative to the gasket 450.

[0375] FIG. 37 shows an example in which the gasket 450 is fixed to the hollow tube 440 and movable relative to the inlet opening 404 of the second container 3300. In this case, the inlet opening may have a portion extending into the second container so as to maintain a seal with the gasket when the gasket is moved relative to the inlet opening 404.

[0376] In some examples, an end cap or pusher cap may be provided for the hollow tube. The end cap may be configured to attach to the first end of the second container and cover the hollow tube. The end cap may have a bore connector at a distal end to connect to the inlet opening of the second container. The end cap may have a bore connector at a proximal end to facilitate filling of the second container with diluent through the bore connector and the lumen of the hollow tube. The end cap may include a gasket for supporting the hollow tube and sealing a space between internal walls of the end cap and the hollow tube.

[0377] An example of an end cap 3800 is shown in FIG. 38. The end cap 3800 comprises a hollow member having walls 3810 and may be cylindrical in shape. The end cap may have an enlarged flange portion 3820 with a large internal and / or external diameter at one end to accommodate a bore connector 404, such as a luer lock, of the second container 400 through which the hollow tube passes. The other end of the end cap 3830 may be sealed to protect the hollow tube. In this way when the end cap is applied it may surround the part of the hollow tube which extends past the inlet opening 404 of the second container. The end cap may be configured to snap fit or clip onto the end of the second container; for instance, it may clip onto a bore connector.

[0378] When attached the end cap 3800 may protect the hollow tube and also occlude or cover the inlet opening 404 of the second container 400. The diluent chamber of the second container may be prefilled with diluent or may be provided empty. If provided empty, the diluentchamber may be filled with diluent through the outlet opening 408 (not shown in FIG. 38) of the second container 400.

[0379] In other examples, the end cap 3800 may have a removable cap or lid or resealable membrane at the distal end 3830, which when removed or opened exposes the hollow tube 440 thereby allowing diluent to be injected through the hollow tube 440 and into the diluent chamber 410. In that case, air displaced by the injected diluent may be expelled from the outlet opening 408 of the second container. The end cap 3800 may include one or more cap gaskets 3840 within the walls 3810 to seal around the hollow tube 440 to prevent accidental ingress of fluid. In some examples the cap gasket 3840 may seal with a proximal aperture 444 or side opening 446 of the hollow tube. The inlet opening 404 of the second container 400 may have a gasket 450 to seal around the hollow tube and further protect from accidental ingress of fluid.

[0380] The partitions may be shaped like an open cone with the partition opening at the tip of the cone, so that bubbles rise towards the centre of the partition 460, 470, 480 and / or partition opening 462, 472, 482 when held with the distal end 324 higher. An example of a diluent chamber with partitions having an open cone shape us shown in FIG. 39, in which like parts are indicated by like reference numerals as in FIG. 32 and FIG. 33.

[0381] This arrangement aids the movement of the bubbles from one partition chamber into a subsequent partition chamber so that the bubbles travel upwards through the partition chambers until being aspirated through the outlet opening 408 of the diluent chamber or container. The cone shape of each partition may be relatively shallow, e.g. the depth of the cone may be 50% or less of the radius of the cone as measured from the base of the cone.

[0382] It will be understood that while the partitions and partition chambers have been described above in relation to a second container having a hollow tube of the type shown in FIG. 21 and FIG. 22, the partitions and related features including assembly from multiple parts, pushing or pulling rods, flexible connectors, bypass conduits etc. described above in Sections 4-10 may be applied to any diluent chamber, including but not limited to diluent chambers without a hollow tube or diluent chambers of a dual chambered syringe as shown in FIG. 24 or diluent chambers connected in fluid communication with a source of pharmaceutical preparation as shown in FIG. 24.

[0383] The presence of multiple partitions in the diluent chamber helps to facilitate a satisfactory drug profile under operation by a fixed rate infusion driver capable only of a constant infusion rate.[0384A] FIG. 47A illustrates an example of a hollow-tube dilution device according in which a syringe is coupled to a second container defining a diluent chamber, and in which the device includes an optional sleeve portion 4700B for receiving at least a distal portion of the syringe to assist alignment during assembly and / or use.[0384B] FIG. 47B illustrates a sectional view of the example of FIG. 47A, showing the relationship between the syringe, a plunger defining the diluent chamber, and internal components of the second container, in an embodiment in which the syringe is received at least partially within a sleeve portion of the second container.[0384C] FIG. 48 illustrates an example of a hollow-tube dilution device including a protective member 4800 associated with the proximal portion of the device, such as a cap or sleeve configured to protect the hollow tube during storage and transit.[0384D] FIG. 49A illustrates an example partitioned diluent chamber embodiment in which there are adjacent movable partitions (e.g., discs). As there is a risk the partitions may rotate relative to each other during use, flow could be inhibited if openings are misaligned when the partitions abut during a later stage of infusion. Therefore as shown by the dashed arrows in FIG. 49A and example partition member structure in FIG. 49B, one or more channels 4901, grooves, or cut-outs 4902 may be provided on the partition member and configured to provide a flow path when adjacent partitions are in an abutting or compressed condition. For example there may be one or more channels at least partially crossing a face of the partition and an annular channel around a circumference of the partition.[0384F] FIG. 49C illustrates an example partition member which has a cone shape, including flow paths 4903 on a face of the partition member configured to allow fluid communication past the partition when adjacent partitions are misaligned and / or in an abutting condition. FIG.49D illustrates a sectional detail of an example interface between adjacent partitions of the type shown in FIG. 49C, showing how a recessed channel, groove, or clearance region can maintain a flow path between partition chambers when the partitions abut.[0384G] FIG. 50 illustrates an example dilution device in which a foam insert is provided within a diluent chamber downstream of a plunger in a hollow-tube embodiment, such that pharmaceutical preparation entering the diluent chamber may pass through and / or interact with the foam insert prior to exiting an outlet, and the foam insert is compressible to assist evacuation of fluid during a later stage of use.

