Valve stopper for a multi-chamber medical injection device

Abstract

Provided herein is a valve stopper positionable within a barrel of an injection device. The valve stopper includes a membrane comprising a proximal face and a distal face and that separates a first chamber and a second chamber of the barrel. A lateral wall is joined to the membrane that defines at least one cavity and provides a circumferential sealing surface that sealingly engages an inner surface of the barrel. The proximal face of the membrane presents a flat surface or a shaped surface protruding proximally, with the membrane including a slit that extends through at least a part of a thickness of the membrane and that is configured to selectively create a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a fluid onto the proximal face, for transferring fluid only from the second chamber to the first chamber.

Description

VALVE STOPPER FOR A MULTI-CHAMBER MEDICAL INJECTION DEVICECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 557,657 entitled “Valve Stopper for a Multi-Chamber Medical Injection Device” filed February 26, 2024 and United States Provisional Patent Application No. 63 / 670,017 entitled “Valve Stopper for a Multi-Chamber Medical Injection Device” filed July 11, 2024, the disclosures of which are hereby incorporated by reference in their entireties.BACKGROUND OF THE INVENTIONField of the Invention

[0002] The present disclosure relates generally to a valve stopper for a medical injection device containing doses of multiple fluids and, in particular, to a valve stopper for a medical injection device that provides sequential expulsion of a first or initial fluid, such as a first type of a medical fluid, followed by a secondary fluid, such as another type of medical fluid.Description of Related Art

[0003] Prefilled injection devices are common containers used to administer liquids (e.g., medications or drugs) to a patient and include syringes, cartridges and auto-injectors or the like. They usually comprise a plunger stopper in gliding engagement within a container, the container being filled with a pharmaceutical composition in order to provide the practitioners with a ready-to-use injection device for patients.

[0004] A container has a substantially cylindrical shape and comprises a proximal end able to be stoppered by a plunger stopper, a distal end wherein the pharmaceutical composition is expelled from the container, and a lateral wall extending between the proximal end and the distal end of the container. In practice, the plunger stopper is aimed at moving, upon the pressure exerted by a plunger rod, from a proximal end of the container towards the distal end of the container, thereby expelling the drug contained into the container.

[0005] When compared to empty injection devices that are filled with a vial-stored pharmaceutical composition just prior to the injection to the patient's body, the use of prefilled injection devices leads to several advantages. In particular, by limiting the preparation prior to the injection, the prefilled injection devices provide a reduction of medical dosing errors, a minimized risk of microbial contamination and an enhanced convenience of use for thepractitioners. Furthermore, such prefilled containers may encourage and simplify selfadministration by the patients which allows reducing the cost of therapy and increasing the patient adherence. Finally, prefilled injection devices reduce loss of valuable pharmaceutical composition that usually occurs when a pharmaceutical composition is transferred from a vial to a non-prefilled injection device. This results in a greater number of possible injections for a given manufacturing batch of pharmaceutical composition, thus reducing buying and supply chain costs.

[0006] Prefilled injection devices can be used to carry out the injection of a plurality of compositions or medicaments to a patient. In such case, the container may include two chambers, including a first chamber adapted to contain a first composition and a second chamber adapted to contain a second composition. The two chambers are separated by a second stopper that may be termed as a sequential stopper that prevents, when the prefilled injection devices is stored or transported, the compositions from passing from one chamber to the other and mixing.

[0007] In some prefilled injection devices that include multiple compositions for injection to a patient, the barrel of the injection device may be modified (from a typical cylindrical barrel) to include one or more bypass channels therein. The bypass channels may provide for a reconstitution of a lyophilized composition (with a composition first flowing through the bypass channel) and a subsequent injection of the reconstituted mixture and / or provide for a sequential injection of the compositions in the barrel (via initial injection of a first / distal composition and a subsequent injection of a second / proximal composition that flows through the bypass (when the stopper is moved distally past the bypass channel). However, it is recognized that the manufacturing of a barrel to include such bypass channels can greatly increase the manufacturing or packaging complexity and costs thereof.

[0008] In other prefilled injection devices that include multiple compositions for injection to a patient, the sequential stopper includes an opening or slit formed therein or therethrough that functions as a valve (i.e., a “valve stopper”) to prevent the mixing of the two solutions during storage or transportation, or before the first solution has been injected, while allowing subsequent injection of the second solution. Existing valve stoppers function to effectively prevent the mixing of the two solutions and provide for a sequential injection of the fluids; however, existing valve stoppers do present a number of drawbacks therewith. As one example, the configuration of the valve stopper may be such that a substantial force may need to be applied onto the plunger to force the second solution through the opening / slit therein andexpelling it out the injection device. As another example, the structure of the valve stopper may be complex - such as being configured as a multi-component stopper where a valve is separate from a stopper body - which may be detrimental for the functioning of the valve assembly and / or its manufacturing. As still another example, the design of existing valve stoppers may make the stoppers prone to tilting when being positioned within the container (e.g., during vent tube or vacuum stoppering) and / or during distal advancement thereof during use, so as to impact the valve stopper functionalities (i.e., prevent mixing of the two solutions and / or glide). As yet another example, existing valve stoppers may not be designed to properly resist external stresses applied thereto, such as shipment vibration, free fall, and pressure variation (e.g., during air shipment of the injection device) that might result in movement of the valve stopper.

[0009] Accordingly, a need exists in the art for an injection device that includes a typical cylindrical barrel and a valve stopper that addresses the aforementioned drawbacks.SUMMARY OF THE INVENTION

[0010] Provided herein is a valve stopper configured to be positioned inside a barrel of a multi-chamber injection device for injecting at least one fluid through a distal end of the barrel. The valve stopper comprises a membrane comprising a proximal face and a distal face, with the membrane being configured to separate a first, distal chamber of the barrel from a second, proximal chamber of the barrel. The valve stopper further comprises a lateral wall joined to the membrane to define at least one cavity, the lateral wall comprising a circumferential sealing surface configured to sealingly engage the inner surface of the barrel. The proximal face of the membrane presents a flat surface or a shaped surface protruding proximally, with the membrane comprising a slit extending through at least a part of a thickness of the membrane between the proximal face and the distal face, the slit configured to selectively create a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a fluid onto the proximal face of the membrane for transferring fluid only from the second chamber to the first chamber.

[0011] In certain configurations, the proximal face of the membrane presents a flat surface.

[0012] In certain configurations, the proximal face of the membrane presents a shaped surface comprising a convex surface.

[0013] In certain configurations, the proximal face of the membrane presents a shaped surface comprising a duckbill shape.

[0014] In certain configurations, the slit is in the form of a single continuous segment comprising a line or a curve.

[0015] In certain configurations, the slit further comprises two end segments formed at opposing ends of the single continuous segment and orthogonal thereto, such that the slit is an I- shaped slit.

[0016] In certain configurations, the slit further comprises two end segments formed at opposing ends of the single continuous segment, each of the end segments having a chevron shape.

[0017] In certain configurations, the slit comprises an X- shaped slit centered on the proximal face and / or distal face of the membrane.

[0018] In certain configurations, the slit comprises a Y-shaped slit centered on the proximal face and / or distal face of the membrane.

[0019] In certain configurations, the slit comprises a notch extending through only a portion of the thickness of the membrane, thereby delimiting a tear apart portion in the thickness of the membrane that is not traversed by the notch, the tear apart portion being configured to tear along the notch under a determined pressure exerted by the fluid to create the fluid path.

[0020] In certain configurations, the tear apart portion of the membrane forms a valve configured to open or close depending on the pressure exerted by the fluid onto the proximal face of the membrane.

[0021] In certain configurations, the slit extends completely through the membrane between the proximal face and the distal fare to form a split configured to open or close depending on the pressure exerted by the fluid onto the proximal face of the membrane.

[0022] In certain configurations, the distal face of the membrane presents one of a flat surface, a concave shape, a convex shape, or a duckbill shape extending away from the proximal face.

[0023] In certain configurations, the sealing surface comprises at least two ribs spaced apart along a length of the valve stopper.

[0024] Also provided herein is a multi-chamber medical injection device for injecting at least one fluid. The multi-chamber medical injection device comprises a barrel extending from a proximal end to a distal end, with the barrel comprising a cylindrical wall, an end wall positioned at the distal end, and a tip extending distally from the end wall. The multi-chamber medical injection device further comprises a plunger stopper adapted to be translationally movable inside the barrel, and a valve stopper arranged between the distal end of the barrel andthe plunger stopper, and adapted to be translationally movable inside the barrel. The valve stopper comprises a membrane comprising a proximal face and a distal face, with the membrane being configured to separate a first, distal chamber of the barrel from a second, proximal chamber of the barrel. The valve stopper further comprises a lateral wall joined to the membrane to define at least one cavity, the lateral wall comprising a circumferential sealing surface configured to sealingly engage the inner surface of the barrel. The proximal face of the membrane presents a flat surface or a shaped surface protruding proximally, with the membrane comprising a slit extending through at least a part of a thickness of the membrane between the proximal face and the distal face, the slit configured to selectively create a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a fluid onto the proximal face of the membrane for transferring fluid only from the second chamber to the first chamber. The lateral wall of the valve stopper sealingly engages the inner surface of the barrel, with a first chamber defined within the barrel between the distal end of the barrel and the valve stopper and a second chamber defined within the barrel between the valve stopper and the plunger stopper.

