Multi-channel sequential stopper for a medical injection device

Abstract

Provided herein is a sequential stopper positionable within a barrel of an injection device. The sequential 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 capillary channels formed therein that extend through a thickness of the membrane. The capillary channels provide a fluid path through the membrane for transferring of a second fluid from the second chamber to the first chamber, with a flow of the second fluid through the fluid path being selectively prevented or allowed depending on the strength of an injection force exerted by the second fluid onto the proximal face of the membrane.

Description

Attorney Docket No.04606-2502111 (P-30019.WO01) MULTI-CHANNEL SEQUENTIAL STOPPER FOR A MEDICAL INJECTION DEVICE CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 646,065 entitled “Multi-Channel Sequential Stopper for a Medical Injection Device” filed May 13, 2024, the disclosure of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention

[0002] The present disclosure relates generally to a sequential stopper for a medical injection device containing doses of multiple fluids and, in particular, to a sequential 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 the 6407943.DOCX Page 1 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) practitioners. Furthermore, such prefilled containers may encourage and simplify self- administration 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 “sequential 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 sequential stoppers function to effectively prevent the mixing of the two solutions and provide for a sequential injection of the fluids; however, existing sequential stoppers do have a number of drawbacks associated therewith. As one example, the configuration of the sequential 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 6407943.DOCX Page 2 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) sequential stopper may be complex – such as being configured as a multi-component stopper where a valve is separate from a stopper body - which may be detrimental for the functioning of the valve assembly and / or its manufacturing. As still further examples, the design of existing sequential 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 sequential stopper that addresses the aforementioned drawbacks. SUMMARY OF THE INVENTION

[0010] Provided herein is a sequential 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 sequential 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 containing the first fluid from a second, proximal chamber of the barrel containing the second fluid. The sequential stopper also includes a lateral wall joined to the membrane, the lateral wall comprising a circumferential sealing surface configured to sealingly engage the inner surface of the barrel. The membrane includes a channel opening area comprising one or more capillary channels that extend through a thickness of the membrane between the proximal face and the distal face, each of the one or more capillary channels providing a fluid path through the membrane from the proximal face to the distal face for only transferring the second fluid from the second chamber to the first chamber, with a flow of the second fluid through the fluid path being selectively prevented or allowed depending on the strength of an injection force exerted by the second fluid onto the proximal face of the membrane.

[0011] In certain configurations, each of the one or more capillary channels has a channel length and a channel diameter that prevent the flow of the second fluid through the fluid path with the multi-chamber injection device at rest or during injection of the first fluid and allow the flow of the second fluid through the fluid path upon application of an injection force of 1 N or more.

[0012] In certain configurations, the flow of the second fluid through the fluid path is caused upon application of an injection force preferably less than 30 N.

[0013] In certain configurations, the channel length is between 0.6 mm and 30 mm.

[0014] In certain configurations, the channel diameter is between 40µm and 1.8mm. 6407943.DOCX Page 3 of 28Attorney Docket No.04606-2502111 (P-30019.WO01)

[0015] In certain configurations, during injection of the first fluid, the flow of the second fluid through the fluid path is prevented by an equilibrated capillary rise of each of the first fluid and the second fluid into the one or more capillary channels, with the channel length being greater than a total length of the capillary rise of the first fluid and the second fluid.

[0016] In certain configurations, during injection of the second fluid, the flow of the second fluid through the fluid path is allowed based on the applied injection force being greater than a flow resistance through the one or more capillary channels, as determined by a capillary rise force and a Hagen Poiseuille flow law for the second fluid through the one or more capillary channels.

[0017] In certain configurations, the membrane is configured to flex between an initial configuration and a deflected configuration, with the membrane flexing in the distal direction.

[0018] In certain configurations, with the membrane in the initial configuration, each capillary channel has a cylindrical or frustoconical shape, and wherein with the membrane in the deflected configuration, each capillary channel has a frustoconical shape or amplified frustoconical shape, where each capillary channel has a first channel diameter at a proximal opening thereof and a second channel diameter at a distal opening thereof, the second channel diameter greater than the first channel diameter.

[0019] In certain configurations, the membrane has a convex shape in the initial configuration and a concave shape in the deflected configuration.