[0384] 7. COMPRESSIBLE FOAM INSERT

[0385] As mentioned above, one aspect of the present disclosure proposes placing a compressible foam insert in the diluent chamber. The compressible foam insert may then act as a physical flow-conditioning element positioned between a plunger and an outlet.

[0386] A compressible foam insert may be used in a variety of medication delivery apparatuses. For example, FIG. 40C illustrates a nested sleeve embodiment in which a foam insert may be located in the diluent chamber downstream of a second plunger. FIG. 50 illustrates another example in which a removably attachable diluent chamber comprising a plunger with a hollow tube, has a compressible foam insert disposed between the plunger and the diluent chamber outlet. In another example, foam insert may be placed in the diluent chamber of a double-plunger syringe. For example, this would result in a dual-plunger syringe having similar to the arrangement shown in FIG. 1A. For example it may have an active agent chamber 130 defined between a first plunger 120 and a second plunger 140 , and a diluent chamber 150 located between the second plunger 140 and an outlet 152. However, unlike FIG.1A, the diluent chamber 150 would include a compressible foam insert.

[0387] The principle of each of these examples is similar. During use, pharmaceutical preparation enters the diluent chamber and mixes with diluent therein while fluid is delivered through the outlet to the patient. In a later portion of an infusion, distal movement of the plunger compresses the foam insert and assists with evacuation of remaining fluid from the diluent chamber through the outlet. In this way, a single device may provide both (i) progressive dilution during an initial portion of an infusion and (ii) evacuation of residual fluid in a later portion of the infusion.

[0388] In some examples, the compressible foam insert 5500 is configured to implement a plurality of partition chambers 5530 within the diluent chamber. This is analogous to the use of multiple partitions described elsewhere in this specification, for example in FIG. 22, FIG, 23, FIG. 46, FIG. 47A, FIG. 47B and FIG. 48 and elsewhere, but with the partitions implemented using a foam insert instead of plungers.

[0389] An example conceptual arrangement is shown in FIG. 55, in which foam portions act as partition portions 5510 and foam spacer portions 5520 maintain separation between adjacent partition portions in an initial state. The use of foam in this manner can provide practical advantages. For example, the foam may be readily compressible and low friction during the evacuation phase, and the foam may have a tendency to expand (or return to a less compressed state) which can assist in maintaining the relative positions and separations of foam-definedpartition portions during transport and storage, thereby supporting repeatable initial partition spacing prior to use. Further, while not shown in FIG. 55, where the foam insert defines partition chambers 5530 in the dilution chamber, it can also define internal channels between non-adjacent chambers (bypasses), to provide the same or similar effect as the bypass channels shown in FIG. 32 which uses plungers (e.g. discs) as the partition members.

[0390] Both the partition portions and spacer portions may be formed of foam. A spacer portion may extend between adjacent partition portions or between a partition portion and end of the diluent chamber or a stop / abutment feature of the dilution chamber. In some examples the spacer portions may be annular and continuously enclose the space between adjacent partitions, in other examples the spacer portions may be semi -annular or strut shaped so that they do not continuously the space between adjacent partitions. Initial state refers to a state before use in which the diluent chamber is filled with diluent and ready for use, but an infusion has not yet been commenced. The foam may have a tendency to expand or return to a less compressed condition, thereby keeping the partitions in place during transit, whereas in contrast when the partitions formed by plungers (including discs) in the diluent chamber are more prone to be dislodged during transport. However, as discussed above the initial position of each partition, or separation of the partitions, may be important to achieve the desired dosage profile in use.

[0391] The foam insert may comprise open-cell foam material, closed-cell foam material, or a combination thereof. As used herein, “open-cell foam” refers to a porous foam having interconnected pores that allow fluid flow through the foam body. “Closed -cell foam” refers to a foam having cells that are substantially not interconnected such that fluid flow through the foam body is inhibited. In the example of FIG. 55 it is envisaged that closed-cell foam may be used. However, use of open-cell foam could be used. Combinations of open-cell and closed-cell foam may be used, for example by layering different foams or by providing different foam regions having different properties. The foam insert may be provided as a single piece of foam (for example, a foam insert located in the diluent chamber as illustrated in FIG. 40C and FIG.50), or as a plurality of foam pieces stacked or arranged along a length of the diluent chamber.

