Variable flow hinged 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 membrane comprises one or more slits formed therein that extend through at least a part of a thickness of the membrane. One or more flaps are defined by the slits and are configured to deflect to create a fluid path through the membrane. One or more hinge elements are formed in the membrane, with a hinge element provided for each of the one or more flaps about which each respective flap pivots when deflected.

Description

VARIABLE FLOW HINGED VALVE STOPPER FOR A MULTI-CHAMBERMEDICAL INJECTION DEVICECROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 638,987 entitled “Variable Flow Hinged Stopper for a Multi-Chamber Medical Injection Device” filed April 26, 2024, the disclosure of which is hereby incorporated by reference in its entirety.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 injection of a first or initial fluid, such as a first type of a medical fluid, followed by a secondary fluid, with such fluids being of the same type or different types.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 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 have a number of drawbacks associated 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 and expelling it out the injection device. As another example, the structure of the valve stoppermay 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 further examples, the design of existing valve stoppers may lead to issues with opening the valve smoothly, providing a desired flux or flowrate through the stopper, and / or maintaining valve robustness or integrity until injection.

[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 includes 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. The membrane comprises one or more slits formed therein that extend through at least a part of a thickness of the membrane between the proximal face and the distal face, one or more flaps forming part of the membrane and that are defined by the one or more slits, each of the one or more flaps configured to selectively deflect depending on the pressure exerted by a fluid onto the proximal face of the membrane, to selectively create a fluid path through the membrane from the proximal face to the distal face for transferring fluid only from the second chamber to the first chamber, and one or more hinge elements formed in the membrane, with a hinge element provided for each of the one or more flaps; wherein, with the one or more flaps deflecting, each respective flap pivots about its respective hinge element.

[0011] In certain configurations, each of the one or more flaps comprises a cantilevered member that pivots and deflects from its respective hinge element.

[0012] In certain configurations, each of the one or more hinge elements comprises a weakened area of the membrane, the weakened area having a hinge thickness that is less than the thickness of the membrane.

[0013] In certain configurations, the hinge thickness is 20% to 70% of the thickness of the membrane.

[0014] In certain configurations, at each weakened area, the membrane comprises a gutter formed in the distal face of the membrane, with the gutter reducing the thickness at the weakened area to the hinge thickness.

[0015] In certain configurations, the gutter is a U-shaped gutter.

[0016] In certain configurations, the gutter is a V-shaped gutter.

[0017] In certain configurations, the flap pivots about a centerline of the gutter.

[0018] In certain configurations, the gutter comprises one of a linear segment, a curved segment, or a mixture of a linear segment and a curved segment that extends across the distal face of the membrane.

[0019] In certain configurations, at each weakened area, the membrane comprises another gutter formed in the proximal face of the membrane, the another gutter in the proximal face being aligned with the gutter in the distal face, to further reduce the thickness at the weakened area to the hinge thickness.

[0020] In certain configurations, at each weakened area, the membrane comprises another slit formed in the proximal face of the membrane and extending partially through the thickness of the membrane, the another slit comprising a hinge slit reducing the thickness at the weakened area to the hinge thickness, with a respective flap pivoting about the hinge slit when deflected.

[0021] In certain configurations, the proximal face of the membrane comprises a flat surface, and wherein the proximal face further comprises a chock formed on the flat surface that extends proximally outward therefrom.

[0022] In certain configurations, the distal face includes a preloaded portion, the preloaded portion including the one or more slits formed therein and forming at least part of the one or more flaps, the preloaded portion extending distally outward from a remainder of the distal face, such that the preloaded portion has an increased thickness.

[0023] In certain configurations, each of the one or more slits comprises a plurality of slit segments that define a respective flap.

[0024] In certain configurations, the one or more slits comprises a single curved or spiral slit that defines the one or more flaps.

[0025] In certain configurations, each of the one or more slits comprises a slit extending completely through the membrane between the proximal face and the distal face.

[0026] In certain configurations, the valve stopper is formed of an elastomer or a thermoplastic material.

[0027] In certain configurations, the membrane is positioned at a proximal end of the valve stopper, with the lateral wall extending distally from the membrane.

[0028] Also provided herein is a medical injection device for injecting at least one fluid. The 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 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 and the plunger stopper, and adapted to be translationally movable inside the barrel. The valve stopper comprises a membrane having 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. 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.

[0029] In certain configurations, the 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.

[0030] In certain configurations, the medical injection device is one of a syringe or a cartridge.