[0020] In certain configurations, the membrane has a flat shape in the initial configuration and a concave shape in the deflected configuration.

[0021] In certain configurations, the membrane has a concave shape in the initial configuration and a more concave shape in the deflected configuration.

[0022] In certain configurations, the sequential stopper is formed of an elastomer or a thermoplastic material.

[0023] In certain configurations, the membrane is positioned at a distal end of the sequential stopper, a proximal end of the stopper, or at a location between the distal end and the proximal end.

[0024] In certain configurations, the membrane extends between a distal end of the sequential stopper and a proximal end of the sequential stopper, such that no cavity provided in the sequential stopper.

[0025] 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 6407943.DOCX Page 4 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 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 sequential stopper arranged between the distal end of the barrel and the plunger stopper, and adapted to be translationally movable inside the barrel. The sequential 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 sequential stopper further comprises a lateral wall joined to the membrane, 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 sequential stopper and a second chamber is defined within the barrel between the sequential stopper and the plunger stopper.

[0026] 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 sequential stopper is spaced apart distally from the end wall to separate the first chamber from the second chamber.

[0027] In certain configurations, the medical injection device is one of a syringe or a cartridge.

[0028] In certain configurations, the sequential stopper comprises one of a 1 mL, 1-3 mL, 5mL, 10mL, or 20mL stopper.

[0029] In certain configurations, the sequential stopper comprises a mono-component, mono-material stopper. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 is a perspective view of a multi-chamber medical injection device, according to a non-limiting embodiment described herein;

[0031] FIG. 2 is an exploded view of the multi-chamber medical injection device of FIG. 1;

[0032] FIG. 3 is a perspective view of a sequential stopper for use in a medical injection device, according to a non-limiting embodiment described herein;

[0033] FIG. 4 is a cross-sectional view of the sequential stopper of FIG. 3;

[0034] FIG. 5 is a cross-sectional view of a sequential stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0035] FIG. 6 is a cross-sectional view of a sequential stopper for use in a medical injection device, according to another non-limiting embodiment described herein; 6407943.DOCX Page 5 of 28Attorney Docket No.04606-2502111 (P-30019.WO01)

[0036] FIG. 7 is a cross-sectional view of a sequential stopper for use in a medical injection device, according to another non-limiting embodiment described herein;

[0037] FIGS.8A and 8B are cross-sectional views of a sequential stopper for use in a medical injection device, with a membrane thereof in an initial configuration and a deflected configuration, respectively, according to a non-limiting embodiment described herein;

[0038] FIGS.9A and 9B are cross-sectional views of a sequential stopper for use in a medical injection device, with a membrane thereof in an initial configuration and a deflected configuration, respectively, according to another non-limiting embodiment described herein;

[0039] FIGS. 10A and 10B are cross-sectional views of a sequential stopper for use in a medical injection device, with a membrane thereof in an initial configuration and a deflected configuration, respectively, according to another non-limiting embodiment described herein;

[0040] FIG. 11 is a detailed view of a capillary channel formed in the membrane of a sequential stopper included in a medical injection device, before and after a distal deflection of the membrane, according to a non-limiting embodiment described herein;

[0041] FIG. 12 illustrates capillary rise of a first fluid and a second fluid through a capillary channel formed in the membrane of a sequential stopper included in a medical injection device, according to a non-limiting embodiment described herein; and

[0042] FIGS. 13A-13D illustrate various configurations of the injection device of FIG. 1 during injection of first and second fluids from the device. DESCRIPTION OF THE INVENTION

[0043] 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.

[0044] 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. 6407943.DOCX Page 6 of 28Attorney Docket No.04606-2502111 (P-30019.WO01)

[0045] 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.

[0046] With reference to the figures, the present disclosure is directed to a sequential 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 sequential 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 sequential stopper 10 comprises a membrane that allows the secondary fluid contained in the proximal chamber of the injection device 100 to pass through the sequential 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.

[0047] As described in further detail herein, the sequential 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 sequential stopper by opening the valve smoothly, providing a desired flux or flowrate through the stopper, and / or maintaining valve robustness or integrity until injection.