[0392] FIG. 55 shows a foam insert used a structural element to define a plurality of partition chambers, which may be collapsed sequentially during the infusion. The spacer portions may have different compressibility and / or thickness such that, during compression of the foam insertby distal movement of the plunger, the partition chambers are arranged to collapse in a predetermined order.

[0393] In some examples, rather than a foam insert having a plurality of partition chambers, the foam insert may be a single solid piece of open cell foam, as shown in Fig. 43 A. In such cases the foam may still shape the flow of fluid, and in particular pharmaceutical preparation through the diluent chamber. As the foam tends to slow down the flow of fluid through the chamber it effects the time taken for the pharmaceutical entering the diluent chamber to leave the diluent chamber and thus tends to reduce the concentration, or reduce the rate of increase in concentration, of pharmaceutical preparation in the fluid exiting the diluent chamber through the outlet, during an early part of the infusion.

[0394] In many cases, where an open cell foam is used, there is a risk of air bubbles becoming trapped in the foam during filling, and released during infusion to flow out of the outlet, especially during compression of the foam during diluent chamber evacuation. As air bubbles are potentially dangerous to the patient, they are to be avoided. For this reason the filling procedure is important, and in some examples the diluent chamber may be pre -filled in a factory under vacuum conditions. By compressing the foam insert under vacuum conditions the foam insert may be substantially saturated with diluent, thereby minimizing the risk of air bubbles.

[0395] FIG. 51 illustrates example experimental results, for an arrangement having a solid block of foam as illustrated in Fig. 40A to 40C, 41A to 41F and 43 A. The approximate change in color saturation of saline in a diluent chamber, into which a coloured fluid was injected from a syringe, was observed over the course of an infusion. It was found that inclusion of a foam insert can moderate (i.e. reduce) the early concentration rise compared to an otherwise identical arrangement without foam, and this effect was more pronounced for thicker (longer) foam inserts. The half foam result in FIG. 51 refers to a foam that was 1.5cm thick vs a full length of foam which 3cm thick for the same type of foam in a standard size syringe. This demonstrates the ability of an open-cell foam to moderate concentration rise and effect the dose profile. It is thought that the density, porosity, tortuosity and overall volume of the foam will also influence the size of effect.

[0396] The foam insert should be positioned in a flow region of the diluent chamber such that at least a portion of the fluid flowing through the diluent chamber passes through the foaminsert. In some examples the compressible foam insert may substantially block passage through the diluent chamber other than through the foam.

[0397] In some examples, the foam insert is configured to include one or more channels or bypass features to allow some of the fluid to bypass at least part of the foam insert during at least part of the infusion. FIGS. 53A to 53C illustrate an example in which the foam insert has a diameter less than the diameter of the second container. This may help to prevent the foam insert becoming wedged into the container during install and manufacture to an extent that it is later unable to expand. As mentioned above, the foam may be compressed during installation and / or filling, but as the position of the foam in the diluent chamber effects the dose profile, it may be desired that the foam expand to a known extent and / or position after filling. The clearance formed by the bypass channel in the arrangement of FIGs. 53A to 53C allows the foam insert to expand back. The front of the foam insert may be kept int place by wedging into a narrower end portion of the second container as shown.

[0398] As shown in FIGs. 53A to 53C , the space between the side of the foam and the second container walls also provides an initial bypass path 5300P that provides a preferential flow path during an early portion of operation. This bypass path progressively reduces as the plunger advances and compresses the foam, such that flow is increasingly directed through the foam body and the bypass path may be reduced or closed during compression. The bypass channel may thus influence flow through the diluent chamber and / or to assist filling of the diluent chamber. In some examples the foam insert may be shaped such that the fluid has to pass through at least a portion of the foam insert before reaching the outlet in at least an initial stage of the infusion, while in other examples the foam insert may be shaped such that the bypass allows a portion of the fluid to bypass the foam insert for some or all of the infusion.

[0399] FIGS. 54A to 54C illustrate various structures which may provide one or more clearance regions that act as bypass channels and / or reduce wedging or frictional engagement of the foam with the container wall during filling, and to allow the foam to expand (or return toward a less compressed state) after filling.

[0400] In some examples, the diluent chamber and foam insert are provided pre -filled with diluent. This can be particularly beneficial where the foam insert comprises open -cell foam, as filling an open-cell foam insert in a clinical setting may risk trapping air bubbles within the foam, which could be undesirable or potentially hazardous if transmitted downstream.Accordingly, in some examples the foam insert is pre-saturated with diluent prior to use. Insome examples, pre-filling is performed in a controlled manufacturing environment (for example using reduced-pressure or vacuum-assisted filling) to reduce entrained air and to promote complete saturation of the foam insert.

[0401] In order to further improve the dose profile and reduce the rate at which the concentration of pharmaceutical preparation leaving the chamber increases during the earlier parts of the infusion, the structure of the foam insert may be modified to promote a desired dose profile. For example, the structure of an open-cell foam insert may be modified to influence how fluid passes through the diluent chamber . For instance, the foam insert may have a non-uniform porosity and / or permeability along a flow direction through the diluent chamber. For instance, FIG. 56A shows a conceptual example, in which the foam insert may comprise one or more compressed regions or a gradually reduced compression and porosity in the axial direction. For instance, as shown in FIG. 56B there may be a plurality of layers of foam having different porosity and / or permeability, for instance stacked pieces of foam of different types.