[0031] 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 includes 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. The membrane also comprises a pair of distally protruding portions and a pair of proximally protruding portions that collectively form a duckbill-type valve, with a first distally protruding portion and a first proximally protruding portion forming a first side of the valve and a second distally protruding portion and a second proximally protruding portion forming a second side of the valve. The membrane further comprises a first gutter and a second gutter formed in the membrane, with the first gutter adjacent the first side of the valve and the second gutter adjacent the second side of the valve. Upon a proximally-directed pressure being applied to the pair of distally protruding portions,the first side of the valve pivots about the first gutter in a first direction and the second side of the valve pivots about the second gutter in a second direction opposite the first direction, to create a fluid path through the membrane from the proximal face to the distal face for transferring fluid only from the second chamber to the first chamber.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 is a perspective view of a multi-chamber medical injection device, according to a non-limiting embodiment described herein;

[0033] FIG. 2 is an exploded view of the multi-chamber medical injection device of FIG. 1;

[0034] 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;

[0035] FIG. 4 is a cross-sectional view of the valve stopper of FIG. 3;

[0036] FIG. 5 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0037] 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;

[0038] FIG. 7 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0039] FIG. 8 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0040] FIG. 9 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0041] FIG. 10 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0042] FIG. 11 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0043] FIG. 12 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0044] FIG. 13 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0045] 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;

[0046] 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;

[0047] 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;

[0048] 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;

[0049] 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;

[0050] FIG. 19 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. 20 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. 21 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. 22 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0054] FIG. 23 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0055] FIG. 24 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0056] FIG. 25 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0057] FIG. 26 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0058] FIG. 27A is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, shown in an undeflected position, according to another non-limiting embodiment described herein;

[0059] FIG. 27B is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, shown in an undeflected position, according to another non-limiting embodiment described herein;

[0060] FIG. 28 is a cross-sectional view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0061] FIG. 29 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0062] FIG. 30 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0063] FIG. 31 is a cross-sectional view of a membrane of a valve stopper included in a medical injection device, according to another non-limiting embodiment described herein;

[0064] FIGS. 32A-32D illustrate various configurations of the injection device of FIG. 1 during injection of first and second compositions from the device; and

[0065] FIGS. 33A-33C illustrate various configurations of an injection device during injection of a single composition from the device, according to another non-limiting embodiment described herein.DESCRIPTION OF THE INVENTION

[0066] 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.

[0067] 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 of the invention. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.

[0068] 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.

[0069] 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-limitingexamples. 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 one or more slits therein that define one or more flaps that function 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 vascular access device (VAD) (e.g., an IV catheter system including a catheter inserted into a patient's vascular system) without needing to attach multiple syringes or fluid containers to the VAD.

[0070] 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 by opening the valve smoothly, providing a desired flux or flowrate through the stopper, and / or maintaining valve robustness or integrity until injection.

[0071] 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.

[0072] 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 himself (when used with an auto-injector), to administer the initial fluidfollowed 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 injection device 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.

[0073] 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. 32A and 32B) followed by a secondary fluid F2 contained in a second or proximal fluid chamber 104 (shown in FIGS. 32A-32D). 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.

[0074] 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 typeand 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.

[0075] 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 other embodiments, the tip 116 may be configured as a needleless connector configured to be connected directly or indirectly to a fluid port, valve, connector for a needle, or another terminal access portion of a vascular access device (VAD).

[0076] 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.

[0077] 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 elastomersinclude, 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, and leakage of a fluid contained in the internal volume of the barrel.

[0078] 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 barrel 106 into the proximal chamber 104 and the distal chamber 102. Specifically, as shown most clearly in FIG. 32A, 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.

[0079] 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 by opening the valve smoothly, providing a desired flux or flowrate through the stopper, and / or maintaining valve robustness or integrity until injection, 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.

[0080] 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 themembrane 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.

[0081] 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.

[0082] 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. That is, the membrane 12 may be positioned so 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.

[0083] According to still another embodiment, and as shown in FIG. 6, the valve stopper 10 may be configured such that the membrane 12 is positioned at a proximal end 25 of the valve stopper 10, such that the lateral wall 14 extends in the distal direction only from the membrane 12, and the cavity 16 is delimited by the inner face 18 of the lateral wall 14 and the distal face 22 of the membrane 12 that constitutes the bottom of the cavity 16.

[0084] 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 such as halobutyl 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.

[0085] As shown in FIGS. 3-6, 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.

[0086] 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, and prevent mixing of the two fluids into the internal volume of the barrel before injection.

[0087] According to aspects of the disclosure, in any / all of the embodiments of the valve stoppers 10 shown in FIGS. 3-6, the membrane 12 may comprise a one or more slits 28 formed therein that define and shape one or more flaps 30 in the membrane 12. The flap(s) 30 may be distally actuated / deflected to an open position or configuration, as shown in phantom in FIGS. 3-6, to permit fluid flow through the membrane 12. The slits 28 extend 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. As used herein, the term “slit” is understood to refer to a cut that is formed through at least a part of the thickness of the membrane 12 - with a slit generally encompassinga cut that is formed through an entirety of a thickness of the membrane 12 or a cut that is formed through only a portion of a thickness of the membrane 12. The slit(s) 28 are arranged / configured to define flaps(s) 30 that may deflect responsive to a pressure applied thereto to selectively provide a “window” or fluid path 32 through the membrane 12 from the proximal face 20 to the distal face 22 of the membrane 12 when opened, as explained in further detail below.