[0025] In certain configurations, the multi-chamber medical injection device is configured to sequentially inject two fluids, with a first fluid contained within the first chamber and a second fluid contained within the second chamber, and wherein the valve stopper is spaced apart distally from the end wall to separate the first chamber from the second chamber.

[0026] In certain configurations, a powder is contained within the first chamber and a fluid is contained within the second chamber, and wherein the valve stopper is spaced apart distally from the end wall to separate the first chamber from the second chamber.

[0027] In certain configurations, the valve stopper is configured so that the membrane is positioned at or adjacent a distal end of the valve stopper, with the lateral wall extending proximally from the membrane.

[0028] In certain configurations, the multi-chamber medical injection device is configured to inject a single fluid, with the single fluid contained within the second chamber, and wherein the valve stopper is positioned to abut the end wall, so that the first chamber comprises a channel within the tip, the first chamber being empty.

[0029] In certain configurations, the valve stopper is configured so that the membrane is positioned at a proximal end of the valve stopper, with the lateral wall extending distally from the membrane.

[0030] In certain configurations, the valve stopper is configured so that the membrane is positioned toward a distal end of the valve stopper, but inset from a distal edge, with the lateral wall extending both proximally and distally from the membrane.

[0031] In certain configurations, the multi-chamber medical injection device is one of a syringe or a cartridge.

[0032] Also provided herein is a pre-filled medical injection device for sequentially injecting a first liquid and a second liquid. The pre-filled medical injection device comprises a barrel extending from a proximal end to a distal end and including a cylindrical wall having a barrel inner diameter, a plunger stopper adapted to be translationally movable inside the barrel, and a valve stopper arranged between the distal end of the barrel and the plunger stopper and adapted to be translationally movable inside the barrel. The valve stopper further comprises a membrane configured to separate a distal chamber of the barrel from a proximal chamber of the barrel and including at least one slit extending through at least a part of a thickness of the membrane between a proximal face and a distal face thereof, with the slit configured to selectively create a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a composition onto the proximal face of the membrane for transferring fluid only from the proximal chamber to the distal chamber, along with a lateral wall joined to the membrane to define at least one cavity, the lateral wall comprising a sealing surface including one or more circumferential ribs configured to sealingly engage the inner surface of the barrel. The pre-filled medical injection device also includes a first liquid contained within the distal chamber comprising a GLP- 1 agonist and a second liquid contained within the proximal chamber comprising an amyline analog.

[0033] In certain configurations, the GLP-1 agonist comprises a calcitonin receptor agonist and the amyline analog comprises a dual amylin.

[0034] In certain configurations, the GLP-1 agonist comprises semaglutide and the amyline analog comprises cagrilintide.

[0035] In certain configurations, the valve stopper presents the successive following positions during a sequential injection: a first position where the fluid path is closed; a second position where the valve stopper is more distal than in the first position, where the fluid path closed, with the proximal face of the membrane being subjected to a pressure that is inferior to a valve opening force of the at least one slit; and a third position, wherein the valve stopper abuts the distal end of the barrel, the fluid path being opened due to a pressure exerted on the proximal face of the membrane that is superior to the valve opening force of the at least oneslot; wherein the first liquid is injected as the valve stopper moves from the second position to the third position; and wherein the second liquid is injected responsive to further distal movement of the plunger stopper with the valve stopper at the third position.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1 is a perspective view of a multi-chamber medical injection device, according to a non-limiting embodiment described herein;

[0037] FIG. 2 is an exploded view of the multi-chamber medical injection device of FIG. 1;

[0038] FIG. 3 is a perspective view of a valve stopper for use in a medical injection device, according to a non-limiting embodiment described herein;

[0039] FIG. 4 is a sectional general view of the valve stopper of FIG. 2;

[0040] FIG. 5 is a sectional general view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0041] FIG. 6 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0042] FIG. 7 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0043] FIG. 8 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0044] FIG. 9 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0045] FIG. 10 is a is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0046] FIG. 11 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0047] FIG. 12 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0048] FIG. 13 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0049] FIG. 14 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0050] FIG. 15 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0051] FIG. 16 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0052] FIG. 17 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0053] FIG. 18 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0054] FIGS. 19A-19D illustrate various configurations of the injection device of FIG. 1 during injection of first and second compositions from the device;

[0055] FIGS. 20A-20C illustrate various configurations of an injection device during injection of a single composition from the device, according to another non-limiting embodiment described herein;

[0056] FIG. 21 is a cross-sectional view of a multi-chamber medical injection device, according to another non-limiting embodiment described herein;

[0057] FIG. 22 is a cross-sectional view of a multi-chamber medical injection device, according to another non-limiting embodiment described herein;

[0058] FIG. 23 is a cross-sectional view of a multi-chamber medical injection device, according to another non-limiting embodiment described herein; and

[0059] FIG. 24 is a cross-sectional view of a multi-chamber medical injection device, according to another non-limiting embodiment described herein.DESCRIPTION OF THE INVENTION

[0060] The following description is provided to enable those skilled in the art to make and use the described embodiments contemplated for carrying out the invention. Various modifications, equivalents, variations, and alternatives, however, will remain readily apparent to those skilled in the art. Any and all such modifications, variations, equivalents, and alternatives are intended to fall within the spirit and scope of the present invention.

[0061] For purposes of the description hereinafter, the terms “upper”, “lower”, “right”, “left”, “vertical”, “horizontal”, “top”, “bottom”, “lateral”, “longitudinal”, and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume various alternative variations, except where expressly specified to the contrary. It is also to be understood that the specific devices illustrated in the attached drawings, and described in the following specification, are simply exemplary embodiments ofthe invention. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.

[0062] In the present disclosure, the distal end of a component or of a device means the end furthest away from the hand of the user and the proximal end means the end closest to the hand of the user, when the component or device is in the use position, i.e., when the user is holding a syringe or other injection device in preparation for or during use. Similarly, in this application, the terms "in the distal direction" and "distally" mean in the direction toward the distal tip of the syringe, and the terms "in the proximal direction" and "proximally" mean in the direction opposite the direction of the distal tip of the syringe.

[0063] With reference to the figures, the present disclosure is directed to a valve stopper 10 for use with a multi-chamber medical injection device 100 (“injection device 100”), with it understood that the term “injection device” as used herein is meant to refer to a syringe used for a direct injection (“naked syringe”), or to a syringe or cartridge that may be used with an injection device (i.e., an auto-injector or pen, or another safety device), as non-limiting examples. The valve stopper 10 is configured to divide a container, such as a syringe barrel or cartridge, into a distal chamber, which contains a first or initial fluid to be injected to a patient, and a proximal chamber, which contains a subsequent or secondary fluid to be delivered to the patient after the initial fluid. The valve stopper 10 comprises a slit therein that functions as a built-in check valve that allows the secondary fluid contained in the proximal chamber of the injection device 100 to pass through the valve stopper 10 only after the initial fluid is expelled from a distal chamber of the injection device 100. Accordingly, the multi-chamber injection device 100 of the present disclosure can be used for fluid delivery of multiple medical fluids through a needle cannula inserted into a patient with only one needle stick and no additional fluid delivery steps to be performed by the practitioner. In other examples, the multi-chamber injection device 100 of the present disclosure can allow for delivery of multiple medical fluids to a patient in sequence through a VAD without needing to attach multiple syringes or fluid containers to the VAD.

[0064] As described in further detail herein, the valve stopper 10 is structured to prevent mixing of the two fluids before complete injection of the first fluid, while also allowing for injection of the second solution through the valve stopper without requiring an excessive force to be applied to a proximal face of the valve stopper to open the slit therein. As an example, the valve stopper 10 is constructed such that an amount of force that must be applied to a plunger rod of the injection device to open the slit of the valve stopper may be reduced, ascompared to existing multi-chamber medical injection devices that include a valve stopper. The valve stopper may further be structured to better resist to bi-directional stresses that may be applied thereto when a pre-filled, multi-chamber injection device is shipped and stored in a pre-injection configuration, such as external stresses applied from shipment vibration, free fall, and / or pressure variation (e.g., pressure drop during air shipment), so as to prolong a shelf-life of the injection device.

[0065] The present disclosure is also directed to features of a prefilled multi-chamber injection device 100 including the valve stopper 10. In particular, the multi-chamber injection device 100 can be configured to expel the initial fluid followed by the secondary fluid from a syringe barrel or cartridge through a fluid port or nozzle of the injection device 100. As previously described, the initial fluid can be a medical fluid, which, as used herein, can refer to a medication or another therapeutic agent used for treatment of chronic or acute conditions, as are known in the art. Exemplary therapeutic agents can include, for example, drugs, chemicals, biological, or biochemical substances that, when delivered in a therapeutically effective amount to the patient, achieve a desired therapeutic effect. The secondary fluid can be another medical fluid, such as another type of therapeutic agent or drug. The secondary fluid can also be a flush solution, such as saline, a heparin lock flush solution, or another flush solution, as are known in the art.

