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 and are configured to create a fluid path through the membrane 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. Each slit is formed off-center in the membrane, so as to not pass through a center point of the membrane.

Description

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

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 631,077 entitled “Valve Stopper for a Multi-Chamber Medical Injection Device” filed April 8, 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 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 the practitioners. Furthermore, such prefilled containers may encourage and simplify selfadministration by the patients which allows reducing the cost of therapy and increasing thepatient 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 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 valveassembly 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 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 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, the one or more slits 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. Each of the one or more slits is formed off-center in the membrane, so as to not pass through a center point of the proximal and / or distal faces of the membrane.

[0011] In certain configurations, the one or more slits comprises a plurality of slits, the plurality of slits including at least a first slit and a second slit that are spaced apart and in parallel, so as to define a beam, and wherein the beam is configured to selectively deflect in a distal direction to create the fluid path through the membrane.

[0012] In certain configurations, the beam has a minimum width of 0.05 mm and a maximum width that is twice a thickness of the membrane.

[0013] In certain configurations, the plurality of slits includes multiple pairs of slits that define a plurality of beams.

[0014] In certain configurations, the slits of a respective pair of slits are joined with the slits from the other pairs of slits, with the multiple pairs or slits meeting at a central junction, with the plurality of beams extending out from the central junction.

[0015] In certain configurations, the plurality of beams are spaced apart from one another about a central region of the membrane, and wherein the plurality of slits further includesinterconnecting slits that extend between adjacent pairs of slits that define the plurality of beams, with the interconnecting slits defining the central region.

[0016] In certain configurations, a portion of each of the plurality of beams extends into the central region of the membrane.

[0017] In certain configurations, each of the one or more slits comprises a long slit, where a total length of the one or more slits is equal to or greater than a diameter, Dcirc, of a theoretical circle on the membrane that circumscribes the one or more slits, with the theoretical circle having a minimum diameter of 1.0 mm and a maximum diameter equal to an inner diameter of the lateral wall, minus (-) 0.05 mm.

[0018] In certain configurations, the maximum diameter of the theoretical circle is equal to the inner diameter of the lateral wall, minus (-) 0.1 mm or more.

[0019] In certain configurations, the one or more slits are formed off-center in the membrane, so as to not pass through a center circle that is centered about the center point, the center circle having a diameter comprised between 1% and 10%, and preferably 1.4%-5%, of an outer diameter of the valve stopper.

[0020] In certain configurations, the one or more slits comprises a single slit, the single slit defining a flap configured to selectively deflect in a distal direction to create the fluid path through the membrane.

[0021] In certain configurations, the single slit comprises a spiral slit.

[0022] In certain configurations, the spiral slit comprises a golden spiral or a linear spiral.

[0023] In certain configurations, the one or more slits comprises a plurality of slits defining a number of flaps configured to selectively deflect in a distal direction to create the fluid path through the membrane, and wherein each flap of the number of flaps is rotated relative to other flaps of the number of flaps that are adjacent thereto by 2K / N radians, where N is an integer > 1.

[0024] In certain configurations, each of the plurality of slits comprises a first slit segment and a second slit segment that define a respective flap.

[0025] In certain configurations, the first slit segment and the second slit segment comprises a linear segment and a circular arc segment, or a pair of linear segments joined at an angle.

[0026] In certain configurations, each of the one or more slits comprises a split extending completely through the membrane between the proximal face and the distal fare.

[0027] In certain configurations, each of the one or more slits comprises a notch extending through only a portion of the thickness of the membrane, thereby delimiting a tear apart portionin 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.

[0028] In certain configurations, the membrane is positioned at a distal end of the valve stopper, with the lateral wall extending proximally from the membrane, or the membrane is positioned at a proximal end of the valve stopper, with the lateral wall extending distally from the membrane.

[0029] In certain configurations, the valve stopper is configured so that the membrane is positioned between a distal end and a proximal end of the valve stopper, with the lateral wall extending both proximally and distally from the membrane, such that the at least one cavity comprises a first cavity formed distally from the membrane and a second cavity formed proximally from the membrane.