[0088] As shown in FIGS. 3-6, in some embodiments, the slits 28 are 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 splits through the membrane 12. In other embodiments, the slits 28 may extend through only a part of the thickness of the membrane 12. In such embodiments, the membrane 12 is configured as a tear-apart membrane that is configured to tear along the slits 28 under a determined pressure exerted by the composition.

[0089] According to aspects of the disclosure, the flap(s) 30 are configured to transition between a closed position (i.e., an undeflected position) where fluid flow through the membrane 12 is prevented, and an open position (i.e., a deflected position) where fluid flow through the membrane 12 can occur (as shown in phantom in FIGS. 3-6), 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 flap(s) 30 - which corresponds to the force / pressure that needs to be exerted onto the proximal face 20 of the membrane 12 for deflecting or raising the flap(s) 30. The flap(s) 30 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 flap(s) 30. The slit(s) 28 and flap(s) 30 are biased to and initially provided in a closed position - with the slits 28 maintained closed under radial compression of the valve stopper 10 within the barrel 106, and the flap(s) 30 in an undeflected position. Accordingly, 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(s) 28 and flap(s) 30 are in the closed position. The flap(s) 30 transition to the open position when the fluid pressure P2 in the proximal chamber 104 substantially increases above the opening force Fopof the flap(s) 30.

[0090] The activation or opening force Fopfor the flap(s) 30 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 rodof a syringe through the syringe barrel. In some examples, the activation or opening force Fopfor the flap(s) 30 may be between 2 N and 25 N, preferably between 2 N and 20 N, and even more preferably between 5 N and 20 N. However, it is recognized that the activation or opening force FOp can 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 flap(s) 30 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 to open 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.

[0091] According to aspects of the disclosure, 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 slit(s) 28 and flap(s) 30 only when the composition / fluid flows in the distal direction, i.e., the direction of injection. In other terms, the flap(s) 30 are 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 flap(s) 30 are 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.

[0092] According to aspects of the disclosure, the valve stopper 10 is designed so that the slit(s) 28 and flap(s) 30 formed in the membrane 12 provide a desired robustness in the valve stopper 10, along with controlling / adjusting the minimum force needed to open the valve stopper 10 (i.e., valve stiffness) and controlling a flux or flow of the second fluid F2 through the valve stopper 10. To provide for such control, the membrane 12 is configured to include one or more hinge elements 34 formed in the membrane 12, with a hinge element 34 provided for each of the one or more flaps 30. Inclusion of the hinge element(s) 34 in membrane 12structure the flap(s) 30 as cantilevered members that are configured to pivot about the hinge element(s) 34 when transitioning from their closed / undeflected position to their open / deflected position. As described in further detail below, the hinge element(s) 34 comprise weakened area(s) of the membrane 12 that have a hinge thickness, Th, that is less than the thickness of the membrane 12. The particular configuration of the hinge element(s) 34 (i.e., a shape, length, and / or depth of the weakened area(s) of the membrane 12 having the reduced hinge thickness) may be selected to tune or otherwise control the valve robustness, valve opening strength, and fluid flow or flux through the valve stopper 10.

[0093] According to one embodiment of the disclosure, each hinge element 34 provided in the membrane 12 may be structured as a trench or gutter 34a that is formed in the membrane 12 that reduces the thickness of the membrane 12 at that location to a hinge thickness, Th. During deflection of a flap 30 when transitioning from its closed position to its open position, the flap 30 pivots about a centerline of the gutter 34a.

[0094] In some embodiments, each gutter 34a is formed on the distal face 22 of the membrane 12 and extends across a portion of the distal face 22. The gutter 34a may comprise one of a linear segment, a curved segment, or a mixture of a linear segment and a curved segment, with the gutter 34a extending across a portion of the distal face 22 of the membrane 12.

[0095] The configuration of each gutter 34a, including the shape and / or depth thereof, may be selected or tuned in order to adjust the opening force Fopof the corresponding flap 30, as well as a speed at which the flap 30 opens. According to embodiments, the depth of the gutter 34a is such that the remaining hinge thickness, Th, of the membrane 12 at the location of the gutter 34a is 20% to 70% of the overall thickness of the membrane 12, Tm, with the hinge thickness impacting the opening force Fopof the corresponding flap 30.