[0066] The injection device 100 of the present disclosure allows a practitioner, such as a medical technician, nurse, physician assistant, physician, or other trained or untrained clinicians or a patient themselves (when used with an auto-injector), to administer the initial fluid followed by the secondary fluid without needing to change syringes or fluid containers between delivery of the initial fluid and the secondary fluid. Further, the injection device 100 of the present disclosure allows the practitioner to provide the sequential delivery of the initial fluid followed by the secondary fluid through a single continuous advancement of a plunger rod of the injection device 100. As used herein, “single continuous advancement of a plunger rod” means that the practitioner is able to push the plunger rod in a distal direction, through the barrel, as a single continuous stroke to expel the initial fluid followed by the secondary fluid from the syringe barrel. The practitioner does not need, for example, to perform multiple needle sticks or to disconnect a syringe or another device from the VAD between delivery of the initial fluid and the secondary fluid. Further, using the injection device 100 of the present disclosure, the practitioner does not need to perform any other action, such as twisting, rotating, or pulling on the plunger rod or pressing another component or mechanism of the injectiondevice 100, in order to perform the sequential delivery of the initial fluid and the secondary fluid. Accordingly, the fluids can be expelled from the injection device 100 in sequence in response solely to the single continuous stroke of the plunger rod in the distal direction by the practitioner, which can be performed as a “single-handed” operation or movement (i.e., the practitioner can hold the injection device 100 and press the plunger rod through the barrel with one hand). Accordingly, the injection device 100 of the present disclosure simplifies processes for administering the initial fluid followed by the secondary fluid to a VAD and / or patient compared to conventional fluid delivery practices.

[0067] FIGS. 1 and 2 illustrate an example of a multi-chamber injection device 100 for sequential expulsion of at least an initial fluid Fl contained in a first or distal fluid chamber 102 (shown in FIGS. 19A and 15B) followed by a secondary fluid F2 contained in a second or proximal fluid chamber 104 (shown in FIGS. 19A-19D). In the illustrated embodiment, the injection device 100 is provided as a syringe, and is thus referred to hereafter as “syringe 100”; however, it is recognized that the injection device could also be provided as a cartridge useable in a pen, according to another non-limiting embodiment.

[0068] As previously described, the initial fluid Fl can be a medical fluid, such as a drug or another therapeutic agent intended for delivery to a patient through a needle cannula or through a VAD, such as a catheter or IV line. The secondary fluid F2 can be another type of therapeutic agent, or a flush solution such as saline solution, and / or an anticoagulant such as heparin. The first fluid Fl and second fluid F2 may have similar or dissimilar properties, including a concentration, viscosity, and / or pressure of the fluids, as non-limiting examples, and the fluid in each chamber could be with a different volume injected in term of dose delivered. The type and amount of solution contained in the proximal chamber 104 and / or the distal chamber 102 may vary depending, for example, on the specific type of needle cannula, catheter, or IV line being used for an injection and / or on the therapeutic effect to be achieved. In some examples, the syringe 100 contains or is configured to contain between about 0.1 mL and 20 mL of the initial fluid Fl and / or the secondary fluid F2.

[0069] In some examples, the syringe 100 comprises a barrel 106 having an open proximal end 108 and a distal end 110. The barrel 106 may be formed of a cylindrical sidewall 112 extending between the proximal end 108 and the distal end 110, along with an end wall 114 and a tip 116 at the distal end 110. The tip 116 may include a channel (not shown) formed therein within which a needle cannula 118 is secured, with the needle 118 providing for injection of the initial fluid Fl and the secondary fluid F2 from the barrel 106. In otherembodiments, the tip 116 may be configured as a needleless connector configured to be connected directly or indirectly to a fluid port, valve, or another terminal access portion of a vascular access device (VAD).

[0070] The syringe 100 further comprises a plunger assembly 120 that includes a plunger rod 122 and a plunger stopper 124. The plunger rod 122 can be a conventional plunger rod used in currently available syringes. The plunger rod 122 can be, for example, an injection molded part formed from a rigid thermoplastic material, such as polyester, polycarbonate, polypropylene, polyethylene, polyethylene terephthalate, or another thermoplastic material, or may be formed of wood or metal, as are known in the art. In some embodiments, the plunger rod 122 can be connected to the plunger stopper 124 by mechanical connectors, threads, fasteners, or adhesives, while in other examples the plunger rod 122 can be integrally formed or co-molded with the plunger stopper 124. In an exemplary embodiment, the plunger rod 122 includes a distal end 126 engaged to the plunger stopper 124. For example, as most clearly seen in FIG. 2, the distal end 126 of the plunger rod 122 can include a threaded connector 128 that is inserted into a corresponding cavity (not shown) extending inwardly from a proximal surface of the plunger stopper 124. The plunger rod 122 also includes a proximal end 130 protruding proximally from the proximal end 108 of the syringe barrel 106. The proximal end 130 of the plunger rod 122 can include a thumb press plate 132 for manipulating the plunger rod 122 to move the plunger stopper through the syringe barrel 106.

[0071] The plunger stopper 124 may include many features of conventional syringe stoppers or plungers, as are known in the art. That is, the plunger stopper 124 can be a substantially cylindrical body formed from a flexible and / or deformable material, such as an elastomer, or a thermoplastic elastomer material. Examples of elastomers and thermoplastic elastomers include, but are not limited to, silicone or synthetic or natural rubber (e.g., isoprene), or combinations thereof. The plunger stopper 124 can include radially extending ribs or rings 134 that seal against an inner surface 136 of the syringe barrel 106 so that the plunger stopper 124 can move fluids through the syringe barrel 106 towards the distal end 110 of the barrel 106. In some examples, the plunger stopper 124 includes one or multiple annular ribs 134 (e.g., at least one, two or three ribs) in order to improve stability and to prevent the plunger stopper 124 from tilting, shifting, or otherwise deforming as the plunger stopper 124 moves through the syringe barrel 106, and to prevent microbial contamination of the internal volume of the barrel.

[0072] As indicated above, the syringe 100 further comprises a valve stopper 10 slidably positioned within the barrel 106 of the syringe 100. The valve stopper 10 separates the barrel106 into the proximal chamber 104 and the distal chamber 102. Specifically, as shown most clearly in FIG. 19A, the proximal chamber 104 is between a distal end of the plunger stopper 124 and a proximal end of the valve stopper 10 and the distal chamber 102 is between a distal end of the valve stopper 10 and the distal end 110 of the barrel 106.

[0073] According to aspects of the disclosure, the valve stopper 10 is structured to prevent mixing of the second fluid initially contained in the proximal chamber 104 with the first fluid initially contained in the distal chamber 102 before complete injection of the first fluid. The valve stopper 10 may be moved distally through the barrel 106 responsive to a distal movement of the plunger stopper 124, with the valve stopper 10 moving in coordination with the plunger stopper 124, even though the stoppers 10 and 124 are not mechanically connected or engaged together. The valve stopper 10 further enables injection of the second fluid through the valve stopper 10 without requiring an excessive force to be applied to the plunger rod 122, as explained in further detail below. The valve stopper 10 may function as a one-way check valve for selectively controlling fluid flow between the proximal chamber 104 and the distal chamber 102. As used herein, a one-way check valve refers to a valve that allows a flow of fluid through the valve in only one direction. For example, the valve stopper 10 can be configured to permit fluid flow from the proximal chamber 104 to the distal chamber 102, while fluid flow from the distal chamber 102 to the proximal chamber 104 is prevented.

[0074] Referring now to FIGS. 3 and 4, shown is a non-limiting embodiment of a valve stopper 10 that may be included in injection device 100, according to one aspect of the disclosure. The valve stopper 10 generally comprises a membrane 12, and a lateral wall 14. The lateral wall 14 may extend proximally, distally, or both proximally and distally from the membrane 12 to define one or more cavities 16, with each cavity comprising a hollow volume delimited by an inner face 18 of the lateral wall, along with a proximal face 20 and / or a distal face 22 of the membrane 12.

[0075] In the embodiment represented in FIGS. 3 and 4, the membrane 12 is positioned at a distal end 23 of the valve stopper 10, such that the lateral wall 14 extends in the proximal direction only from the membrane 12, and the cavity 16 is delimited by the inner face 18 of the lateral wall 14 and the proximal face 20 of the membrane 12 that constitutes the bottom of the cavity 16.

[0076] According to another embodiment, and as shown in FIG. 5, the valve stopper 10 may be configured such that the lateral wall 14 extends both proximally and distally from the membrane 12. According to the embodiment of FIG. 5, the membrane 12 may be positionedso as to be offset proximally from the distal end 23 of the valve stopper 10, such that the lateral wall 14 extends both proximally and distally therefrom to provide two separate respective cavities 16, including a proximal cavity delimited by the inner face 18 of the lateral wall 14 and the proximal face 20 of the membrane 12, and a distal cavity delimited by the inner face 18 of the lateral wall 14 and the distal face 22 of the membrane 12. The membrane 12 may be positioned closer to the distal end 23 of the valve stopper 10 than the proximal end 31, such that the cavity 16 distal from the membrane 12 is smaller than the cavity 16 proximal from the membrane 12.