[0030] 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.

[0031] 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.

[0032] In certain configurations, the medical injection device is one of a syringe or a cartridge.BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 is a perspective view of a multi-chamber medical injection device, according to a non-limiting embodiment described herein;

[0034] FIG. 2 is an exploded view of the multi-chamber medical injection device of FIG. 1;

[0035] 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;

[0036] FIG. 4 is a cross-sectional view of the valve stopper of FIG. 3;

[0037] 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;

[0038] 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;

[0039] 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;

[0040] FIG. 8 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0041] FIG. 9 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0042] FIG. 10 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0043] FIG. 11 is a top view of a valve stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0044] FIG. 12 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. 13 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. 14 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. 15 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. 16 is a cross-sectional view of the valve stopper of FIG. 14, showing the valve in an open configuration;

[0049] FIG. 17 is a top view of a valve stopper for use in a medical injection device, illustrating slit sizing in a membrane thereof, according to another non-limiting embodiment described herein;

[0050] 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;

[0051] 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;

[0052] 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;

[0053] 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;

[0054] 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;

[0055] FIGS. 23A-23D illustrate various configurations of the injection device of FIG. 1 during injection of first and second compositions from the device; and

[0056] FIGS. 24A-24C 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

[0057] 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.

[0058] 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.

[0059] 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 thisapplication, 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.

[0060] 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 one or more slits therein 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 multichamber 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.

[0061] 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.

[0062] 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 therapeuticallyeffective 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.

[0063] 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 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.

[0064] 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. 23A and 23B) followed by a secondary fluid F2 contained in a second or proximal fluid chamber 104 (shown in FIGS. 23A-23D). 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.

[0065] 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.

[0066] 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, or another terminal access portion of a vascular access device (VAD).

[0067] 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 130protruding 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.

[0068] 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.

[0069] 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. 23 A, 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.

[0070] 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 flowfrom the proximal chamber 104 to the distal chamber 102, while fluid flow from the distal chamber 102 to the proximal chamber 104 is prevented.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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. In someembodiments, and as shown in phantom in FIGS. 3-7, the valve stopper 10 may also include films, coatings, layers, or other barriers on distal- and proximal-facing sides thereof, that may improve gliding of the valve stopper 10 within the syringe barrel 106, for example.

[0076] According to some non-limiting embodiments, the membrane 12 of the valve stopper 10 may have a thickness that is between 0.2-7.0 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.

[0077] 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.

[0078] 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.

[0079] In some embodiments, an outer diameter of the ribs, rib_OD, is controlled based on an inner diameter of the barrel 106, barrel_ID, to provide a desired amount of compression of the ribs 26 or, put differently, to provide a desired amount of interference between the valve stopper 10 and the barrel 106. As one example, the rib thickness and the outer diameter of the ribs, rib_OD, is such that a compression rate of the ribs 26 is between 1% and 20%, and preferably between 2% and 12%, as defined according to:Compression Rate = (1 - (barrel_ID / rib_OD)) x 100.

[0080] With a compression rate of the ribs 26 within the range specified above, the ribs 26 function to maintain a consistent contact pressure against the syringe barrel 106, so as to prevent leakage of the second fluid in the proximal chamber 104 into the first fluid in the distal chamber 102, while not presenting an excessive amount of friction between the valve stopper 10 and inner surface 136 of the barrel 106 as the valve stopper 10 is moved distally through the syringe barrel, such that a gliding force for advancing the valve stopper 10 is kept at an acceptable level.

[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. 3-6, or a “shaped” surface that extends or protrudes proximally or distally. When presenting a shaped surface, the proximal face 20 of the membrane 12 may comprise a convex shape, a concave shape, or another suitable shape, as non-limiting examples. 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. 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.