[0096] FIGS. 4-26 present various configurations of a membrane 12 that may be provided in valve stopper 10 - with the number, shaping, and location of various slits 28, flaps 30, and gutters 34a provided in the membrane 12 being selected to control and set the structural and operational characteristics of the valve stopper 10. For each of the membrane configurations, the membrane 12 may be positioned at the distal end 23 of the valve stopper 10, the proximal end 25 of the valve stopper 10, or at a location between the distal and proximal ends 23, 25 (e.g., offset proximally from the distal end 23 of the valve stopper 10, such that the lateral wall 14 extends both proximally and distally therefrom).

[0097] According to aspects of the disclosure, each gutter 34a may have one of a number of suitable cross-sectional shapes. According to exemplary embodiments, a gutter 34a may beformed as a semi-circular or U-shaped gutter, as shown in FIGS. 4-6, or as a triangular or V- shaped gutter, as shown in FIG. 7, with such a gutter 34a formed in the membrane 12 during molding, for example. According to another embodiment, a gutter 34a may be formed as a square or rectangular gutter as shown in FIG. 8, with such a gutter 34a being laser cut / etched into the membrane 12.

[0098] In some embodiments, and as shown in FIGS. 9 and 10, in addition to having one or more gutters 34a formed in the distal face 22 of the membrane 12, membrane 12 may also include one or more gutters 34b formed in the proximal face 20 of the membrane 12. The additional gutter(s) 34b formed on the proximal face 20 of the membrane 12 are aligned with the gutter(s) 34a in the distal face 22, to further reduce the thickness at the weakened area to the hinge thickness, Th. While the gutters 34a, 34b shown in FIGS. 9 and 10 are formed as semi-circular / U-shaped gutters, it is recognized that the gutters 34a, 34b could instead be formed as triangular / V- shaped gutters or square / rectangular gutters, according to other embodiments, with the gutter(s) 34a and the additional gutter(s) 34b having identical shapes.

[0099] In the embodiment of FIG. 10, the membrane 12 is configured to include multiple flaps 30, with a hinge element 34 provided for each flap 30. In the illustrated embodiment, each hinge element 34 is formed by a pair of aligned gutters 34a, 34b on the distal face 22 and proximal face 20 of the membrane 12. In other embodiments, each hinge element 34 could be formed by a gutter 34a only on the distal face 22 of the membrane 12.

[0100] Referring now to FIG. 11, in some embodiments, membrane 12 is configured as a “preloaded” membrane, meaning that at least some portions of the membrane 12 have an increased thickness as compared to a membrane 12 having flat proximal and distal faces 20, 22. In the illustrated embodiment, the central region 35 of the membrane 12 has an increased thickness as compared to the outer circumferential region of the membrane 12, such as by the distal face 22 of membrane 12 having a conical or triangular configuration, with slit(s) 28 formed in the preloaded region. The surplus of material provided in the preloaded membrane 12 functions to control opening of a fluid path 32 through the membrane 12, such as by increasing the opening force Fopneeded to open the flap(s) 30 formed in the membrane 12.

[0101] Referring now to FIG. 12, in some embodiments, membrane 12 may include a chock 36 feature formed on the distal face 22 of the membrane 12. In the illustrated embodiment, the distal face 22 of the membrane 12 is structured as a flat surface, and a triangular- shaped chock 36 is formed on the distal face 22 - with the chock 36 provided on a flap 30 formed in membrane 12. The chock 36 functions to prevent obturation in the syringe 100 that might occur as the flap 30 deflects distally when moving from the closed position tothe open position, such as by the flap 30 covering the channel 118 in syringe barrel 106 when in the open position. The chock 36 may provide spacing between the flap 30 and the channel 118, to ensure that channel 118 remains open during an injection of fluid from syringe 100. While chock 36 is shown in FIG. 12 as a triangular- shaped member, it is recognized that chock 36 may have any or a number of suitable shapes, according to other embodiments.

[0102] Referring now to FIGS. 13-26, various configurations of slit(s) 28, flap(s) 30, and gutter(s) 34a formed in membrane 12 are illustrated, according to various embodiments. As described above, slit(s) 28, flap(s) 30, and gutter(s) 34a formed in membrane 12 may be selected to tune or otherwise control the valve robustness, valve opening strength, and fluid flow or flux through the valve stopper 10.

[0103] FIGS. 13 and 14 illustrate membranes 12 including a singular flap 30 and a singular gutter 34a about which the flap 30 deflects and pivots. In the embodiment of FIG. 13, the flap 30 is formed as a triangular flap that is formed / defined by a slit 28 composed of a pair of joined slit segments 28s. In the embodiment of FIG. 14, the flap 30 is formed as a semi-circular flap that is formed / defined by a single curved slit 28.