[0048] The present disclosure is also directed to features of a prefilled multi-chamber injection device 100 including the sequential stopper 10. In particular, the multi-chamber injection device 100 can be configured to expel the initial fluid followed by the secondary fluid 6407943.DOCX Page 7 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 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.

[0049] 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 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.

[0050] FIGS. 1 and 2 illustrate an example of a multi-chamber injection device 100 for sequential expulsion of at least an initial fluid F1 contained in a first or distal fluid chamber 6407943.DOCX Page 8 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 102 (shown in FIGS. 13A and 13B) followed by a secondary fluid F2 contained in a second or proximal fluid chamber 104 (shown in FIGS. 13A-13D). 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.

[0051] As previously described, the initial fluid F1 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 F1 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 F1 and / or the secondary fluid F2.

[0052] 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 F1 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).

[0053] 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 6407943.DOCX Page 9 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 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.

[0054] 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, and leakage of a fluid contained in the internal volume of the barrel.

[0055] As indicated above, the syringe 100 further comprises a sequential stopper 10 slidably positioned within the barrel 106 of the syringe 100. The sequential stopper 10 separates the barrel 106 into the proximal chamber 104 and the distal chamber 102. Specifically, as shown most clearly in FIG. 13A, the proximal chamber 104 is between a distal end of the plunger stopper 124 and a proximal end of the sequential stopper 10 and the distal chamber 102 is between a distal end of the sequential stopper 10 and the distal end 110 of the barrel 106.

[0056] According to aspects of the disclosure, the sequential 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 sequential stopper 10 may be moved distally through the barrel 106 responsive to a distal movement of the plunger stopper 124, with the sequential 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 sequential stopper 10 further enables 6407943.DOCX Page 10 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) injection of the second fluid through the sequential stopper 10 by opening a fluid path therethrough, 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 sequential stopper 10 functions to selectively control fluid flow between the proximal chamber 104 and the distal chamber 102, with the sequential stopper 10 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.

[0057] Referring now to FIGS.3 and 4, shown is a non-limiting embodiment of a sequential stopper 10 that may be included in injection device 100, according to one aspect of the disclosure. The sequential 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.

[0058] In the embodiment represented in FIGS. 3 and 4, the membrane 12 is positioned at a distal end 23 of the sequential 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.

[0059] According to another embodiment, and as shown in FIG.5, the sequential 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 sequential 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.

[0060] According to still another embodiment, and as shown in FIG. 6, the sequential stopper 10 may be configured such that the membrane 12 is positioned at a proximal end 25 of the sequential 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.

[0061] In still another embodiment, and as shown in FIG. 7, the sequential stopper 10 may be constructed so as to not include a cavity 16 therein – i.e., a “plain” or solid stopper. That is, 6407943.DOCX Page 11 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) the sequential stopper 10 is formed so that membrane 12 forms an entire height / thickness of the stopper 10, with a lateral wall 14 provides about the membrane 12 to provide a sealing surface configured to sealingly engage the inner surface 136 of the barrel 106, as explained in further detail below. A sequential stopper 10 with such a plain construction may be desirable for larger volume stoppers / syringes, such as a 20 mL stopper / syringe, as a non-limiting example.

[0062] The sequential stopper 10 may be made of any material with elastomeric properties usually used to manufacture stoppers for medical injection devices. For example, the sequential stopper 10 may be made of elastomer, rubber such as halobutyl rubber, thermoplastic elastomer, or liquid silicon rubber. In an exemplary embodiment, the sequential 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 sequential stopper 10 allowing for flexing and / or deformation of the membrane 12 thereof. According to some non-limiting embodiments, the membrane 12 of the sequential stopper 10 may have a thickness that is between 0.6-30 mm, depending on the configuration / shape of the membrane (e.g., flat, convex, or concave) and a sizing of the sequential 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 channel opening area 28 that includes capillary channels 30 therein, as explained in further detail below), the thickness of the membrane 12 will preferably be from 0.6 to 3.0 mm.