[0082] 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 plurality of slits 28 formed therein that define and shape one or more beams 30 in the membrane 12 that may be actuated / deflected for permitting fluid flow through the membrane 12 when the beam(s) 30 is / are in an open position or configuration - i.e. when the beam(s) is / are deflected distally or “raised.” The slits 28 extend through at least a part of the thickness of the membrane 12 betweenthe 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 encompassing a “split” that comprises a cut formed through an entirety of a thickness of the membrane 12 and / or a “notch” that comprises a cut formed through only a portion of a thickness of the membrane 12, as described in more detail below. The slits 28 are arranged / configured to define beam(s) 30 that may deflect or raise 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.

[0083] 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 28a through the membrane 12.

[0084] In other embodiments, the slits 28 may extend through only a part of the thickness of the membrane 12, as shown in FIG. 7. 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, so as to define beams(s) 30 and create the fluid path 32 through the membrane 12 from the proximal face 20 to the distal face 22. To do so, the slits 28 form one or more notches 28b that are aligned with localized weakened zones in the membrane 12, i.e., tear apart portions, which cause 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 portions are tom, the notches 28b act as a guide for the flow of the composition along the fluid path 32 thus formed. The depth of the notches 28b is preferably comprised between about 20% to 100% of the thickness of the membrane 12 and, more preferably, between 50% and 100% of the thickness of the membrane 12.

[0085] According to aspects of the disclosure, the slits 28 formed in membrane 12 may be provided as coated or uncoated slits. That is, in embodiments where the slits 28 are formed by a lubricated blade that cuts through the membrane 12, then the slits 28 (i.e., the inner sides of membrane through which each slit is formed) may be coated with a lubricant, such as silicone as a non-limiting example. In embodiments where the slits 28 are formed by other means, then the then the slits 28 may be provided as uncoated slits with no lubricant therein / thereon.

[0086] According to aspects of the disclosure, the beam(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 or raised position), where fluid flow through the membrane 12 can occur, thereby establishing fluid communicationbetween 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 beam(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 beam(s) 30. The beam(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 beam(s) 30. In some examples, the slits 28 and beam(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 beam(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 slits 28 and beam(s) 30 are in the closed position. The beam(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 beam(s) 30.

[0087] The activation or opening force Fopfor the beam(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 rod of a syringe through the syringe barrel. In some examples, the activation or opening force Fopfor the beam(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 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 beam(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.

[0088] 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 slits 28 and beam(s) 30 only when the composition / fluid flows in the distal direction, i.e., the direction of injection. In other terms, the beam(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 beam(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.

[0089] According to aspects of the disclosure, the valve stopper 10 is designed so that the slits 28 and beam(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. In particular, the positioning, shape, length, depth, and spacing between slits 28 (to define beam width) may be selected to tune or otherwise control the valve robustness, valve opening strength, and fluid flow or flux through the valve stopper 10.

[0090] FIGS. 8-15 present various slit and beam configurations that may be implemented in the membrane 12, according to embodiments of the disclosure. In each of the slit configurations, the slits 28 are formed in membrane 12 so as to be off-center from a center point 34 of the membrane 12. That is, none of the slits 28 formed in membrane 12 cross over / through the center point 34 of the membrane 12, as it is recognized that the center point 34 is the convergence point of all forces acting on the membrane 12, and that it is desirable to preserve the integrity / stability of the center point. Additionally, in each of the slit configurations, at least a portion of the slits 28 is arranged in pairs to define one or more beams 30 in the membrane 12 - with each pair of slits 28 spaced apart and arranged generally in parallel to define a respective beam 30. That is, a first slit 28i and a second slit 28ii of a respective pair of slits 28 are spaced apart - such as by a minimum distance of 0.05 mm and a maximum distance defined as twice a thickness of the membrane 12. The first slit 28i and second slit 28ii of a respective pair of slits 28 are formed in membrane 12 so as to have a generally similar configuration / profile and are arranged generally along a same path - i.e., the first slit 28i and the second slit 28ii are parallel, co-linear, etc.