[0104] FIGS. 15-17 illustrate membranes 12 that include a pair of flaps 30 and a singular gutter 34a about which both of the flaps 30 deflect and pivot - i.e., each of flaps 30 deflects / pivots about a common centerline 38 of the gutter 34a. In each of the embodiments, the flaps 30 are arranged opposite from each other across a central gutter 34a. In the embodiment of FIG. 15, a pair of rectangular flaps 30 is formed about a single gutter 34a, with each flap 30 being formed / defined by a slit 28 composed of a plurality of joined slit segments 28s. In the embodiment of FIG. 16, a pair of triangular flaps 30 is formed about a single gutter 34a, with each flap 30 being formed / defined by a slit 28 composed of a pair of joined slit segments 28s. In the embodiment of FIG. 17, a pair of semi-circular flaps 30 is formed about a single gutter 34a, with each flap 30 being formed / defined by a single curved slit 28.

[0105] FIG. 18 illustrates a membrane 12 similar to those provided in FIGS. 15-17, in that each of a pair of flaps 30 in membrane 12 share a common gutter 34a. However, in the membrane 12 of FIG. 18, each of flaps 30 has an arc-shaped construction, with the pair of arcshaped flaps 30 arranged to encircle a region of the membrane 12. For each flap 30, a gutter 34a is provided at each of opposing ends of the arc shaped flap 30 (on opposing sides of the region), with each of the gutters 34a being shared by the pair of flaps 30.

[0106] FIGS. 19-22 illustrate membranes 12 that include a plurality of flaps 30 that share at least one common junction, as formed by a slit or slits 28 (or a segment of a slit) betweenadjacent flaps 30. Each of the flaps 30 includes a dedicated gutter 34a about which the respective flap 30 deflects and pivots.

[0107] In the embodiment of FIG. 19, a pair of rectangular flaps 30 is formed in membrane 12 that share a common slit or slit segment 28, 28s, with the gutters 34a for the flaps formed on opposing ends of the pair of flaps 30. With the pair of flaps 30 meeting along a common slit 28 and each pivoting / deflecting about the hinge formed at / by its respective gutter 34a, the flaps 30 can collectively pivot / deflect to form an enlarged window or fluid path 32 through the membrane 12.

[0108] In the embodiment of FIG. 20, a grouping of four triangular flaps 30 is formed that share a plurality of common slits or slit segments 28, 28s, with the slits 28 all meeting at a central junction 40. The gutters 34a for the respective flaps 30 are formed adjacent one another and collectively surround the grouping of flaps 30. With the flaps 30 all meeting at a common central junction 40 and each pivoting / deflecting about the hinge formed at / by its respective gutter 34a, the flaps 30 can collectively pivot / deflect to form an enlarged window or fluid path 32 through the membrane 12.

[0109] In the embodiment of FIG. 21, a grouping of three triangular flaps 30 is formed that share a plurality of common slits or slit segments 28, 28s, with the slits 28 all meeting at a central junction 40. The gutters 34a for the respective flaps 30 are formed adjacent one another and collectively surround the grouping of flaps 30. With the flaps 30 all meeting at a common central junction 40 and each pivoting / deflecting about the hinge formed at / by its respective gutter 34a, the flaps 30 can collectively pivot / deflect to form an enlarged window or fluid path 32 through the membrane 12.

[0110] In the embodiment of FIG. 22, a pair of trapezoidal flaps 30 and a pair of triangular flaps 30 are formed in membrane 12 that share a plurality of common slit or slit segments 28, 28s. The gutters 34a for the respective flaps 30 are formed adjacent one another and collectively surround the grouping of flaps 30. With the pair of trapezoidal flaps 30 and the pair of triangular flaps 30 meeting along common slits 28 and each pivoting / deflecting about the hinge formed at / by its respective gutter 34a, the flaps 30 can collectively pivot / deflect to form an enlarged window or fluid path 32 through the membrane 12.

[0111] FIG. 23 illustrates a membrane 12 including a single slit 28 configured as an S-shaped curve, with the S-shaped slit 28 defining a pair of symmetrical curved flaps 30 in the membrane 12. The membrane 12 also includes gutters 34a for the flaps, with the gutters 34a formed between bends of the S-shaped slit 28 and aligned lengthwise with each other on the distal face 22 of the membrane 12. With the gutters 34a arranged as such, each flap 30 maydeflect and pivot about its respective gutter 34a to provide respective fluid paths 32 through the membrane 12.

[0112] FIG. 24 illustrates a membrane 12 including a single slit 28 configured as a curved spiral (i.e., golden spiral), with the spiral slit 28 defining a single, spiral shaped flap 30. A gutter 34a is formed in membrane 12 between bends of the spiral slit 28, such that the gutter 34a and the spiral slit 28 define the flap 30. With the gutter 34a positioned as such, the spiral flap 30 may deflect and pivot about the gutter 34a and open along the slit 28, to provide the fluid path 32 through the membrane 12.

[0113] FIG. 25 illustrates a membrane 12 including a single slit 28 configured as a linear spiral, with the linear spiral slit 28 defining a single, linear spiral shaped flap 30. A gutter 34a is formed in membrane 12 between segments of the linear spiral slit 28, such that the gutter 34a and the linear spiral slit 28 define the flap 30. With the gutter 34a positioned as such, the linear spiral flap 30 may deflect and pivot about the gutter 34a and open along the slit 28, to provide the fluid path 32 through the membrane 12.