[0402] In some examples, the foam insert may define one or more channels or bores formed in the open-cell foam insert and extending at least part-way through the foam insert. For instance, FIG.56C shows a conceptual example in which the foam insert may define a channel extending through the foam insert between a proximal end region and distal end region allowing a portion of the fluid entering the foam insert to pass through the channel and thereby bypass the majority of the foam insert body. FIG 56D shows a cross section of the channel. The channel may narrow towards the distal end to reduce the rate of fluid leaving the channel , as shown in FIG. 56E.

[0403] A bore is a channel which starts at a distal or proximal face of the foam insert and terminates before reaching the other side of the foam insert. Before reaching a bore or after leaving the bore, the fluid must pass through the remaining portion of the foam which changes the spread and or flow rate of the fluid. A bore the extends from a face of the foam insert into the foam insert but only extends a part of the length within the foam insert and does not reach the other side of the foam insert. FIG 55F shows a conceptual example in which there are one or more bores extending from one end of the foam insert into the foam insert body.

[0404] In some examples, the foam insert may define one or more voids configured to receive fluid during use. FIG. 55G shows one conceptual example, in which the foam insert comprises1at least one void chamber formed within the foam, and surrounded by the foam insert body to facilitate mixing of diluent with pharmaceutical preparation within the void chamber.

[0405] The voids, bores or channels may for example be formed by cutting a piece of foam in half with a knife, cutting the desired void, bore or channel and then re-assembling the foam and / or securing or gluing the pieces together before placing the insert in the diluent chamber.

[0406] In the examples disclosed herein, where there are no foam insert or partitions in the diluent chamber the syringe or plunger may be driven according to an infusion protocol as described in WO 2021 / 113925 and WO 2022 / 261708 in which the infusion rate varies continuously or in a stepped fashion over the course of the infusion. In that respect where the diluent chamber has a hollow tube, the protocol and infusion rate may be modified to take into that both the active agent (drug) chamber and the diluent chamber may be emptying together for a portion of the infusion, whereas where a nested approach in which the drug chamber empties before the diluent chamber is used, then the infusion would not need this modification. Where there is a foam insert or partitions, a protocol in which the infusion rate is constant, and can use a constant rate infusion driver, may be possible; while in some circumstances an infusion protocol in which the infusion rate varies continuously or in a stepped fashion over the course of the infusion may be used.

[0407] EXEMPLARY EMBODIMENTS

[0408] The following are example numbered embodiments in accordance with the present disclosure

[0409] 1. A medication delivery apparatus comprising: a syringe comprising a first plunger and a first container which together define an active agent chamber for receiving a pharmaceutical preparation; a second container comprising a diluent chamber, a first end having an inlet opening and a second end having an outlet opening; wherein the first end of the second container is removably attachable to a distal end of the first container in a manner which puts the first container and second container in fluid communication; whereby movement of the first plunger in a distal direction is operable to eject pharmaceutical preparation from the active agent chamber into the diluent chamber to mix with the diluent and eject a mixture of pharmaceutical preparation and diluent through the outlet opening of the second container to a patient.

[0410] 2. The medication delivery apparatus of embodiment 1 wherein: a second plunger is positioned between the first end and the second end of the container; a hollow tube extendsback from the second plunger through the inlet opening of the second container and the distal opening of the first container into the first container; the hollow tube has a lumen in fluid communication with an aperture of the second plunger through which an active agent may be injected into the diluent chamber to mix with the diluent; and wherein the first plunger when moved in the distal direction is operable to abut against and push the hollow tube so as to move the second plunger in the distal direction.

[0411] 3. The medication delivery apparatus of embodiment 1 wherein the second container has a divider positioned between the first end and second end of the second container, and wherein the diluent chamber is defined by the space between the divider and the second end of the second container.

[0412] 4. The medication delivery apparatus of any one of embodiments 1 to 3 wherein the diluent chamber has one or more partitions which separate the diluent chamber into a plurality of partition chambers.

[0413] 5. The medication delivery apparatus of any one of embodiments 1 to 4 wherein diluent chamber has an arrangement to generate at least two divergent jets of pharmaceutical preparation or pharmaceutical preparation and diluent in order to promote mixing in the diluent chamber.

[0414] 6. A medication delivery apparatus comprising: a first plunger and a first container which together define an active agent chamber for receiving a pharmaceutical preparation;

[0415] a second container defining a diluent chamber, the second container having a first end and a second end, the first end of the second container being removably attachable to a distal end of the first container; a second plunger positioned between the first end and second end of the second container; a hollow tube attached to the second plunger and extending back from the second plunger into the first container, a lumen of the hollow tube being in communication with an aperture of the second plunger; whereby movement of the first plunger in a distal direction is operable to eject pharmaceutical preparation from the active agent chamber through the lumen of the hollow tube into the diluent chamber to mix with the diluent and eject a mixture of pharmaceutical preparation and diluent through an outlet opening of the second container; and wherein the first plunger when moved in the distal direction is operable to abut against and push the hollow tube so as to move the second plunger in the distal direction.