[0091] FIGS. 8 and 9 illustrate membranes 12 including a pair of slits 28 arranged to form a single beam 30. The slits 28 may be configured as linear slits (FIG. 8) or wavy / sinusoidal slits (FIG. 9), according to non-limiting embodiments. The slits 28 are formed off-center on the membrane 12, so as to not extend across the center point 34 of membrane 12, although the beam 30 may extend across the center point 34. As described previously, a first slit 28i and a second slit 28ii of the pair of slits 28 may be spaced apart by a minimum distance of 0.05 mm and a maximum distance defined as twice a thickness of the membrane 12. This thickness of the beam 30 provides for stability thereof and sets the predetermined opening force Fo, of the beam 30 at an acceptable level that is not too low (to prevent unwanted deflection / opening of the beam 30) and is not too high (so as to require excessive force to deflect / open the beam 30).

[0092] FIGS. 10 and 11 illustrate membranes 12 including multiple pairs of slits 28 arranged to form a plurality of beams 30. In the illustrated embodiments, three pairs of slits 28 and three corresponding beams 30 are provided in the membranes 12, although it is recognized that other numbers of slits 28 and beams 30 could be formed in membrane 12. The slits 28 may be configured as linear slits (FIG. 10) or curved, arc-shaped slits (FIG. 11), according to nonlimiting embodiments. The slits 28 are formed off-center on the membrane 12, so as to not extend across the center point 34 of membrane 12. As shown, the slits 28 are further provided as juncted slits - meaning that the slits 28 from each pair of slits are joined with the slits 28 from other pairs of slits. In the illustrated embodiments, the pairs or slits 28 all meet at a central junction 36, with beams 30 defined thereby forming a three-legged arrangement of beams 30 extending out from the central junction 36.

[0093] FIGS. 12 and 13 illustrate membranes 12 including multiple pairs of slits 28 arranged to form a plurality of beams 30, along with additional interconnecting slits 28x provided between the pairs of slits 28. In the illustrated embodiments, the slits 28 are configured as linear slits, with three pairs of slits 28 and three corresponding beams 30 (FIG. 12) or four pairs of slits 28 and four corresponding beams 30 (FIG. 13) being provided in the membranes 12, although it is recognized that other numbers of slits 28 and beams 30 could be formed in membranes 12. As shown, each pair of slits 28 is spaced apart from the other pairs of slits 28, but the interconnecting slits 28x are formed to extend between adjacent pairs of slits 28. With the arrangement of slits 28 as described, a central region 38 is thus defined by / within the arrangement of interconnecting slits 28x, with a portion of each of the beams 30 extending into the central region 38.

[0094] FIG. 14 illustrates a membrane 12 including multiple pairs of slits 28 arranged to form a plurality of beams 30. In the illustrated embodiment, three pairs of slits 28 and threecorresponding beams 30 are provided in the membrane 12, although it is recognized that other numbers of slits 28 and beams 30 could be formed in membrane 12. The slits 28 may be configured as curved, arc- shaped slits 28 that are formed off-center on the membrane 12, so as to not extend across the center point 34 of membrane 12. As shown, the pairs of slits 28 (and the beams 30 formed thereby) are arranged about a central region 38, with the slits 28 in each pair radially offset and staggered relative to the slits 28 in the adjacent pairs. The beams 30 formed in membrane 12 are thus positioned such that ends thereof are adjacent the ends of the other beams 30, but the beams 30 are separately defined due to the staggering / offsetting thereof.

[0095] FIG. 15 illustrates a membrane 12 including an arrangement of slits 28 arranged to collectively form a plurality of beams 30. In the illustrated embodiments, three slits 28 are formed in membrane to form three corresponding beams 30 in the membrane, although it is recognized that other numbers of slits 28 and beams 30 could be formed in membrane 12. Each of the slits 28 is formed of a pair of linear segments 28s joined at an angle (e.g., an acute or right angle, as non-limiting examples). The slits 28 are formed off-center on the membrane 12, so as to not extend across the center point 34 of membrane 12, and are arranged about a central region 38. Each of the slits 28 is formed adjacent to the other slits 28, but such that the slit 28 is offset or staggered relative to the other slits 28 - with the slits 28 thus arranged so that pairs of slit segments 28s may define the beams 30 in membrane. The beams 30 formed in membrane 12 are positioned such that ends thereof are adjacent the ends of the other beams 30, with the beams 30 arranged about the central region 38.