[0063] As shown in FIGS.3-7, the sequential stopper 10 has a substantially cylindrical shape, which corresponds to the shape of the barrel 106 of the injection device in which the sequential stopper 10 is intended to be inserted. Accordingly, the lateral wall 14 of the sequential 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 sequential stopper 10 and forms a ring. Since the continuous surface extends between the outer face of the lateral wall 14 of the sequential stopper 10 and the inner surface 136 of the barrel 106 of the injection device 100, any passage of a composition between the sequential stopper 10 and the barrel 106 is prevented. Optimal sealing is thus ensured.

[0064] 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 6407943.DOCX Page 12 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) optimize the sealing depending on the dimensions of the sequential stopper 10 and the barrel 106. According to the illustrated embodiment, the sequential 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 sequential stopper 10 and the inner surface 136 of the barrel 106 of the injection device 100, compared to a plane lateral wall of the sequential stopper 10, thus improving the gliding performance of the sequential stopper 10 relative to the barrel 106. As a result, the force that needs to be exerted onto the sequential 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 sequential stopper 10 increases the stability of the sequential 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.

[0065] According to aspects of the disclosure, in any of the embodiments of the sequential stoppers 10 shown in FIGS. 3-7, the membrane 12 (in at least the channel opening area 28) may comprise a flat or planar member or may comprise a “shaped” member having a convex or concave shape, as shown in FIGS. 8-10. That is, with the membrane 12 in its initial / undeflected configuration, the membrane 12 may have a generally flat configuration (FIG. 8A), a convex configuration (FIG. 9A), or a concave configuration (FIG. 10A). When the membrane 12 is caused to flex in the distal direction (responsive to a fluid force applied thereof by the second fluid F2, as explained in further detail below), the initial configuration deforms / flexes to a deflected configuration, such as by the flat configuration flexing to a concave configuration (FIG. 8B), the convex configuration flexing to a concave configuration (FIG. 9B), or the concave configuration flexing to a more concave configuration (FIG. 10B). As defined herein, the term “convex”, as relates to membrane 12, means that the membrane 12 is curved and that the apex of the curvature extends in the proximal direction, while the term “concave”, as relates to the membrane 12, means that the membrane 12 is curved and that the apex of the curvature extends in the distal direction.

[0066] According to aspects of the disclosure, in any of the embodiments of the sequential stoppers 10 shown in FIGS. 3-7 and FIGS. 8-10, the membrane 12 includes one or more capillary channels 30 formed therein that function to selectively prevent or allow fluid flow through the membrane 12. While each of the sequential stoppers 10 shown in FIGS.3-10 show the membrane 12 as including three (3) capillary channels 30 formed therein, it is recognized that a greater or lesser number of capillary channels 30 could be included in membrane 12. As illustrated, each of the capillary channels 30 extends through the full thickness of the membrane 6407943.DOCX Page 13 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 12, between the proximal face 20 and the distal face 22 of the membrane 12, to provide a fluid path 32 through the membrane 12 from the proximal face 20 to the distal face 22 of the membrane 12, as explained in further detail below. In embodiments where three or more capillary channels 30 are included in membrane 12, it may be desirable to form / place the capillary channels 30 along a hypothetical segment, triangle, square, pentagon, circle, etc., where the capillary channels 30 are not regularly disposed on the membrane 12, in order to respect manufacturing tolerances during fabrication of the sequential stopper 10.

[0067] According to aspects of the disclosure, the capillary channels 30 function to selectively prevent or allow fluid flow through the membrane 12 based on controlling of a capillary-based flow of fluids therethrough. In particular, a channel length Lcand a channel diameter Dcof the capillary channels 30 may be selected that prevents a flow of the first and / or second fluids F1, F2 through the capillary channels 30 when the syringe 100 is “at rest” (i.e., no injection is being performed) and when an injection of the first fluid F1 is occurring. However, upon application of a sufficient distally directed fluid force being applied onto the proximal face 20 of the membrane 12 (by second fluid F2), a flow of the second fluid F2 in the proximal-to-distal direction through the capillary channels 30 may be enabled.