[0416] 7. The apparatus of embodiment 6 wherein the first container has a proximal opening for receiving the first plunger and a distal opening for receiving the hollow tube.

[0417] 8. The apparatus of embodiment 6 or embodiment 7 wherein the hollow tube extends through an inlet opening at the first end of the second container and through the distal opening of the first container into the first container.

[0418] 9. The apparatus of any one of embodiments 6 to 8 wherein the diluent chamber is defined by the space between the second plunger and the second end of the second container.

[0419] 10. The apparatus of any one of embodiments 6 to 9 wherein the diluent chamber is filled with diluent.

[0420] 11. The apparatus of any one of embodiments 6 to 10 comprising a valve to control flow of fluid from the active agent chamber to the diluent chamber.

[0421] 12. The apparatus of any one of embodiments 6 to 11 wherein the lumen of the hollow tube has a distal opening at a distal end of the hollow tube and a proximal opening at a proximal end of the hollow tube.

[0422] 13. The apparatus of any one of embodiments 6 to 12 wherein the hollow tube extends between a proximal end and a distal end and has a side opening between the distal end and proximal end and in fluid communication with the lumen.

[0423] 14. The apparatus of any one of embodiments 6 to 13 wherein there is an opening (air vent) in the second container between the first end of the second container and an initial position of the second plunger.

[0424] 15. The apparatus of any one of embodiments 7 to 14 wherein the distal opening of the first container comprises a bore connector.

[0425] 16. The apparatus of any one of embodiments 6 to 15 wherein the outlet opening at the second end of the second container comprises a bore connector.

[0426] 17. The apparatus of any one of embodiments 8 to 16 wherein the inlet opening at the first end of the second container comprises a bore connector.

[0427] 18. The apparatus of any one of embodiments 8 to 17 wherein a gasket seals a space between the hollow tube and the inlet opening.

[0428] 19. The apparatus of embodiment 18 wherein the gasket is fixed relative to the inlet opening and the hollow tube is movable relative to the gasket.

[0429] 20. The apparatus of embodiment 18 wherein the gasket is fixed to the hollow tube and the gasket is movable relative to the inlet opening and wherein the inlet opening optionally hasa portion extending into the second container so as to maintain a seal with the gasket when the gasket is moved relative to the inlet opening.

[0430] 21. The apparatus of any one of embodiments 6 to 20 wherein the apparatus is configured so that the first plunger abuts the hollow tube in an initial position of the first plunger and the second plunger.

[0431] 22. The apparatus of any one of embodiments 6 to 20 wherein the apparatus is configured so that the first plunger is spaced a distance apart from the hollow tube in an initial position of the first plunger and the second plunger and wherein the first plunger is movable in the distal direction to abut the hollow tube.

[0432] 23. The apparatus of any one of embodiments 6 to 22 wherein the apparatus is configured to simultaneously reduce the active agent chamber volume and the diluent chamber volume for at least a part of the infusion process.

[0433] 24. The apparatus any one of embodiments 6 to 21 wherein the apparatus is configured to simultaneously reduce the active agent chamber volume and the diluent chamber volume for the whole infusion process.

[0434] 25. The apparatus of any one of embodiments 6 to 24 wherein, in an initial position of the second plunger, the hollow tube extends a first distance into the first container which is substantially equal to a second distance between a distal side of the second plunger and the outlet opening of the second container.

[0435] 26. The apparatus of any one of embodiments 6 to 25 comprising an end cap which is configured to attach to the first end of the second container and cover the hollow tube.

[0436] 27. The apparatus of embodiment 26 wherein the end cap has a bore connector at a distal end to connect to the inlet opening of the second container.

[0437] 28. The apparatus of embodiment 26 or 27 wherein the end cap has a bore connector at a proximal end to facilitate filling of the second container with diluent through the bore connector and the lumen of the hollow tube.

[0438] 29. The apparatus of any one of embodiments 26 to 28 wherein the end cap comprises a gasket for supporting the hollow tube and sealing a space between internal walls of the end cap and the hollow tube.

[0439] 30. The apparatus of any one of embodiments 6 to 29 wherein the diluent chamber has one or more partitions which separate the diluent chamber into a plurality of partition chambers.

[0440] 31. A diluent chamber for diluting a pharmaceutical preparation prior to administration to a patient, the diluent chamber comprising: an inlet end including an inlet opening for receiving pharmaceutical preparation; an outlet end including an outlet opening for ejecting diluted pharmaceutical preparation; a container body extending at least between the inlet end and the outlet end of the diluent chamber; and one or more movable partitions which split the diluent chamber into a plurality of partition chambers, the partitions configured to move within the container body during use, the partitions being movable directly or indirectly by a syringe plunger; wherein each partition has a channel for allowing fluid communication between the partition chambers on either side of the partition.

[0441] 32. The diluent chamber of embodiment 31 wherein the channel is an opening in the partition or a passage which extends from a first side of the partition to a second side of the partition.

[0442] 33. The diluent chamber of embodiment 31 wherein each channel comprises a partition valve.

[0443] 34. The diluent chamber of embodiment 33 wherein the partition valve is located in a recess of the partition.

[0444] 35. The diluent chamber of any one of embodiments 31 to 34 wherein a proximal side of each partition conforms to a shape of a distal side of the adjacent partition in the distal direction.