[0077] The valve stopper 10 may be made of any material with elastomeric properties usually used to manufacture stoppers for medical injection devices. For example, the valve stopper 10 may be made of elastomer, rubber, thermoplastic elastomer, or liquid silicon rubber. In an exemplary embodiment, the valve stopper 10 is formed as a single, integral component (i.e., the membrane 12 and lateral wall 14 are integrally formed) and of a single material (i.e., a mono-component and mono-material stopper), with the elastomeric properties of the valve stopper 10 allowing for flexing and / or deformation of the membrane 12 thereof. According to some non-limiting embodiments, the membrane 12 of the valve stopper 10 may have a thickness that is between 0.2-7 mm, depending on the configuration / shape of the membrane (e.g., flat, convex, concave or other shaped face and a sizing of the valve stopper 10 (e.g., 1, 10 or 20 mL stopper), to provide for deflection / deformation thereof when forces are applied to the membrane 12. In the region of the membrane 12 that is collapsible or deformable (i.e., generally, a region that includes a slit 28 therein), the thickness of the membrane will preferably be from 0.2 to 3.0 mm.

[0078] As shown in FIGS. 3 and 4 (and FIG. 5), the valve stopper 10 has a substantially cylindrical shape, which corresponds to the shape of the barrel 106 of the injection device in which the valve stopper 10 is intended to be inserted. Accordingly, the lateral wall 14 of the valve stopper 10 has a generally cylindrical or tubular construction. The lateral wall 14 is provided with an outer sealing surface 24 configured to sealingly engage the inner surface 136 of the barrel 106. The sealing surface 24 is continuous, which means that it extends continuously about the circumference of the valve stopper 10 and forms a ring. Since the continuous surface extends between the outer face of the lateral wall 14 of the valve stopper 10 and the inner surface 136 of the barrel 106 of the injection device 100, any passage of a composition between the valve stopper 10 and the barrel 106 is prevented. Optimal sealing is thus ensured.

[0079] According to a preferred embodiment, the sealing surface 24 may comprise one or more sealing ribs 26. The number of ribs 26 as well as the dimensions of each rib 26, such as height, width, and the distance between two adjacent ribs, may be adapted to as to further optimize the sealing depending on the dimensions of the valve stopper 10 and the barrel 106. According to the illustrated embodiment, the valve stopper 10 comprises two ribs 26. The inclusion of two ribs 26 on sealing surface 24 reduces the contact surface between the lateral wall 14 of the valve stopper 10 and the inner surface 136 of the barrel 106 of the injection device 100, compared to a plane lateral wall of the valve stopper 10, thus improving the gliding performance of the valve stopper 10 relative to the barrel 106. As a result, the force that needs to be exerted onto the valve stopper 10 for displacing it inside the barrel 106 is reduced, which makes the injection easier for the user. Additionally, the inclusion of the pair of spaced apart ribs 26 on valve stopper 10 increases the stability of the valve stopper 10 during insertion thereof into barrel 106 (e.g., during vent tube stoppering) and during injection of the first fluid.

[0080] In some embodiments, and as shown in FIGS. 4 and 5, the valve stopper 10 may further include films, coatings, layers, or other barriers on distal- and proximal-facing sides thereof. Specifically, the valve stopper 10 may include a first or distal barrier film 27 applied to a distal-facing side of the valve stopper 10 and a second or proximal barrier film 29 applied to a proximal-facing side of the valve stopper 10. In some embodiments, the first or distal barrier film 27 may be applied to the distal face 22 of the membrane and a distal-most rib 26. In some embodiments, the second or proximal barrier film 29 may be applied to the proximal face 20 of the membrane and to the inner face 18 of the lateral wall 14 that defines the cavity 16. The barrier films 27, 29 can be formed from the same or different materials, with the material(s) being biocompatible and inert, so as to not exhibit detrimental effects to the therapeutic agents or other medical solutions in the syringe barrel 106. Thus, according to nonlimiting embodiments, the barrier films 27, 29 can optionally be formed from a fluoropolymer material, such as a polymer formed from a polytetrafluoroethylene resin (PTFE), an ethylenetetrafluoroethylene resin (ETFE), expanded polytetrafluoroethylene (ePTFE), or may be formed from an alternative to a fluropolymer, such as an ultra-high-molecular-weight polyethylene (UHMWPE), silicone, or a thermoplastic elastomer (TPE) free of per- and poly- fluoroalkyl substances (PFAS). Alternatively, gliding properties and integrity of the valve stopper 10 may be ensured without any film.

[0081] According to aspects of the disclosure, the proximal face 20 of the membrane 12 may present a flat or planar surface, as shown in FIGS. 3-5, or a “shaped” surface that extends orprotrudes proximally. When presenting a shaped surface, the proximal face 20 of the membrane 12 may comprise a convex shape or a duckbill shape that protrudes proximally, as non-limiting examples.

[0082] The term “convex”, as relates to a face of the membrane 12, means that the face is curved and that the apex of the curvature extends away from a plane orthogonal to the distal- proximal direction and comprising the middle of the thickness of the membrane 12 in the thinnest region thereof (see, for example, the plane P in FIG. 6). Hence, the apex of the curvature of the proximal face 20 of the membrane 12, presenting a convex shape, extends away from the distal face 22 of the membrane 12.

[0083] The term “duckbill”, as relates to a face of the membrane 12, means that the face includes first and second protrusions or “flaps” positioned and shaped to form a face having a shape like the beak of a duck, i.e., a tapered shaped. The proximal face 20 will thus have flaps with opposed, sloping / tapered surfaces that meet together at a proximal end of the flaps.

[0084] While the proximal face 20 of the membrane 12 may present a flat / planar surface or a proximally shaped surface, the distal face 22 of the membrane 12 may similarly present a flat or planar surface or a “shaped” surface that extends or protrudes proximally or distally. When presenting a shaped surface, the distal face 22 of the membrane 12 may comprise a convex shaped, concave shape or a duckbill shape, as non-limiting examples. The term “concave”, as relates to a face of the membrane 12, means that the face is curved and that the apex of the curvature is directed towards the plane P.

[0085] FIGS. 6-9 present non-limiting embodiments of various constructions of the membrane 12 that may be included on the valve stopper 10, including the constructions of the proximal face 20 and distal face 22 thereof. While FIGS. 6-9 illustrate that the membrane 12 is provided at the distal end 23 of the valve stopper 10, it is recognized that other embodiments may have the membrane 12 at the proximal end 31 of the valve stopper 10, or at a location between the distal and proximal ends, according to embodiments of the disclosure.

[0086] FIG. 6 illustrates a membrane 12 having a convex proximal face 20 and a flat distal face 22.

[0087] FIG. 7 illustrates a membrane 12 having a duckbill- shaped proximal face 20 and a flat distal face 22.

[0088] FIG. 8 illustrates a membrane 12 having a flat proximal face 20 and a duckbill- shaped distal face 22.

[0089] FIG. 9 illustrates a membrane 12 having a convex proximal face 20 and a concave distal face 22.

[0090] Referring now to FIGS. 10-13, still additional embodiments of a valve stopper 10 are shown. The valve stopper in each of the embodiments of FIGS. 10-13 is similar to the valve stopper 10 of FIG. 5, in that the membrane 12 is positioned so as to be offset from the distal end 23 and the proximal end 31 of the valve stopper 10, such that the lateral wall 14 extends both proximally and distally from the membrane 12. However, in the embodiments of FIGS. 10-13, the valve stopper 10 is configured as a “symmetrical stopper,” where the membrane 12 is identically shaped on both sides - i.e., the proximal face 20 and distal face 22 are symmetrical - and the membrane 12 is centered lengthwise between the distal end 23 and the proximal end 31.

[0091] Referring first to FIGS. 10 and 11, valve stoppers 10 are shown where a symmetrical membrane 12 is centered lengthwise between the distal end 23 and the proximal end 31 and where the membrane 12 has a flat proximal face 20 and flat distal face 22. In the embodiment of FIG. 10, the valve stopper 10 includes two annular ribs 134, with the membrane 12 positioned at a lengthwise location equidistant between the two ribs 134. In the embodiment of FIG. 11, the valve stopper 10 includes three annular ribs 134, with the membrane 12 positioned at a lengthwise location that is aligned with the center rib 134.

[0092] Referring next to FIGS. 12 and 13, valve stoppers 10 are shown where a symmetrical membrane 12 is centered lengthwise between the distal end 23 and the proximal end 31 and where the membrane 12 has a convex proximal face 20 and convex distal face 22. In the embodiment of FIG. 12, the valve stopper 10 includes two annular ribs 134, with the membrane 12 positioned at a lengthwise location equidistant between the two ribs 134. In the embodiment of FIG. 13, the valve stopper 10 includes three annular ribs 134, with the membrane 12 positioned at a lengthwise location that is aligned with the center rib 134.

[0093] It is recognized that the proximal face 20 may be constructed to have other shapes not specifically shown herein, including a cross-shaped protrusion that extends proximally from the proximal face 20, as a non-limiting example.