[0096] Referring now to FIG. 16, illustration of beams 30 being deflected and raised responsive to an opening force, Fo, being applied thereto is illustrated, according to an embodiment of the disclosure. While the beam deflection illustrated in FIG. 16 is directed specifically to the membrane 12 of FIG. 14 - with beams 30 surrounding a central region 38 - similar deflection of the beam(s) occurs in the other membranes 12 illustrated in FIGS. 8-13 and 15. As described previously, one or more beams 30 may be caused to deflect or raise when the fluid pressure P2 in the proximal chamber 104 of the syringe barrel 106 (see FIG. 23A) is greater than or equal to the predetermined opening force Fo, of the beams 30, with a fluid path or window 32 provided through the membrane 12 when the beams 30 are raised. As shown in FIG. 16, with the beams 30 forced to a raised position, the central region 38 is also raised up from a remainder of the membrane 12.

[0097] While embodiments of various membranes 12 are shown in FIGS. 8-16 as including a plurality of slits 28 formed in the membrane 12 that are arranged to define one or more beams30 in the membrane 12, other embodiments of membrane 12 may include one or more “long” slits 28 formed therein that define and shape one or more flaps 40 in the membrane 12 for permitting fluid flow therethrough when the flap(s) 40 is / are in an open position / configuration. As defined herein, a “long slit” refers to a slit 28 or slits 28 that - when the length(s) thereof are totaled together - have a collective length that is equal to or greater than a diameter of a theoretical circle 42 (on membrane 12) that circumscribes the slit(s) 28, with the theoretical circle having a diameter, Dcirc, as shown in FIG. 17. The theoretical circle has a minimum diameter of 1 mm, and a maximum diameter equal to or less than the inner diameter of the internal cavity, IDv, formed by the lateral wall 14, minus (-) 0.05 mm, and preferably minus (- ) 0.1 mm or more. The slit(s) 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 to define the flap(s) 40, with the flap(s) 40 selectively providing a fluid path or window 32 through the membrane 12 from the proximal face 20 to the distal face 22 of the membrane 12 when opened.

[0098] According to aspects of the disclosure, the flap(s) 40 are configured to transition between a closed position (i.e., undeflected position), where fluid flow through the membrane 12 is prevented, and an open position (i.e., deflected 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 FOp of the flap(s) 40 - which corresponds to the force / pressure that needs to be exerted onto the proximal face 20 of the membrane 12 for opening the flap(s) 40. The flap(s) 40 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) 40.

[0099] The activation or opening force Fopfor the flap(s) 40 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 flap(s) 40 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 isconfigured such that the activation or opening pressure for the flap(s) 40 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.

[0100] As previously described, in some embodiments, the slit(s) 28 may be 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 split(s) 28a through the membrane 12. In some examples, a single split 28a may be formed as a single continuous segment (e.g., line, curve, spiral, etc.). In other examples, multiple splits 28a may be formed that collectively form flaps 40 of a desired configuration. In any configuration, the split(s) 28a and the flap(s) defined thereby function as a valve configured to open or close the fluid path 32 depending on the pressure exerted by a composition onto the proximal face 20 of the membrane 12, as described in detail above.

[0101] In other embodiments, the slit(s) 28 may be provided as notches 28b (see FIG. 7) that 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 slit(s) 28 under a determined pressure exerted by the composition, so as to define flap(s) 40 and create the fluid path 32 through the membrane 12 from the proximal face 20 to the distal face 22. When the tear apart portion(s) are torn, the notch(es) 28b act as a guide for the flow of the composition along the fluid path 32 thus formed. The tear apart portion(s) form flap(s) 40 that define a valve configured to open or close the fluid path 32 depending on the pressure exerted by the composition onto the proximal face 20 of the membrane 12. The depth of the notch(es) 28b 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.