[0445] 36. The diluent chamber of any one of embodiments 31 to 35 wherein a proximal side of each partition has a concave surface and the partition opening is at an apex of the concave surface.

[0446] 37. The diluent chamber of any one of embodiments 31 to 36 wherein each partition chamber has the same initial length.

[0447] 38. The diluent chamber of any one of embodiments 31 to 36 wherein at least one of the partition chambers has a different initial length to at least one other partition chamber.

[0448] 39. The diluent chamber of any one of embodiments 31 to 38 wherein one or more of the partitions are movable separation plungers.

[0449] 40. The diluent chamber of any one of embodiments 31 to 39 wherein the container body comprises a plurality of parts which have a dis -assembled state in which the parts are separate and an assembled state in which the parts fit together to form the container body, the position of the one or more partitions being adjustable when the container body is in the disassembled state.

[0450] 41. The diluent chamber of any one of embodiments 31 to 40 wherein each partition is connected to an adjacent partition by a flexible connector, the flexible connector being compressible but resistant to extension beyond a predetermined length.

[0451] 42. The diluent chamber of any one of embodiments 31 to 41 further comprising a pusher rod extending into the container through a pusher rod opening, whereby a position of one or more of the partitions is adjustable by movement of the pusher rod.

[0452] 43. The diluent chamber of any one of embodiments 31 to 42 wherein the inlet end of the diluent chamber is formed by a first end of the container body and the outlet end of the diluent chamber is formed by a second end of the container body.

[0453] 44. The diluent chamber of any one of embodiments 31 to 42 wherein:

[0454] the inlet end of the diluent chamber is formed by a movable plunger disposed between the first end and the second end of the container body;

[0455] the movable plunger has an opening through which pharmaceutical preparation can be ejected into the diluent chamber;

[0456] and a hollow tube is attached to and extends back from the movable plunger and through an opening in the first end of the container body, a lumen of the hollow tube being in fluid communication with the opening of the movable plunger.

[0457] 45. The diluent chamber of embodiment 44 wherein the partition chambers are collapsable in sequential order by pushing of the movable plunger by the hollow tube towards the second end of the container body.

[0458] 46. The diluent chamber of any one of embodiments 31 to 45 wherein the container comprises a bypass conduit between a first one of the plurality of partition chambers and second one of the plurality of partition chambers.

[0459] 47. The diluent chamber of embodiment 46 wherein the bypass conduit is between non-adjacent partitions.

[0460] 48. The diluent chamber of embodiment 46 or 47 wherein the apparatus is configured to allow fluid to flow through the bypass conduit between the first one and second one of the partition chambers when the second plunger is moved towards the second end of the container body and configured so that fluid substantially ceases to flow though the bypass conduit after the second plunger has passed an inlet point of the bypass conduit.

[0461] 49. The diluent chamber of any one of embodiments 31 to 48 wherein the diluent chamber is attachable to a distal end of a syringe to form a medication delivery apparatus according to embodiment 4 or embodiment 30.

[0462] 50. A medication delivery apparatus comprising a syringe including a container body extending between a proximal end and a distal end, a first plunger disposed at least partially within the container body and a second plunger being disposed in the container body between the first plunger and the distal end, an active agent chamber for receiving a pharmaceutical preparation defined by a space between the first plunger and the second plunger, and a diluent chamber defined by a space between the second plunger and the distal end, wherein the diluent chamber is a diluent chamber according to any one of embodiments 31 to 48 and wherein the second plunger acts as the first end of the diluent chamber and has an aperture acting as the inlet opening for receiving pharmaceutical preparation ejected from the active agent chamber.

[0463] 55. A medical device for connection to the outlet of a syringe, the medical device comprising: a container extending between a first end having an inlet opening and a second end having an outlet opening; the inlet opening comprising a bore connector for attachment to the outlet of a syringe; a plunger positioned between the first end and the second end of the container, wherein a space between the plunger and the second end of the container defines a diluent chamber for containing diluent; and a hollow tube having a lumen in fluid communication with an aperture of the plunger and extending back from the plunger through the inlet opening of the second container; the hollow tube being insertable into an outlet of a syringe and providing a conduit through which an active agent may be injected into the diluent chamber to mix with the diluent; and wherein the hollow tube is pushable to move the plunger towards the second end of the second container to force a mixture of diluent and active agent out of the diluent chamber through the outlet opening.

[0464] 56. The medical device of embodiment 55 wherein the diluent chamber is pre -filled with diluent.

[0465] 57. The medical device of embodiment 55 or 56 wherein the container has an air vent between the first end of the container and the plunger.

[0466] 58. The medical device of any one of embodiments 55 to 57 wherein the diluent chamber is a diluent chamber according to embodiment 49.

[0467] 59. A system for delivering medicament, the system comprising: an apparatus according to any one of embodiments 1 to 30; and an infusion driver for moving the first plunger in the distal direction.

[0468] 60. The system of embodiment 59 wherein the infusion driver is configured to drive the first plunger at a constant speed.

[0469] 61. The system of embodiment 59 wherein the infusion driver is configured to drive the first plunger at a plurality of speeds according to a predetermined dose profile.