[0114] FIG. 25 illustrates a membrane 12 including a pair of semi-circular flaps 30 and a singular gutter 34a about which both of the flaps 30 deflect and pivot - i.e., each of flaps 30 deflects / pivots about a common centerline 38 of the gutter 34a. Similar to the membrane 12 of FIG. 17, the pair of semi-circular flaps 30 is formed / defined by a single curved slit 28. However, whereas the slits 28 forming the flaps 30 for the membrane 12 of FIG. 17 are separated by a non-overlapping gap or space, the slit 28 in the membrane 12 of FIG. 25 may be continuous along one edge / side of the flaps 30. Thus, when the flaps 30 deflect and pivot about the gutter 34a when moving from their closed to their open position, a single continuous fluid path 32 may be provided through the membrane 12 rather than two distinct / separate fluid paths, as in the membrane 12 of FIG. 17.

[0115] Referring now to FIGS. 27 A and 27B, according to another embodiment of the disclosure, a membrane 12b is provided that includes hinge element(s) 34 in the form of gutter(s) 34a - similar to the membrane(s) 12 previously described for the embodiments of FIGS. 3-26 - but the membrane 12b is structured according to a different operating principle from the membrane 12 previously described. That is, rather than including a slit or slits 28 that define one or more flaps 30 in the membrane 12, membrane 12b includes protruding portions (i.e., distally protruding portions 42 and proximally protruding portions 44) that collectively form a duckbill- shaped valve 46 that may be selectively opened / closed to provide a fluid path 32 through the membrane 12b. A first distally protruding portion 42a and a first proximally protruding portion 44a may form a first portion of the valve 46, while a second distallyprotruding portion 42b and a second proximally protruding portion 44b may form a second portion of the valve 46 - with the first and second portions of the valve 46 defining an opening therethrough that may be selectively opened and closed. According to aspects of the disclosure, the distally protruding portions 42 of the valve 46 are configured as stiff portions, while the proximally protruding portions 44 are configured as flexible portions that may bend / deform. The flexible proximally protruding portions 44a, 44b have the same shape / dimensions and are in a face-to-face arrangement, in order that the portions 44a, 44b meet, to ensure tightness of the duckbill valve 46 when in an initial position, as explained further below.

[0116] In operation, the valve 46 is initially in a closed state, with the flexible proximally protruding portions 44 of the valve 46 being kept in contact with each other to close a fluid path 32 through the membrane 12b, as shown in FIG. 27A. Actuation of the valve 46 may be provided responsive to the valve stopper 10 being brought into contact with the distal end 108 of the barrel 106 (FIGS. 1 and 2), with the valve 46 opening according to a cam operating principle. That is, as the valve stopper 10 is brought / pushed into contact with the distal end 108 of the barrel 106, the stiff distally protruding portions 42 function as a cam, with the distally protruding portions 42 and proximally protruding portions 44 being deflected proximally and caused to rotate about the hinge elements 34 (i.e., gutters 34a). That is, the first distally protruding portion 42a and first proximally protruding portion 44a forming the first portion of the valve 46 are caused to rotate in a first direction about one gutter 34a, while the second distally protruding portion 42b and second proximally protruding portion 44b forming the second portion of the valve 46 are caused to rotate in a second (opposite) direction about the other gutter 34a. Rotation of the protruding portions 42, 44 in this manner causes the flexible first proximally protruding portion 44a to separate from the flexible second proximally protruding portion 44b, to provide a gap therebetween that opens the fluid path 32 through the valve 46, as shown in FIG. 27B.

[0117] Referring now to FIG. 28, according to another embodiment of the disclosure, each hinge element 34 provided in the membrane 12 may be structured as a hinge slit 34c that is formed in the membrane 12 and that extends partially through the membrane, so as to effectively reduce the thickness of the membrane 12 at that location to a hinge thickness, Th. During deflection of a flap 30 when transitioning from its closed position to its open position, the flap 30 pivots about the hinge slit 34c.

[0118] In some embodiments, each hinge slit 34c is formed in the proximal face 20 of the membrane 12 and extends through a portion of the thickness of the membrane 12. The hinge slit 34c may comprise one of a linear segment, a curved segment, or a mixture of a linearsegment and a curved segment, with the hinge slit 34c extending along a portion of the proximal face 20 of the membrane 12.

[0119] The configuration of each hinge slit 34c, including the shape and / or depth thereof, may be selected or tuned in order to adjust the opening force Fopof the corresponding flap 30, as well as a speed at which the flap 30 opens. According to embodiments, the depth of the hinge slit 34c is such that the remaining hinge thickness, Th , of the membrane 12 at the location of the hinge slit 34c is 20% to 70% of the overall thickness, Tm, of the membrane 12, with the hinge thickness impacting the opening force Fopof the corresponding flap 30.