[0094] In any / all of the embodiments of the valve stoppers 10 shown in FIGS. 3-13, the membrane 12 comprises a slit 28 formed therein for permitting fluid flow through the membrane 12 when the slit is in an open position / configuration. The slit 28 extends through at least a part of the thickness of the membrane 12 between the proximal face 20 and the distal face 22 of the membrane 12 and is configured to create a fluid path 30 through the membrane12 from the proximal face 20 to the distal face 22 of the membrane 12 when the slit 28 is opened.

[0095] According to aspects of the disclosure, the slit 28 is configured to transition between a closed position, where fluid flow through the membrane 12 is prevented, and an open position, where fluid flow through the membrane 12 can occur, thereby establishing fluid communication between the proximal chamber 104 and the distal chamber 102 through the valve stopper 10. In some examples, the valve stopper 10 can be configured to remain in the closed position when a fluid pressure P2 in the proximal chamber 104 of the syringe barrel 106 is below a predetermined opening force Fopof the slit 28 - which corresponds to the force / pressure that needs to be exerted onto the proximal face 20 of the membrane 12 for opening the slit 28. The slit 28 of valve stopper 10 can be configured to transition to the open position when the fluid pressure P2 in the proximal chamber 104 of the syringe barrel 106 is greater than or equal to the predetermined opening force Fopof the slit 28. In some examples, the slit 28 is biased to and initially provided in the closed position (i.e., maintained closed under radial compression of the valve stopper 10 within the barrel 106), meaning that when fluid pressure P2 in the proximal chamber 104 is nominal or is substantially equal to fluid pressure Pi in the distal chamber 102, the slit 28 is in the closed position. The slit 28 transitions to the open position when the fluid pressure P2 in the proximal chamber 104 substantially increases above the opening force Fopof the slit 28.

[0096] The activation or opening force Fopfor the slit 28 can be selected based on fluid pressures / forces that commonly occur when a stopper is manually moved through a barrel of a conventional syringe at a reasonable rate, as occurs when a practitioner pushes a plunger rod of a syringe through the syringe barrel. In some examples, the activation or opening force Fopfor the slit 28 may be between 2 N and 25 N, preferably between 2N and 20N, and even more preferably between 5N and 20N. However, it is recognized that the activation or opening force Fopcan be selected or optimized for different syringe designs taking into account, for example, the size, shape, and materials of the valve stopper 10, the syringe barrel 106, and other components of the multi-chamber syringe 10. In some examples, the syringe 10 is configured such that the activation or opening pressure for the slit 28 is greater than a pressure required to infuse the drug (i.e., the pressure required to expel the first fluid from the distal chamber 102 through the tip 116 and to the patient through the needle cannula and / or through the VAD). Accordingly, the practitioner may be required to apply a greater force to a plunger rod 122 of the syringe 10 connected to the plunger stopper 124 in order to cause the valve stopper 10 toopen than is required to move the valve stopper 10 (and plunger stopper 124) through the barrel 106. Due to these differences in the force that must be applied to the plunger rod 122, the practitioner can receive feedback (i.e., a feeling that increased force on the plunger rod is needed) indicating that the initial fluid has been expelled from the syringe 10 and that the valve stopper 10 is in its distal-most position in the barrel 106.

[0097] As previously described, the membrane 12 is a one-way membrane that functions as a check valve, which means that the membrane 12 is configured to allow a composition / fluid to pass through the membrane 12 via the open slit 28 only when the composition / fluid flows in the distal direction, i.e., the direction of injection. In other terms, the slit 28 is configured to open only for allowing the second fluid F2 in proximal chamber 104 to pass through the membrane 12 in a distal direction and into the distal chamber 102, while the first fluid Fl in distal chamber 102 may not pass through the membrane 12 in a proximal direction and into the proximal chamber 104. The slit 28 is configured to remain closed for preventing the first fluid Fl to pass through the membrane 12 in the proximal direction - i.e., flowing from where the fluid contacts the distal face 22 of the membrane 12 to where the composition contacts the proximal face 20 of the membrane 12.

[0098] According to embodiments of the disclosure, the flat surface and / or proximally shaped surface of the proximal face 20 of the membrane 12 sets the valve opening force Fop, for opening of the slit 28 at a desirable level, to enable the injection of a composition located proximally relative to the valve stopper 10, while allowing the valve to function as a check valve. Additionally, the flat surface and / or proximally shaped surface of the proximal face 20 of the membrane 12 allows the valve stopper 10 to better manage bi-directional stresses to which valve stopper may be exposed during a lifecycle of the injection device 100. That is, the valve stopper 10 will be exposed to various stresses that are not always oriented in one direction, i.e., uni-directionally oriented forces in the valve opening direction, but instead may be exposed to bi-directional stresses. Examples of bi-directional stresses to which the valve stopper 10 should be resistant include: shipment resistance, free fall resistance as per ISO11608 standard, resistance during syringe fill and finish processes as vacuum filling and / or stoppering (e.g., if done on proximal chamber 104).

[0099] As shown in FIGS. 3-13, in some embodiments, the slit 28 is formed to extend through an entirety of the membrane 12, between the proximal face 20 and the distal face 22 thereof, so as to form or provide a split 28a through the membrane 12. In some examples, the split 28a may be formed as a single continuous segment (e.g., line or curve) that extends acrossthe proximal face 20 (and down through to the distal face 20). The split 28a may be centered on the proximal face 20 or positioned off-center, according to various embodiments. In other examples, the split 28a can include multiple segments that collectively form a split of a desired configuration. In any configuration, the split 28a functions as a valve configured to open or close the fluid path 30 depending on the pressure exerted by a composition onto the proximal face 20 of the membrane 12, as described in detail above.

[0100] As shown in FIG. 14, in some embodiments, the split 28a is in the form of a straight line 32 passing through the center of the proximal face 20 of the membrane 12. In embodiments where the membrane 12 has a duckbill- shaped proximal face 20, the split 28a may be formed along a top (i.e., proximal end) of the flaps of the duckbill- shaped proximal face 20, with a line 32 along a length of the flaps, and the line 32 of the split 28a may also further extend down along a portion of the side surfaces of the duckbill- shaped proximal face 20.

[0101] As shown in FIG. 15, in another configuration, the split 28a includes a line portion 32, as well as a pair of end segments 34 on each of opposing ends of the line 32, with each end segment 34 comprising a linear segment that is oriented orthogonal to the line 32. The split 28a may thus be formed to have an “I” shape. This embodiment achieves a greater opening of the split 28a.

[0102] As shown in FIG. 16, in another configuration, the split 28a includes a line portion 32, as well as a pair of end segments 36 on each of opposing ends of the line, with each end segment 36 comprising a chevron- shaped segment. This embodiment again achieves a greater opening of the split 28a - i.e., allows a wide opening and then a gain to transfer with a lower liquid resistance when the second fluid F2 flows though the membrane 12.

[0103] As shown in FIG. 17, in another configuration, the split 28a may have a “X” shape, with a plurality of linear segments 38 that meet at a common center point.

[0104] As shown in FIG. 18, in another configuration, the split 28a may have a “Y” shape, with a plurality of linear segments 38 that meet at a common center point.

[0105] While the slit 28 is described above as a split 28a that extends through a full thickness of the membrane 12, between the proximal face 20 and the distal face 22 thereof, it is recognized that in other embodiments, the slit 28 may extend through only a part of the thickness of the membrane 12. In such embodiments, the membrane 12 is configured as a tearapart membrane that is configured to tear along the slit 28 under a determined pressure exerted by the composition, so as to create the fluid path 30 through the membrane 12 from the proximal face 20 to the distal face 22. To do so, the slit 28 forms a notch that is aligned withlocalized weakened zone in the membrane 12, i.e., a tear apart portion, which causes the membrane 12 to tear when a determined pressure is applied onto the proximal face 20 by the composition to be injected. When the tear apart portion is tom, the notch acts as a guide for the flow of the composition along the fluid path 30 thus formed. The tear apart portion forms a valve configured to open or close the fluid path 30 depending on the pressure exerted by the composition onto the proximal face 20 of the membrane 12. The depth of the notch is preferably comprised between about 20% to 100% of the thickness of the membrane 12, and more preferably between 25% and 35% of the thickness of the membrane 12.

[0106] Referring now to FIGS. 19A-19D, functioning of an injection device including a valve stopper 10 is illustrated, in accordance with an embodiment of the disclosure. In some embodiments, the injection device may be a pre-filled, multi-chamber syringe 100 as previously shown and described in FIGS. 1 and 2, including barrel 106, valve stopper 10 and a plunger assembly 120 (including plunger rod 122 and plunger stopper 124), with the syringe being manually actuated by a user. In other embodiments, the injection device may be a prefilled cartridge (stand-alone cartridge or integrated in an auto-injector or safety device), with the cartridge including barrel 106, valve stopper 10, and a plunger stopper 124.