[0470] 62. A medication delivery apparatus, system, diluent chamber or medical device according to any one of the above embodiments that is configured to provide a dose profile in which for all cumulative doses after 0.1% of the therapeutic dose, the order of magnitude delay (OMD) is at least 5 minutes.

[0471] 63. The medication delivery apparatus of embodiment 62 wherein the dose profile is such that for all cumulative doses after 0.05% of the therapeutic dose, the order of magnitude delay (OMD) is at least 5 minutes.

[0472] 64. A method of delivering an infusion using the system or apparatus of any of embodiments 59 to 63 comprising using the infusion driver to drive fluid from an active agent chamber or source of pharmaceutical preparation into the diluent chamber causing the pharmaceutical preparation to mix with the diluent in the diluent chamber and simultaneously eject fluid through an outlet opening of the diluent chamber for delivery to the patient.

Claims

ClaimsWhat is claimed is:

1. A medication delivery apparatus comprising:(a) a syringe comprising a first plunger and a first container which together define an active agent chamber (for receiving a pharmaceutical preparation);(b) a second container comprising:(i) a first end having a first opening configured to receive at least a distal portion of the syringe, (ii) a second end having an outlet opening for delivering a mixture of diluent and pharmaceutical preparation to a patient,(iii) a second plunger movable within the second container between the first end and the second end, and(iv) a diluent chamber located between the second plunger and the second end;wherein at least a distal end of the syringe is insertable through the first opening of the second container to nest within the second container;wherein the apparatus has a flow path for allowing flow of fluid from the active agent chamber into the diluent chamber during use, whereby movement of the first plunger is operable to eject pharmaceutical preparation into the diluent chamber to mix with diluent and eject a mixture of pharmaceutical preparation and diluent through the outlet opening.

2. The medication delivery apparatus of claim 1 wherein the second container is removably secured to an infusion driver.

3. The medication delivery apparatus of claim 2 wherein, during use, the infusion driver is operable to: (i) advance the first plunger to deliver pharmaceutical preparation from the active agent chamber into the diluent chamber; and(ii) thereafter advance the syringe and the second plunger toward the second end to expel fluid from the diluent chamber through the outlet opening.

4. The medication delivery apparatus of any one of claims 1 to 3, wherein an initiation force required to start movement of the second plunger relative to the second container is greater than an initiation force required to start movement of the first plunger relative to the syringe, such that the syringe is substantially emptied before the syringe advances within the second container to drive the second plunger toward the second end.

5. The medication delivery apparatus of any one of the above claims wherein the second plunger comprises a valve configured to allow flow from the syringe into the diluent chamber, which may be a one-way valve configured to inhibit fluid from the diluent chamber into the syringe.

6. The medication delivery apparatus of any one of the above claims wherein a compressible foam insert is disposed in the diluent chamber.

7. The medication delivery apparatus of any one of the above claims wherein the second plunger comprises a pierceable seal configured to inhibit leakage of diluent from the diluent chamber prior to connection of the syringe, the seal being pierceable by a distal end of the syringe during assembly.

8. A medication delivery apparatus comprising:(a) a syringe comprising a first plunger and a first container which together define an active agent chamber for receiving a pharmaceutical preparation;(b) a second container including a diluent chamber, the second container having a first end with a first opening and a second end with an outlet opening;(c) wherein the second container is removably attachable to the first container to allow fluid communication between the active agent chamber and the diluent chamber during use; and(d) whereby movement of the first plunger in a distal direction is operable to eject pharmaceutical preparation from the active agent chamber into the diluent chamberto mix with diluent therein and eject a mixture of diluent and pharmaceutical preparation through the outlet opening to a patient, such that a concentration of the pharmaceutical preparation in the diluent chamber increases during an infusion process.

9. The medication delivery apparatus of claim 8 wherein a second plunger is positioned within the second container between the first end and the second end.

10. The medication delivery apparatus of claim 9 wherein the second plunger comprises a valve for allowing pharmaceutical preparation to flow into the diluent chamber, optionally configured to inhibit fluid from flowing from the diluent chamber into the syringe.

11. The medication delivery apparatus of any one of claims 8 to 10 wherein one or more partitions are disposed within the diluent chamber to separate the diluent chamber into two or more partition chambers.

12. A medication delivery apparatus comprising:(a) a container forming part of a syringe or configured to be attached to a syringe;(b) a plunger movable within the container;(c) a diluent chamber for containing diluent, the diluent chamber located between the plunger and a distal end of the container;(d) an outlet at the distal end of the container for delivery of fluid to a patient;(e) a flow path configured, during use, to allow pharmaceutical preparation to enter the diluent chamber; and(f) a compressible foam insert disposed in the diluent chamber, wherein the foam insert is positioned in a flow region between the plunger and the outlet.

13. The medication delivery apparatus of claim 12 wherien the foam insert comprises one or more partition portions arranged within the diluent chamber to define a plurality of partition chambers, and one or more spacer portions configured to (i) maintain a separation between adjacent partition portions in an initial state and / or (ii) maintain a position of a partition portion relative to the diluent chamber in an initial state.

14. The medication delivery apparatus of any one of claims 12 to 13 wherein the spacer portions have different compressibility and / or thickness.