[0120] While only a single slit 28, flap 30, and hinge slit 34c is shown in membrane 12 in the embodiment of FIG. 28, it is recognized that various configurations of slit(s) 28, flap(s) 30, and hinge slit(s) 34c may be formed in membrane 12, similar to any of the membrane configurations shown in FIGS. 13-27. As described above, slit(s) 28, flap(s) 30, and gutter(s) 34a - now hinge slits 34c - formed in membrane 12 may be selected to tune or otherwise control the valve robustness, valve opening strength, and fluid flow or flux through the valve stopper 10.

[0121] Referring now to FIGS. 29-31, according to still additional embodiments of the disclosure, a hinge element 34 provided in the membrane 12 may be structured as an enlarged depression or valley 34d that covers a larger area of the membrane 12, as compared to a gutter 34a. A valley 34d may be formed in the distal face 22 of the membrane 12 (FIGS. 29 and 30) or in both the proximal and distal faces 20, 22 of the membrane 12 (FIG. 31 ), so as to effectively reduce the thickness of the membrane 12 at that location to a hinge thickness, Th. During deflection of a flap or flaps 30 when transitioning from a closed position to an open position, the flap(s) 30 may deflect and pivot about a “hinge” formed at a transition between the full thickness portion(s) of the membrane 12 and the reduced hinge thickness of the valley 34d, such as along edges of the valley 34d.

[0122] Referring now to FIGS. 32A-32D, 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.

[0123] 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(s) 28, flap(s) 30 and / or hinge element(s) 34.

[0124] 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 or categories may include analgesics, vitamins, vaccines (and boosters), monoclonal antibodies, diabetes and obesity treatments, and the like.

[0125] One exemplary embodiment of a liquid- liquid combination of a first fluid Fl and second fluid F2 that may be sequentially injected from the distal chamber 102 and proximal 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.

[0126] 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.

[0127] 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 non-limiting 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 distal chamber 102 and proximal 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.

[0128] FIG. 32A 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(s) 28 and flap(s) 30 being maintained closed under radial compression of the valve stopper 10, such that the fluid path 32 is closed. That is, when the valve stopper 10 is inserted in the barrel 106 of the injection device 100, the slit(s) 28 and flap(s) 30 is / are 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 slit 28, so that the flap(s) 30 defined by slit(s) 28 thus remain closed (i.e., the flap(s) 30 are not distally deflected or “raised”). The closed flap(s) 30 prevent 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.

[0129] Referring now to FIG. 32B, 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.

[0130] In the configuration of FIG. 32B, the valve stopper 10 is in a sealing position, with the flap(s) 30 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 fluidthrough 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 flap(s) 30. 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 flap(s) 30. The flap(s) 30 thus remain 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. 32B.

[0131] Referring now to FIG. 32C, 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 flap(s) 30. As a result, the flap(s) 30 in membrane 12 are caused to deflect and pivot about hinge element(s) 34, thereby moving the flap(s) 30 to the open position and allowing the second fluid to pass through the window(s) or fluid path(s) 32 and to / through the channel 118 in tip 116 for the injection. In this configuration, the valve stopper 10 is in an injection position.

[0132] As shown in FIG. 32D, 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.

[0133] 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.

[0134] Referring now to FIG. 33A, 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. 32A-32D regarding barrel 106 (including end wall 114 and tip 116) and plunger stopper 124; however, the valve stopper 10 is initially positioned at the fardistal 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.

[0135] The functioning of the valve stopper 10 and the injection device comprising the valve stopper 10 will now be described here below, in reference to FIGS. 33A to 33C.

[0136] FIG. 33A 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(s) 28, along with flap(s) 30, being maintained closed under radial compression of the valve stopper 10, such that the fluid path 32 is closed. That is, when the valve stopper 10 is inserted in the barrel 106 of the injection device 100, the slit(s) 28 are 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 flap(s) 30, so that flap(s) 30 thus remains closed. The closed flap(s) 30 prevent the single fluid from leaking into channel 118 of tip 116.

[0137] Referring now to FIG. 33B, 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 flap(s) 30 in membrane 12 is / are caused to deflect and pivot about hinge element(s) 34, thereby moving the flap(s) 30 to the open position and allowing the single fluid to pass through the window(s) / fluid path(s) 32 defined by the flap(s) 30 and to / through the channel 118 in tip 116 for the injection. In this configuration, the valve stopper 10 is in an injection position.

[0138] As shown in FIG. 33C, 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 exertedby the plunger stopper 124, which reduces the volume of the cavity 16, and the dead volume is thus injected.