[0107] As previously described, the injection device 100 enables the sequential delivery of an initial fluid Fl and a second fluid F2 through a single continuous advancement of a plunger rod 122 of the injection device 100. The first fluid Fl and second fluid may have similar or dissimilar properties, including a concentration, viscosity, and / or pressure of the fluids, as nonlimiting examples. The type and amount of solution contained in the proximal chamber 104 and / or the distal chamber 102 may vary depending, for example, on the specific configuration of the injection device 100 and / or on the therapeutic effect to be achieved. In some examples, the injection device 100 contains or is configured to contain between about 0.1 mL and 20 mL of the initial fluid Fl and / or the secondary fluid F2. Additionally, the structure of the valve stopper 10 - in particular membrane 12 - may be specifically configured based on properties of the fluids Fl, F2 contained within the syringe. That is, the pressure and / or viscosity of the fluids Fl, F2 may dictate the thickness of the membrane 12 and / or a configuration and sizing of the slit 28.

[0108] According to aspects of the disclosure, the first fluid Fl and the second fluid F2 may - in general - comprise a liquid-liquid combination of pharmaceuticals in one of a number of drug classes or categories designed to treat a recognized condition. Such drug classes orcategories may include analgesics, vitamins, vaccines (and boosters), monoclonal antibodies, diabetes and obesity treatments, and the like.

[0109] One exemplary embodiment of a liquid- liquid combination of a first fluid Fl and second fluid F2 that may be sequentially injected from the first chamber 102 and second chamber 104 comprises a fixed-dose combination of diabetes / obesity drugs - where the first fluid Fl and the second fluid F2 contained within the distal chamber 102 and the proximal chamber 104 of injection device may comprise a GLP-1 agonist and an amyline analog, respectively. The GLP-1 agonist may be a calcitonin receptor agonist, including any of Dulaglutide, Exenatide, Semaglutide, or Liraglutide, as non-limiting examples. The amyline analog may be dual amylin, including any of Cagrilintide or pramlintide, as non-limiting examples.

[0110] In one exemplary embodiment, the injection device 100 enables a delivery / injection of CagriSema to a patient, with the first fluid Fl comprising cagrilintide and the second fluid F2 comprising semaglutide, and with the cagrilintide and semaglutide being sequentially delivered / injected through a single continuous advancement of the plunger rod 122 of the injection device 100.

[0111] Injection of a medication / treatment such as CagriSema - where a GLP-1 agonist and an amyline analog are sequentially injected (via injection device 100) - is provided only a nonlimiting example, and it is recognized that other liquid-liquid combinations of a first fluid Fl and second fluid F2 may be sequentially injected from the first chamber 102 and second chamber 104 of the injection device 100. As indicated above, injection device 100 may also be utilized for sequential injections of other liquid-liquid combination of pharmaceuticals, including analgesics, vitamins, vaccines (and boosters), monoclonal antibodies, and the like.

[0112] FIG. 19A corresponds to the configuration of the injection device 100 before injection of the first fluid. In this configuration, the plunger stopper 124 is in a proximal position and the valve stopper 10 is in a rest position, with the slit 28 (i.e., split 28a or tear apart notch) being maintained closed under radial compression of the valve stopper, such that the fluid path 30 is closed. That is, when the valve stopper 10 is inserted in the barrel 106 of the injection device 100, the slit 28 is maintained closed under radial compression of the valve stopper 10, the valve stopper 10 being itself subjected to radial compression of the barrel 106. With the plunger stopper 124 in the proximal position, the pressure Pi in the distal chamber 102 and the pressure P2 in the proximal chamber 104 are substantially equal, such that the differential pressure AP=P2-PI is substantially null, and thus much lower than the valve opening force Fopof the slit28, so that the slit 28 thus remains closed. The closed slit 28 prevents the mixing of the first and second fluid, by preventing the first fluid from entering the proximal chamber 104 and the second fluid from entering the distal chamber 102. Additionally, the ribs 26 of the valve stopper 10 sealingly engage the inner surface 136 of the barrel 106, so that the first and the second fluids cannot pass from a chamber to another via a passage between the valve stopper 10 and the barrel 106.

[0113] According to aspects of the disclosure, the geometry of the membrane 12 allows for a prolonged shelf-life of the injection device 100 when in the pre-injection configuration of FIG. 19A. That is, with the membrane 12 having a proximal face 20 with a flat or proximally shaped configuration, the membrane 12 (and lateral wall 14) is / are resistant to bi-directional stresses that may be applied thereto when the injection device 100 is shipped and / or stored in its pre-injection configuration. A flat proximal face 20 brings, by definition, a balance profile on both sides of the valve stopper 10, so as to provide resistance to opening thereof from stress / liquid pressure on the deflectable area of the membrane 12, i.e., a resistance that is bidirectionally globally balanced. A convex proximal face 20 brings, by definition, a higher stress resistance with a threshold principle (resistance before deflection), to allow a resistance, for example, to the impact of an auto-injector rod on the proximal legacy stopper (i.e., plunger stopper 124). The membrane 12 (and lateral wall 14) is / are configured to resist external stresses that may be experienced by the injection device 100, such as shipment vibration, free fall, and pressure variation (e.g., pressure drop during air shipment of the injection device 100). Accordingly, the valve stopper 10 may exhibit an increased “break loose force” that is required to move the valve stopper 10 within barrel 106 during exposure to such external forces. Thus, as one example, the valve stopper 10 may remain closed / stationary during and after a free fall as defined by ISO Standard 11608.

[0114] Referring now to FIG. 19B, the injection device 100 is shown being actuated by a user to perform the injection of the first fluid. The force applied to the plunger stopper 124 is transmitted to the proximal chamber 104 and then to the valve stopper 10, which results in a pressure P2 exerted by the second fluid onto the proximal face 20 of the membrane 12 of the valve stopper 10 - which causes the valve stopper 10 to be advanced / displaced distally within barrel 106. The displacement of the valve stopper 10 in the distal direction pushes the first / initial fluid in the distal direction, so that the first / initial fluid is expelled from the injection device 100 through the channel 118 of tip 116.

[0115] In the configuration of FIG. 19B, the valve stopper 10 is in a sealing position, with the slit 28 remaining closed. That is, the displacement of the valve stopper 10 builds up pressure in the distal chamber 102, since the diameter of the channel 118 is much smaller than the diameter of the barrel 106. This increase of the pressure Pi not only forces the first fluid through the channel 118 for injection, but also applies force onto the distal face 22 of the membrane 12 of the valve stopper 10 in opposition to the displacement of the valve stopper 10. As a result, the valve stopper 10 is subjected to substantially equal and opposite pressures Pi and P2 respectively exerted by the first fluid and the second fluid onto the proximal face 20 and the distal face 22 of the membrane 12. As a consequence, the differential pressure AP is substantially null, and thus much lower than the valve opening force Foprequired to open the slit 28. During the displacement of the valve stopper 10, the differential pressure AP may not be substantially null but remains lower than the valve opening force Fopof the slit 28. The slit 28 thus remains closed. The injection continues until the valve stopper 10 abuts the end wall 114 at the distal end 108 of the barrel 106, as illustrated in FIG. 19B.

[0116] Referring now to FIG. 19C, the user continues to apply a distally directed force to the plunger stopper 124. Since the valve stopper 10 cannot move further distally, the pressure P2 in the proximal chamber 104 increases as the plunger stopper 124 continues to advance distally, and thus the force differential AP becomes superior to the valve opening force Fopof slit 28. As a result, the slit 28 in membrane 12 is caused to open (or a tear-apart portion is caused to tear), thereby allowing the second fluid to pass through the slit 28 and to / through the channel 118 in tip 116 for the injection. In this configuration, the valve stopper 10 is in an injection position.

[0117] As shown in FIG. 19D, at the end of the injection of the second fluid, the plunger stopper 124 abuts the valve stopper 10. At this stage, a fraction of the second fluid may remain in a “dead volume” of the proximal chamber 104 - i.e., within the cavity 16 of valve stopper 10, which is open to the proximal chamber 104. This fraction of the second fluid may be forced out from the proximal chamber 104 by collapsing the valve stopper 10 (i.e., collapsing the lateral wall 14) under the pressure exerted by the plunger stopper 124, which reduces the volume of the cavity 16, and the dead volume is thus injected.

[0118] As shown in the embodiment of FIGS. 19A-19D, the valve stopper 10 is oriented / arranged within the barrel 106 of injection device 100 such that the membrane 12 is at a distal end of the valve stopper 10. With the membrane 12 positioned as such, the valve stopper 10 may more easily be positioned within the barrel 106 during an initial insertion, suchas may be performed via a vent tube stoppering process. That is, with the membrane 12 positioned at the distal end of the valve stopper 10, an insertion rod (not shown) of a vent tube or vacuum stoppering system may be engaged with cavity 16, to proper for precise insertion of the valve stopper 10 within barrel 106 and to prevent tilting thereof during insertion.