[0068] In some embodiments, and as shown in FIG. 11, the shape of the capillary channels 30 in membrane 12 may change upon flexing / deflection of the membrane 12 from the initial configuration to the deflected configuration. That is, with the membrane 12 is in the initial configuration (such as shown in FIGS. 8A, 9A and 10A), each capillary channel 30 may have a cylindrical or a frustroconical shape, but upon flexing / deflection of the membrane 12 to the deflected configuration (such as shown in FIGS. 8B, 9B and 10B), each capillary channel 30 may be actuated to have a frustoconical shape or an amplified frusctroconical shape, where each capillary channel 30 has a first channel diameter Dc1at a proximal opening 34 thereof and a second channel diameter Dc2 at a distal opening 36 thereof, with the second channel diameter Dc2 greater than the first channel diameter Dc1. When the capillary channel 30 has a frustroconical shape, the diameter of the channel 30 at its proximal face 20 (i.e., first channel diameter Dc1 at a proximal opening 34) is lower than the diameter of the channel 30 at its distal face 22 (second channel diameter Dc2 at a distal opening 36).

[0069] With regard to the structure of the capillary channels 30, it is recognized that the smaller the channel diameter Dcof the capillary channels 30, the larger the strength / pressure (i.e., injection strength) that is required to cause a flow of the second fluid through the capillary channels 30. Conversely, the larger the channel diameter Dc of the capillary channels 30, the greater the risk of mixing the first and second fluids F1, F2 from each side of the capillary 6407943.DOCX Page 14 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) channels 30 in a non-controlled manner, due to a capillary rise of the first and second fluids F1, F2 into / through the capillary channels 30. As known, capillary rise and force (CRc) may be described as follows: ℎ=^^^^^^^^ ^= ℎ^^^^^^+ ^^^ ^where ℎ is the length of the capillary rise under pressure equilibrium and ^ is the height at thetop of the meniscus (of the fluid), = 0,072%. &'( surface tension for water for injection,^ = 100° − 120° is the Droplet Contact angle between liquid and the sequential stoppermaterial (for bromobutyl rubbers), , = 1000-.. &' / for water density, g = 9,8m. s'^, ^^ isthe radius of the capillary channel, and ^^^^is the force exerted by the capillary rise.

[0070] With it known that there is a capillary rise of the first and second fluids F1, F2 into / through the capillary channels 30, a capillary channel length Lc must be provided (which is also the thickness Tm of the membrane 12, at least in the channel opening area 28) that is sufficient to prevent mixing of the first and second fluids F1, F2 with such a capillary rise. That is, as illustrated in FIG. 11, capillary channels 30 are provided having a capillary channel length Lc that is greater than a combined height of the capillary rise (CR) of the first and second fluids, indicated as CR1 and CR2, to prevent mixing of the first and second fluids F1, F2.

[0071] Regarding the initiation of a flow of the second fluid F2 through the capillary channels 30 when injecting the second fluid F2, the injection force is driven by the capillary rise force (positive or negative depending on sequential stopper material water contact angle) and the Hagen Poiseuille flow law for the second fluid F2 through the capillary channels (HPc). The Hagen Poiseuille law is described as follows:where: Δ^4, ^DE4, Δ^^and ^DE^are respectively the pressure difference and flow rate resistance force to flow through the needle 118, and the pressure difference and flow rate resistance force through the capillary channels 30; ΔP_n is the pressure difference between the two ends; ^@is 6407943.DOCX Page 15 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) the internal radius of the syringe barrel 106 (typically, 6.35mm for 1mlL barrel format, 8,65mm for 1-3 ml barrel format, or larger for larger format (e.g. 5ml, 10ml, 20ml, 50ml)); H4is the length of the needle 118, spanning from typically down to 12.45mm (for 8mm exposed needle length) to typically up to 21.5mm (for 5 / 8’’ exposed needle length) or more for longer needles (e.g. 1’’, 1’’ ¼ or 1 ½’’ needles); ^4is the internal radius of the needle 118, spanning from typically from 0.1 mm for 27G Regular Wall to 0.17 mm for 27G ultra-thin wall or more for larger needles (e.g. 25G, 23G, 22G, 21G, 20G, 19G); H^is the length of the capillary channel; is the radius of the capillary channel; %^is the number of capillary channels 30 in the membrane 12; η is the dynamic viscosity; and Dvis the volumetric flow rate.