[0139] 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 membrane including one or more slits formed therein through at least a part of a thickness of the membrane that selectively define one or more flaps that open to create a fluid path or paths 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. By selectively providing a fluid path through the membrane from a proximal side to a distal side, the membrane provides for the sequential injection of multiple fluids from the injection device, with the membrane preventing mixing of the fluids. Hinge elements, such as gutters or hinge slits, are formed in the membrane about which the flap(s) may pivot as they are deflected to the open position, with the hinge elements allowing for the tuning / controlling of the valve robustness, valve opening strength, and / or fluid flow or flux through the valve stopper 10. The construction of the valve stopper also provides desirable isostatic properties and sliding / gliding of the stopper within the syringe barrel.

[0140] 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 membrane comprises: one or more slits formed therein that extend through at least a part of a thickness of the membrane between the proximal face and the distal face; one or more flaps forming part of the membrane and that are defined by the one or more slits, each of the one or more flaps configured to selectively deflect depending on the pressure exerted by a fluid onto the proximal face of the membrane, to selectively create a fluid path through the membrane from the proximal face to the distal face for transferring fluid only from the second chamber to the first chamber; and one or more hinge elements formed in the membrane, with a hinge element provided for each of the one or more flaps; wherein, with the one or more flaps deflecting, each respective flap pivots about its respective hinge element.

2. The valve stopper of claim 1, wherein each of the one or more flaps comprises a cantilevered member that pivots and deflects from its respective hinge element.

3. The valve stopper of claim 1, wherein each of the one or more hinge elements comprises a weakened area of the membrane, the weakened area having a hinge thickness that is less than the thickness of the membrane.

4. The valve stopper of claim 3, wherein the hinge thickness is 20% to 70% of the thickness of the membrane.

5. The valve stopper of claim 3, wherein at each weakened area, the membrane comprises a gutter formed in the distal face of the membrane, with the gutter reducing the thickness at the weakened area to the hinge thickness.

6. The valve stopper of claim 5, wherein the gutter is a U-shaped gutter.

7. The valve stopper of claim 5, wherein the gutter is a V-shaped gutter.

8. The valve stopper of claim 5, wherein the flap pivots about a centerline of the gutter.

9. The valve stopper of claim 5, wherein the gutter comprises one of a linear segment, a curved segment, or a mixture of a linear segment and a curved segment that extends across the distal face of the membrane.

10. The valve stopper of claim 5, wherein at each weakened area, the membrane comprises another gutter formed in the proximal face of the membrane, the another gutter in the proximal face being aligned with the gutter in the distal face, to further reduce the thickness at the weakened area to the hinge thickness.

11. The valve stopper of claim 3, wherein at each weakened area, the membrane comprises another slit formed in the proximal face of the membrane and extending partially through the thickness of the membrane, the another slit comprising a hinge slit reducing the thickness at the weakened area to the hinge thickness, with a respective flap pivoting about the hinge slit when deflected.

12. The valve stopper of claim 1, wherein the proximal face of the membrane comprises a flat surface, and wherein the proximal face further comprises a chock formed on the flat surface that extends proximally outward therefrom.

13. The valve stopper of claim 1, wherein the distal face includes a preloaded portion, the preloaded portion including the one or more slits formed therein and forming at least part of the one or more flaps, the preloaded portion extending distally outward from a remainder of the distal face, such that the preloaded portion has an increased thickness.

14. The valve stopper of claim 1, wherein each of the one or more slits comprises a plurality of slit segments that define a respective flap.

15. The valve stopper of claim 1, wherein the one or more slits comprises a single curved or spiral slit that defines the one or more flaps.

16. The valve stopper of claim 1, wherein each of the one or more slits comprises a slit extending completely through the membrane between the proximal face and the distal face.

17. The valve stopper of any of claims 1-16, wherein the valve stopper is formed of an elastomer or a thermoplastic material.

18. The valve stopper of claim 1, wherein the membrane is positioned at a proximal end of the valve stopper, with the lateral wall extending distally from the membrane.

19. A 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 claim 1, 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.

20. The medical injection device of claim 19, wherein the 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.

21. The medical injection device of claim 19, being one of a syringe or a cartridge.

22. 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 membrane comprises: a pair of distally protruding portions and a pair of proximally protruding portions that collectively form a duckbill-type valve, with a first distally protruding portion and a first proximally protruding portion forming a first side of the valve and a second distally protruding portion and a second proximally protruding portion forming a second side of the valve; and a first gutter and a second gutter formed in the membrane, with the first gutter adjacent the first side of the valve and the second gutter adjacent the second side of the valve; wherein upon a proximally-directed pressure being applied to the pair of distally protruding portions, the first side of the valve pivots about the first gutter in a first direction and the second side of the valve pivots about the second gutter in a second direction opposite the first direction, to create a fluid path through the membrane from the proximal face to the distal face for transferring fluid only from the second chamber to the first chamber.

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