15. The medication delivery apparatus of any one of claims 12 to 14 wherein the foam insert comprises a single piece of foam or a plurality of foam pieces stacked or arranged along a length of the diluent chamber.

16. The medication delivery apparatus of claim 12 the foam insert defines one or more channels or bores formed in the foam insert and extending at least part -way through the foam insert.

17. The medication delivery apparatus of claim 12 wherein the foam insert defines one or more voids configured to receive fluid during use.

18. The medication delivery apparatus of claim 12 wherein the foam insert has a non-uniform porosity and / or permeability along a flow direction through the diluent chamber.

19. The medication delivery apparatus of claim 12 wherein the foam insert comprises open-cell foam material, closed-cell foam material, or a combination thereof.

20. The medication delivery apparatus of claim 12 wherein the diluent chamber is filled with diluent (and if the foam insert is open-cell foam material the foam insert is saturated with diluent).

21. The medication delivery apparatus of claim 12 wherein the foam insert is configured such that at least a portion of the pharmaceutical preparation entering the diluent chamber passes through the foam insert before exiting the outlet.

22. A medical device for connection to the outlet of a syringe, the medical device comprising:(a) a container extending between a first end having an inlet opening and a second end having an outlet opening;(b) the inlet opening configured to receive at least a distal end of a syringe;(c) a plunger positioned between the first end and the second end of the container, wherein a space between the plunger and the second end of the container defines a diluent chamber for containing diluent; and(d) a hollow tube having a lumen in fluid communication with an aperture of the plunger and extending back from the plunger;the hollow tube being insertable into an outlet of a syringe and providing a conduit through which an active agent may be injected into the diluent chamber to mix with the diluent; andwherein the hollow tube is pushable to move the plunger towards the second end of the second container to force a mixture of diluent and active agent out of the diluent chamber through the outlet opening.

23. The medical device of claim 22 wherein the plunger comprises a valve arranged to control flow of fluid from the hollow tube and into the diluent chamber.

24. The medical device of claim 22 wherein the hollow tube extends between a proximal end and a distal end and has a side opening between the distal end and proximal end and in fluid communication with the lumen.

25. The medical device of claim 22 wherein there is an opening (airvent) in the second container between the first end of the container and an initial position of the plunger.

26. The medical device of claim 22 wherein the outlet opening at the second end of the second container comprises a bore connector and the inlet opening at the first end of the second container comprises a bore connector.

27. The medical device of claim 22 wherein a gasket seals a space between the hollow tube and the inlet opening.

28. The medical device of claim 22 wherein one or more partitions are disposed within the diluent chamber to separate the diluent chamber into a plurality of partition chambers.

29. The medical device of claim 28 wherein the partitions are movable so as to allow the partition chambers to be collapsed (e.g. sequentially) to evacuate fluid.

30. A dilution device for removable attachment to a syringe to dilute pharmaceutical preparation ejected by the syringe before delivery to a patient, the device comprising:(a) a container body having a first end with a first opening configured for removable attachment to the syringe and a second end with an outlet opening for delivering a mixture of diluent and pharmaceutical preparation to a patient;(b) a plunger movable within the container body;(c) a diluent chamber located between the plunger and the second end of the container body; and (d) a flow path configured to allow pharmaceutical preparation from the syringe to enter the diluent chamber during use,whereby a concentration of pharmaceutical preparation in the diluent chamber increases during infusion as pharmaceutical preparation enters and mixes with diluent therein.

31. The dilution device of claim 30 wherein the diluent chamber comprises one or more partitions which separate the diluent chamber into two or more partition chambers.

32. The dilution device of claim 30 wherein a compressible foam insert is disposed in the diluent chamber.

33. The dilution device of claim 30 wherein the flow path comprises a valve in the plunger configured to allow flow from the syringe into the diluent chamber, and optionally configured to inhibit fluid from the diluent chamber into the syringe.

34. The dilution device of claim 30 wherein at least one of the plunger and the container body comprises a bore connector configured to releasably connect to an outlet of a syringe.

35. The dilution device of claim 30 wherein the container body comprises an external clamp interface configured to be removably engaged by an infusion driver.

36. The dilution device of claim 30 wherein the first opening is configured to receive at least a distal portion of a syringe such that the syringe is received at least partially within the container body.

37. The dilution device of claim 30 wherein the diluent chamber is pre-filled with diluent.

38. The dilution device of claim 30 wherein a seal covers the first opening to inhibit leakage of diluent before use (the seal may be a foil).

39. The dilution device of claim 30 wherein the plunger comprises a pierceable seal configured to inhibit leakage of diluent from the diluent chamber prior to connection of the syringe, the seal being pierceable by a distal end of the syringe during assembly.

40. The dilution device of claim 30 wherein a hollow tube extends back from the plunger, the hollow tube having a lumen in fluid communication with an aperture of the plunger through which a pharmaceutical preparation may be injected into the diluent chamberto mix with the diluent.

41. The dilution device of claim 30 wherein the hollow tube is configured to extend into the outlet of a syringe and be contacted by a syringe plunger during use such that movement of the syringe plunger pushes the hollow tube to move the plunger of the dilution device towards the second end.

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