[0119] Additionally, orienting of the valve stopper 10 within barrel 106 so that the membrane 12 is at a distal end of the valve stopper 10 allows for improved quality control and testing inspection of injection device via camera. That is, after drugs / fluids are filled into barrel 106, an inspection of the fluids is performed via a camera system 100%. The main steps of the inspection are performed with the syringe or cartridge “tip-up” (i.e., - distal side up). To ease this inspection and allow an accuracy check of the drug / fluid, it is desirable to have the drug / fluid fully visible (to avoid the drug / fluid being hidden in a cavity of the stopperlO), and the arrangement of the valve stopper 10 within barrel 106 so that the membrane 12 is at a distal end of the valve stopper 10 enables such full visibility of the drug / fluid.

[0120] While embodiments of the disclosure described above are directed to use of a valve stopper 10 in a multi-chamber injection device 100 for performing of a sequential injection of a first fluid and a second fluid therefrom, it is recognized that valve stopper 10 may also be used in an injection device 100 for the injection of a single fluid therefrom.

[0121] Referring now to FIG. 20A, inclusion of a valve stopper 10 (as previously described) in an injection device 100 for injecting a single fluid is illustrated, in accordance with another embodiment of the disclosure. The structure of injection device 100 may be identical to that previously described in FIGS. 19A-19C regarding barrel 106 (including end wall 114 and tip 116) and plunger stopper 124; however, the valve stopper 10 is initially positioned at the far distal end 108 of the barrel 106, so as to abut the end wall 114. In this position, the valve stopper 10 separates two “chambers” of the barrel 106, including a distal chamber 102 defined as the channel 118 within tip 116, and a proximal chamber 104 between the valve stopper 10 and the plunger stopper 124. In some embodiments, the distal chamber 102 (i.e., channel 118) may be empty, i.e., the “first fluid” in the distal chamber 102 is air, while the proximal chamber 104 contains a single pharmaceutical fluid.

[0122] As shown in FIG. 20A, the valve stopper 10 is oriented / arranged within barrel 106 such that the membrane 12 is at the proximal end of the valve stopper 10. In other embodiments, the valve stopper 10 may be constructed and arranged within barrel such that the membrane 12 is adjacent the distal end of the valve stopper 10, but proximally offset from a distal edge of the valve stopper 10, such as previously shown in FIG. 5. In eitherconfiguration / arrangement, the membrane 12 of the valve stopper 10 will be proximally offset from the end wall 114 of barrel 106, so as to allow for deflection / deformation of the membrane 12 for purposes of opening the slit 28 therein.

[0123] The functioning of the valve stopper 10 and the injection device comprising the valve stopper 10 will now be described herebelow, in reference to FIGS. 20A to 20C.

[0124] FIG. 20A corresponds to the configuration of the injection device 100 before injection of the single fluid. In this configuration, the plunger stopper 124 is in a proximal position and the valve stopper 10 is in a rest position, with the slit 28 being maintained closed under radial compression of the valve stopper 10, such that the fluid path 30 is closed. That is, when the valve stopper 10 is inserted in the barrel 106 of the injection device 100, the slit 28 is maintained closed under radial compression of the valve stopper 10, the valve stopper 10 being itself subjected to radial compression of the barrel 106. With the plunger stopper 124 in the proximal position, the pressure P2 in the in the proximal chamber 104 is much lower than the valve opening force Fopof the split, so that the slit 28 thus remains closed. The closed slit 28 prevents the single fluid from leaking into channel 118 of tip 116.

[0125] Referring now to FIG. 20B, the injection device 100 is shown being actuated by a user to perform the injection of the single fluid. The force applied to the plunger stopper 124 causes the pressure P2 in the proximal chamber 104 to increase as the plunger stopper 124 continues to advance distally, which results in a pressure P2 being applied by the single fluid onto the proximal face 20 of the membrane 12 of the valve stopper 10 that becomes superior to the valve opening force Fop. As a result, the slit 28 in membrane 12 is caused to open, thereby allowing the single fluid to pass through the slit 28 and to / through the channel 118 in tip 116 for the injection. In this configuration, the valve stopper 10 is in an injection position.

[0126] As shown in FIG. 20C, at the end of the injection of the single fluid, the plunger stopper 124 abuts the valve stopper 10. At this stage, a fraction of the single fluid may remain in a “dead volume” of the proximal chamber 104 - i.e., within the cavity 16 of valve stopper 10. This fraction of the single fluid may be forced out from the proximal chamber 104 by collapsing the valve stopper 10 (i.e., collapsing the lateral wall 14) under the pressure exerted by the plunger stopper 124, which reduces the volume of the cavity 16, and the dead volume is thus injected.

[0127] While embodiments of the injection device 100 described above include only a single valve stopper 10 therein, it is recognized that other embodiments of injection devices mayinclude one or more additional valve stoppers 10 therein - such that a multi-chamber injection device may be used to sequentially inject a plurality of different fluids.

[0128] Referring now to FIGS. 21 and 22, embodiments of a multi-chamber injection device 100 are shown that include two separate valve stoppers 10a, 10b therein for separating a plurality of fluids and allow for sequential injection of those fluids.

[0129] In FIG. 21, the multi-chamber injection device 100 includes a first valve stopper 10a and a second valve stopper 10b that - along with plunger stopper 124 and barrel 106 - define a first chamber 140 that contains a first fluid Fl, a second chamber 142 that contains a second fluid F2, and a third chamber 144 that contains a third fluid F3.

[0130] In an initial configuration before injection of the first fluid Fl, the plunger stopper 124 is in a proximal position and the valve stoppers 10a, 10b are in a rest position, with the slit 28 in each valve stopper 10a, 10b being maintained closed under radial compression thereof.

[0131] The injection device 100 may then be actuated by a user to perform the injection of the first fluid Fl - with a distally directed force applied to the plunger stopper 124. The force applied to the plunger stopper 124 is transmitted to the valve stoppers 10a, 10b via pressure from the second and third fluids F2, F3, which causes the stoppers 10a, 10b to be advanced / displaced distally within barrel 106. The displacement of the stoppers 10a, 10b in the distal direction pushes the first fluid Fl in the distal direction, so that the first fluid Fl is expelled from the injection device 100 through the channel 118 of tip 116. During expulsion of the first fluid Fl, the stoppers 10a, 10b remain in a sealing position - with the slit 28 in each valve stopper remaining closed. The injection of the first fluid Fl continues until the valve stopper 10a abuts the end wall 114 at the distal end 108 of the barrel 106.

[0132] The injection device 100 may then be actuated by a user to perform the injection of the second fluid F2 - with a distally directed force applied to the plunger stopper 124. Since the valve stopper 10a cannot move further distally, the pressure in the second chamber 142 increases as the plunger stopper 124 continues to advance distally, and thus the force differential AP becomes superior to the valve opening force Fopof slit 28 in the membrane 12 of first valve stopper 10a. As a result, the slit 28 in membrane 12 is caused to open, thereby allowing the second fluid F2 to pass through the slit 28 and to / through the channel 118 in tip 116 for the injection. At the same time that the second fluid F2 is flowing through slit 28 of valve stopper 10a, the valve stopper 10b is displaced in the distal direction. During expulsion of the second fluid F2, the stopper 10b remains in a sealing position. The injection of the second fluid F2 continues until the valve stopper 10b abuts the valve stopper 10a.

[0133] As the user continues to apply a further distally directed force to the plunger stopper 124, pressure in the third chamber 144 increases as the plunger stopper 124 continues to advance distally, and thus the force differential AP becomes superior to the valve opening force FOp of slit 28 in both the valve stoppers 10a, 10b. As a result, the slit 28 in the membrane 12 of each valve stopper 10a, 10b is caused to open, thereby allowing the third fluid F3 to pass through the slits 28 and to / through the channel 118 in tip 116 for the injection.

[0134] In FIG. 22, the multi-chamber injection device 100 includes a first valve stopper 10a and a second valve stopper 10b that - along with plunger stopper 124 and barrel 106 - define a first chamber 140 that remains empty, a second chamber 142 that contains a first fluid Fl, and a third chamber 144 that contains a second fluid F2. In this embodiment, valve stopper 10a is initially positioned at the far distal end 108 of the barrel 106, such that first chamber 140 is defined as the channel 118 within tip 116.

[0135] Operation of the injection device 100 in FIG. 22 may proceed similarly to as previously described for the injection devices of FIGS. 19A-19D, 20A-20C and 21, and thus is not described in detail herein.

[0136] Referring now to FIGS. 23 and 24, embodiments of a multi-chamber injection device 100 are shown that include three separate valve stoppers 10a, 10b, 10c therein for separating a plurality of fluids and allow for sequential injection of those fluids.

[0137] In FIG. 23, the multi-chamber injection device 100 includes a first valve stopper 10a, a second valve stopper 10b, and a third valve stopper 10c that - along with plunger stopper 124 and barrel 106 - define a first chamber 140 that contains a first fluid Fl, a second chamber 142 that contains a second fluid F2, a third chamber 144 that contains a third fluid F3, and a fourth chamber 146 that contains a fourth fluid F4.

[0138] Operation of the injection device 100 in FIG. 23 may proceed similarly to as previously described for the injection device of FIG. 21, except that an additional round of valve stopper advancement and opening is included, due to the additional valve stopper and fluid provided.