[0102] According to aspects of the disclosure, the valve stopper 10 is designed so that the slit(s) 28 formed in the membrane 12 are configured to provide a desired valve robustness, 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.In particular, the positioning, shape, length, depth, and junction distance between slits 28 (when multiple slits) 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. 18-22 present various “long” slit configurations that may be implemented in the membrane 12, according to embodiments of the disclosure. In each of the slit configurations, the slit(s) 28 are formed in membrane 12 so as to be off-center from a center circle, O, of the membrane 12, i.e., a circle centered about a center point 34 of membrane 12. That is, none of the slits 28 formed in membrane 12 cross over / through a center circle, O, of the membrane 12, as it is recognized that the center circle, O, is the convergence point of all forces acting on the membrane 12, and that it is desirable to preserve the integrity / stability thereof. According to embodiments the center circle, O, may have a diameter between 1% and 10% of the outer diameter of the valve stopper 10, and preferably between 1.4% and 5% of the outer diameter of the valve stopper 10. In some embodiments, the center circle, O, may thus have a diameter of 0.1 mm or greater.

[0104] FIG. 18 illustrates a membrane 12 including a single slit 28 configured as a circular arc. The circular arc slit 28 is formed off-center on the membrane 12, so as to not extend into an area of central circle, O. Additionally, the circular arc slit 28 is formed on the membrane 12 so as to be inset from the lateral wall 14 of valve stopper 10 - with the slit 28 spaced apart a minimum of 0.5 mm from the inner diameter of the lateral wall 14, and preferably 1.0 mm or more. A single, semi-circular flap 40 is thus defined that opens along the slit 28, to provide the fluid path 32 through the membrane 12.

[0105] FIG. 19 illustrates a membrane 12 including a single slit 28 configured as a curved spiral (i.e., golden spiral). The spiral slit 28 is formed off-center on the membrane 12, so as to not extend into an area of central circle, O. Additionally, the spiral slit 28 is formed on the membrane 12 so as to be inset from the lateral wall 14 of valve stopper 10 - with the slit 28 spaced apart a minimum of 0.5 mm from the inner diameter of the lateral wall 14, and preferably 1.0 mm or more. A single, spiral shaped flap 40 is thus defined that opens along the slit 28, to provide the fluid path 32 through the membrane 12.

[0106] FIG. 20 illustrates a membrane 12 including a single slit 28 configured as a linear spiral (i.e., linear segments connected / arranged in a spiral pattern). The linear spiral slit 28 is formed off-center on the membrane 12, so as to not extend into an area of central circle, O. Additionally, the linear spiral slit 28 is formed on the membrane 12 so as to be inset from the lateral wall 14 of valve stopper 10 - with the slit 28 spaced apart a minimum of 0.05 mm from the inner diameter of the lateral wall 14, and preferably 0.1 mm or more. A single, linear spiralshaped flap 40 is thus defined that opens along the slit 28, to provide the fluid path 32 through the membrane 12.

[0107] FIGS. 21 and FIG. 22 illustrate membranes 12 that each include an arrangement of identical slits 28, with each slit 28 formed of a pair of segments 28 s. In the embodiment of FIG. 21, each of the slits 28 is formed of a linear segment joined with a circular arc segment - such that each slit 28 defines a fin-shaped flap 40. In the embodiment of FIG. 22, each of the slits 28 is formed of a pair of linear segments 28s joined at an acute angle - such that each slit 28 defines a triangular flap 40. For each embodiment, an arrangement of four (4) slits 28 is positioned about the central circle, O, of membrane 12, with the slits 28 formed in membrane 12 such that each flap 40 is rotated relative to the flaps 40 adjacent thereto. In some embodiments, each flap 40 is rotated relative to the flaps 40 adjacent thereto by 2K / N radians, where N is an integer > 1. Additionally, the slits 28 are formed on the membrane 12 so as to be inset from the lateral wall 14 of valve stopper 10 - with each of the slits 28 having its segments 28s spaced a minimum of 0.5 mm from the inner diameter of the lateral wall 14, and preferably 1.0 mm or more.