[0139] In FIG. 24, the multi-chamber injection device 100 includes a first valve stopper 10a, a second valve stopper 10b, and a third valve stopper 10c that - along with plunger stopper 124 and barrel 106 - define a first chamber 140 that remains empty, a second chamber 142 that contains a first fluid Fl, and a third chamber 144 that contains a second fluid F2, and a fourth chamber 146 that contains a third fluid F3.

[0140] Operation of the injection device 100 in FIG. 24 may proceed similarly to any of the previously described injection devices of FIGS. 19-23, and thus is not described in detail herein.

[0141] While the injections devices 100 shown and described in FIGS. 21-24 are illustrated as including valve stoppers 10 configured as “symmetrical stoppers” such as shown and described in FIG. 10, it is recognized that that the valve stoppers 10 may have any suitable description previously described in the present disclosure, including the valve stoppers 10 in any of FIGS. 3-18, according to embodiments of the disclosure.

[0142] Beneficially, embodiments of the invention thus are directed to a valve stopper and associated injection device. The valve stopper includes a membrane having a proximal face and a distal face, with the proximal face presenting a flat surface or a shaped surface protruding proximally, and with the membrane including a slit formed therein through at least a part of a thickness of the membrane that selectively creates a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a fluid onto the proximal face of the membrane. The membrane may thus provide for the sequential injection of multiple fluids from the injection device, with the membrane preventing mixing of the fluids. The configuration of the proximal face of the membrane as a flat or proximally shaped surface provides an acceptable opening force for the slit, and also provides stability for the membrane and valve stopper as a whole when in a pre-injection configuration, so as to ensure a resistance to external forces and a prolonged shelf life.

[0143] Although the present disclosure has been described in detail for the purpose of illustration based on what is currently considered to be the most practical and preferred embodiments or aspects, it is to be understood that such detail is solely for that purpose and that the present disclosure is not limited to the disclosed embodiments or aspects, but, on the contrary, is intended to cover modifications and equivalent arrangements that are within the spirit and scope of the appended claims. For example, it is to be understood that the present disclosure contemplates that, to the extent possible, one or more features of any embodiment may be combined with one or more features of any other embodiment.

Claims

THE INVENTION CLAIMED IS1. A valve stopper configured to be positioned inside a barrel of a multichamber injection device for injecting at least one fluid through a distal end of the barrel, the valve stopper comprising: a membrane comprising a proximal face and a distal face, the membrane being configured to separate a first, distal chamber of the barrel from a second, proximal chamber of the barrel; and a lateral wall joined to the membrane to define at least one cavity, the lateral wall comprising a circumferential sealing surface configured to sealingly engage the inner surface of the barrel; wherein the proximal face of the membrane presents a flat surface or a shaped surface protruding proximally, with the membrane comprising a slit extending through at least a part of a thickness of the membrane between the proximal face and the distal face, the slit configured to selectively create a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a fluid onto the proximal face of the membrane for transferring fluid only from the second chamber to the first chamber.

2. The valve stopper of claim 1, wherein the proximal face of the membrane presents a flat surface.

3. The valve stopper of claim 1, wherein the proximal face of the membrane presents a shaped surface comprising a convex surface.The valve stopper of claim 1, wherein the proximal face of the membrane presents a shaped surface comprising a duckbill shape.

5. The valve stopper of claim 1, wherein the slit is in the form of a single continuous segment comprising a line or a curve.

6. The valve stopper of claim 5, wherein the slit further comprises two end segments formed at opposing ends of the single continuous segment and orthogonal thereto, such that the slit is an I- shaped slit.

7. The valve stopper of claim 5, wherein the slit further comprises two end segments formed at opposing ends of the single continuous segment, each of the end segments having a chevron shape.

8. The valve stopper of claim 1, wherein the slit comprises an X- shaped slit centered on the proximal face and / or distal face of the membrane.

9. The valve stopper of claim 1, wherein the slit comprises a Y-shaped slit centered on the proximal face and / or distal face of the membrane.

10. The valve stopper of any of claims 1-9, wherein the slit comprises a notch extending through only a portion of the thickness of the membrane, thereby delimiting a tear apart portion in the thickness of the membrane that is not traversed by the notch, the tear apart portion being configured to tear along the notch under a determined pressure exerted by the fluid to create the fluid path.

11. The valve stopper of claim 10, wherein the tear apart portion of the membrane forms a valve configured to open or close depending on the pressure exerted by the fluid onto the proximal face of the membrane.

12. The valve stopper of any of claims 1-9, wherein the slit extends completely through the membrane between the proximal face and the distal fare to form a split configured to open or close depending on the pressure exerted by the fluid onto the proximal face of the membrane.

13. The valve stopper of any of claims 1-12, wherein the distal face of the membrane presents one of a flat surface, a concave shape, a convex shape, or a duckbill shape extending away from the proximal face.

14. The valve stopper of any of claims 1-13, wherein the sealing surface comprises at least two ribs spaced apart along a length of the valve stopper.

15. A multi-chamber medical injection device for injecting at least one fluid, comprising: a barrel extending from a proximal end to a distal end, the barrel comprising a cylindrical wall, an end wall positioned at the distal end, and a tip extending distally from the end wall; a plunger stopper adapted to be translationally movable inside the barrel; and the valve stopper of any of claims 1-14, arranged between the distal end of the barrel and the plunger stopper, and adapted to be translationally movable inside the barrel, wherein the lateral wall of the valve stopper sealingly engages the inner surface of the barrel; wherein a first chamber is defined within the barrel between the distal end of the barrel and the valve stopper and a second chamber is defined within the barrel between the valve stopper and the plunger stopper.

16. The multi-chamber medical injection device of claim 15, wherein the multi-chamber medical injection device is configured to sequentially inject two fluids, with a first fluid contained within the first chamber and a second fluid contained within the second chamber, and wherein the valve stopper is spaced apart distally from the end wall to separate the first chamber from the second chamber.

17. The multi-chamber medical injection device of claim 15, wherein a powder is contained within the first chamber and a fluid is contained within the second chamber, and wherein the valve stopper is spaced apart distally from the end wall to separate the first chamber from the second chamber.

18. The multi-chamber medical injection device of claim 16 or claim 17, wherein the valve stopper is configured so that the membrane is positioned at or adjacent a distal end of the valve stopper, with the lateral wall extending proximally from the membrane.

19. The multi-chamber medical injection device of claim 15, wherein the multi-chamber medical injection device is configured to inject a single fluid, with the single fluid contained within the second chamber, and wherein the valve stopper is positioned to abut the end wall, so that the first chamber comprises a channel within the tip, the first chamber being empty.

20. The multi-chamber medical injection device of claim 19, wherein the valve stopper is configured so that the membrane is positioned at a proximal end of the valve stopper, with the lateral wall extending distally from the membrane.

21. The multi-chamber medical injection device of claim 19, wherein the valve stopper is configured so that the membrane is positioned toward a distal end of the valve stopper, but inset from a distal edge, with the lateral wall extending both proximally and distally from the membrane.

22. The multi-chamber medical injection device of any of claims 15-22, being one of a syringe or a cartridge.

23. A pre-filled medical injection device for sequentially injecting a first liquid and a second liquid, the injection device comprising: a barrel extending from a proximal end to a distal end, the barrel comprising a cylindrical wall having a barrel inner diameter; a plunger stopper adapted to be translationally movable inside the barrel; and a valve stopper arranged between the distal end of the barrel and the plunger stopper and adapted to be translationally movable inside the barrel, the valve stopper comprising: a membrane configured to separate a distal chamber of the barrel from a proximal chamber of the barrel, the membrane comprising at least one slit extending through at least a part of a thickness of the membrane between a proximal face and a distal face thereof, with the slit configured to selectively create a fluid path through the membrane from the proximal face to the distal face depending on the pressure exerted by a composition onto the proximal face of the membrane for transferring fluid only from the proximal chamber to the distal chamber; and a lateral wall joined to the membrane to define at least one cavity, the lateral wall comprising a sealing surface including one or more circumferential ribs configured to sealingly engage the inner surface of the barrel; a first liquid contained within the distal chamber, the first liquid comprising a GLP-1 agonist; anda second liquid contained within the proximal chamber, the second liquid comprising an amyline analog.

24. The pre-filled medical injection device of claim 23, wherein the GLP-1 agonist comprises a calcitonin receptor agonist and the amyline analog comprises a dual amylin.

25. The pre-filled medical injection device of claim 23, wherein the GLP-1 agonist comprises semaglutide and the amyline analog comprises cagrilintide.

26. The pre-filled medical injection device of claim 23, wherein the valve stopper presents the successive following positions during a sequential injection: a first position where the fluid path is closed; a second position where the valve stopper is more distal than in the first position, where the fluid path closed, with the proximal face of the membrane being subjected to a pressure that is inferior to a valve opening force of the at least one slit; and a third position, wherein the valve stopper abuts the distal end of the barrel, the fluid path being opened due to a pressure exerted on the proximal face of the membrane that is superior to the valve opening force of the at least one slot; wherein the first liquid is injected as the valve stopper moves from the second position to the third position; and wherein the second liquid is injected responsive to further distal movement of the plunger stopper with the valve stopper at the third position.

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