[0108] With the slit(s) 28 in membrane 12 positioned and sized as described above, a valve stopper 10 is provided that increases a flow rate or flux therethrough, while allowing for tuning of a valve robustness that avoids membrane destruction or leak issues, and for tuning of a minimum opening force Fo, needed to open a fluid path 32 through the membrane 12. That is, the robustness of the valve stopper 10 may be increased as compared to a valve stopper having a slit 28 extending across a center point 34 / center circle, O, of the membrane 12, while the configuration, arrangement, and length of the slit(s) 28 provide for an increased flux / flow through the membrane 12 with a desired flow pattem / shape and for tuning of a minimum opening force Fo, needed to open a fluid path 32 through the membrane 12.

[0109] It is recognized that the exact construction / configuration of any of the valve stoppers 10 of FIGS. 3-22 - including the height and diameter of the stopper 10, the thickness of the membrane 12, and / or the size / shape / number of slits 28 - may be controlled to provide desired operational characteristics of the valve stopper 10. That is, during an injection, the flow through each window / fluid path 32 created by beam / flap lifting in membrane 12 (due to back chamber pressure) is controlled by the Hagen-Poiseuille law, which is defined as:Flow (Q) = (7tAPr4) / 8nlwhere AP is a pressure difference across the valve stopper 10, r is the radius of the valve stopper 10, n is a viscosity of the second fluid F2, and Z is a length of the valve stopper 10.

[0110] By taking into account the Hagen-Poiseuille law, the construction of valve stopper 10 may be tuned to have a highest value of flow, Q.

[0111] Referring now to FIGS. 23A-23D, 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.

[0112] 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.

[0113] 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.

[0114] 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 proximalchamber 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.

[0115] 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.

[0116] 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.

[0117] FIG. 23A 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 (i.e., split 28a or tear apart notch 28b) 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 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 beam(s) 30 or flap(s) 40 defined by slit(s) 28 thus remain closed (i.e., the beam(s) 30 or flap(s) 40 are not distally deflected or “raised”). The closed beam(s) 30 or flap(s) 40 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.

[0118] Referring now to FIG. 23B, 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.

[0119] In the configuration of FIG. 23B, the valve stopper 10 is in a sealing position, with the beam(s) 30 or flap(s) 40 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 beam(s) 30 or flap(s) 40. 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 beam(s) 30 or flap(s) 40. The beam(s) 30 or flap(s) 40 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. 15B.

[0120] Referring now to FIG. 23C, 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 beam(s) 30 or flap(s) 40. As a result, the beam(s) 30 or flap(s) 40 in membrane 12 are caused to deflect and open, thereby 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.

[0121] As shown in FIG. 23D, 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 stopper10, 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.

[0122] 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.

[0123] Referring now to FIG. 24A, 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. 23A-23C 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.

[0124] 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. 24A to 24C.

[0125] FIG. 24A 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 beam(s) 30 or flap(s) 40, 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 beam(s) 30 or flap(s) 40, so that beam(s) 30 or flap(s) 40 thus remains closed. The closed beam(s) 30 or flap(s) 40 prevent the single fluid from leaking into channel 118 of tip 116.

[0126] Referring now to FIG. 24B, 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 124causes 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 beam(s) 30 or flap(s) 40 in membrane 12 is / are caused to deflect / raise and open, thereby allowing the single fluid to pass through the window(s) / fluid path(s) 32 defined by the beam(s) 30 or flap(s) 40 and to / through the channel 118 in tip 116 for the injection. In this configuration, the valve stopper 10 is in an injection position.

[0127] As shown in FIG. 24C, 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.

[0128] 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 beams or 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. 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 membrane - including the number, length, shape, and spacing of slits formed therein - may be optimized to provide for injection of a 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.

[0129] 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 presentdisclosure 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, the one or more slits 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; and wherein each of the one or more slits is formed off-center in the membrane, so as to not pass through a center point of the proximal and / or distal faces of the membrane.

2. The valve stopper of claim 1, wherein the one or more slits comprises a plurality of slits, the plurality of slits including at least a first slit and a second slit that are spaced apart and in parallel, so as to define a beam, and wherein the beam is configured to selectively deflect in a distal direction to create the fluid path through the membrane.

3. The valve stopper of claim 2, wherein the beam has a minimum width of 0.05 mm and a maximum width that is twice a thickness of the membrane.

4. The valve stopper of claim 1, wherein the plurality of slits includes multiple pairs of slits that define a plurality of beams.

5. The valve stopper of claim 4, wherein the slits of a respective pair of slits are joined with the slits from the other pairs of slits, with the multiple pairs or slits meeting at a central junction, with the plurality of beams extending out from the central junction.

6. The valve stopper of claim 5, wherein the plurality of beams are spaced apart from one another about a central region of the membrane, and wherein the plurality of slits further includes interconnecting slits that extend between adjacent pairs of slits that define the plurality of beams, with the interconnecting slits defining the central region.

7. The valve stopper of claim 6, wherein a portion of each of the plurality of beams extends into the central region of the membrane.

8. The valve stopper of claim 1, wherein each of the one or more slits comprises a long slit, where a total length of the one or more slits is equal to or greater than a diameter, of a theoretical circle on the membrane that circumscribes the one or more slits, with the theoretical circle having a minimum diameter of 1.0 mm and a maximum diameter equal to an inner diameter of the lateral wall, minus (-) 0.05 mm.

9. The valve stopper of claim 8, wherein the maximum diameter of the theoretical circle is equal to the inner diameter of the lateral wall, minus (-) 0.1 mm or more.

10. The valve stopper of claim 8, wherein the one or more slits are formed off-center in the membrane, so as to not pass through a center circle that is centered about the center point, the center circle having a diameter comprised between 1% and 10%, and preferably 1.4%-5% of the outer diameter of the stopper.

11. The valve stopper of claim 8, wherein the one or more slits comprises a single slit, the single slit defining a flap configured to selectively deflect in a distal direction to create the fluid path through the membrane.

12. The valve stopper of claim 11, wherein the single slit comprises a spiral slit.

13. The valve stopper of claim 12, wherein the spiral slit comprises a golden spiral or a linear spiral.

14. The valve stopper of claim 1, wherein the one or more slits comprises a plurality of slits defining a number of flaps configured to selectively deflect in a distal direction to create the fluid path through the membrane, and wherein each flap of the number of flaps is rotated relative to other flaps of the number of flaps that are adjacent thereto by 2K / N radians, where N is an integer > 1.

15. The valve stopper of claim 14, wherein each of the plurality of slits comprises a first slit segment and a second slit segment that define a respective flap.

16. The valve stopper of claim 15, wherein the first slit segment and the second slit segment comprises a linear segment and a circular arc segment, or a pair of linear segments joined at an angle.

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

18. The valve stopper of claim 1, wherein each of the one or more slits 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.

19. The valve stopper of claim 1, wherein the membrane is positioned at a distal end of the valve stopper, with the lateral wall extending proximally from the membrane; or wherein the membrane is positioned at a proximal end of the valve stopper, with the lateral wall extending distally from the membrane.

20. The valve stopper of claim 1, wherein the valve stopper is configured so that the membrane is positioned between a distal end and a proximal end of the valve stopper, with the lateral wall extending both proximally and distally from the membrane, such that the at least one cavity comprises a first cavity formed distally from the membrane and a second cavity formed proximally from the membrane.

21. 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 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, 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, the one or more slits 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; and wherein each of the one or more slits is formed off-center in the membrane, so as to not pass through a center point of the proximal and / or distal faces of the membrane; 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.

22. The medical injection device of claim 21, 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.

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

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