[0072] With the afore-mentioned definitions and equations provided, the main parameters of the capillary channels 30, which are the channel length, channel radius (and diameter), andnumber of channels (H^ , ^^ and %^, respectively), can be selected to enable proper performanceof the syringe 100 when at rest, during an injection of the first fluid F1, and during injection of the second fluid F2. In general, the number of capillary channels 30 formed in membrane 12 may be between 1 and 10 channels, and preferably between 3 and 5 channels, while the channel length of the capillary channels 30 may be between 0.6 mm and 30 mm and the channel diameter of the capillary channels 30 may be between 40 µm and 1.8 mm. The specific dimensions / numbers for these capillary channel parameters will be dependent on each other, and on the size of the syringe 100 in which the valve member 10 is use.

[0073] Following here below, an operational sequence of the syringe 100 is described, withselection of the channel length, channel radius / diameter, and number of channels (H^ , ^^ and%^, respectively), being a function of the dimensioning constraints discussed here below.

[0074] First, it is recognized that a capillary channel diameter Dc (or radius Rc) must beprovided that allows the capillary phenomena need to occur, according to: ^^ ≤ min^LM; LO ^.

[0075] Regarding the syringe 100 and use thereof, the syringe 100 will be provided in an initial configuration, where the syringe 100 is at rest. In such a condition, the capillary channel length Lcmust be sufficient to keep the first and second fluids F1, F2 separated in each capillary channel 30 while in the rest condition, according to: H^ ≥ 2^^M + ^O^,where ^Mis the capillary height for the first fluid and ^Ois the capillary height for the second fluid F2. 6407943.DOCX Page 16 of 28Attorney Docket No.04606-2502111 (P-30019.WO01)

[0076] The capillary channel length Lcmust also be sufficient to keep the first and second fluids F1, F2 separated in each capillary channel 30 considering pressure variations in the capillary headspace during pressure variations to which the syringe 100 may be exposed (e.g., transport, storage, manufacturing process, misuse, etc.), according to:where ^(is a first pressure when container is at rest and ^^is another pressure during transport,storage, manufacturing processes, etc., and where ^^ / ^( = 1, preferably ^^ / ^( = 2, morepreferably ^^ / ^( = 5, even more preferably ^^ / ^( = 10. With the Boyle-Marriott law drivingliquid separation during pressure variations being: ^(T( = ^^T^ , where ^( andare thepressure and capillary channel “headspace” in initial state, ^^is the absolute pressure variation during process, transport, storage, etc., and T^is the minimum volume to maintain liquidinterfaces separate defined by a minimum liquid separation height of 2^^M + ^O^. To maintainseparation of the first and second fluids F1, F2, it is thus required to solve: 2^^^^^H^ − ^^M + ^O^. ^( ≥ 2^^^^.2^^M + ^O^. ^^which gives H^as follows:

[0077] The capillary channel length Lcmust also be sufficient to keep the first and second fluids F1, F2 separated through the %^capillary channels 30 and considering headspace of volume TMand TOrespectively in the first or distal chamber 102 (A) and the second or proximal chamber 104 (B), according to:where ^^ / ^(can vary from 0.1 to 10, and TMand TOare the headspace remaining in each chamber after stoppering process. Depending on the stoppering process (vacuum vs vent-tube) and the format of syringe barrel 106, TMand TOcan vary each from 0&[ to 0.2&[ for typical 6407943.DOCX Page 17 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 1mlL format and up to 3&[ for the largest barrel format (20ml). With the Boyle-Marriott lawdriving liquid separation during pressure variations being: ^(T( = ^^T^ , where ^( andarethe pressure and capillary channels “headspace” in additional to total headspace in the first and second fluids F1, F2 at the initial state, ^^is the absolute pressure variation during process, transport, storage, etc., and T^is the minimum volume to maintain liquid interfaces separatedefined by a minimum liquid separation height of 2^^M + ^O^ in each capillary channel. Tomaintain separation of the first and second fluids F1, F2, it is thus required to solve:2^%^^^^^H^ − ^M − ^O^. ^( − 2^%^^^^.2^^M + ^O^. ^^ ≥ −^TM + TO^. ^(2^%^^^^[^H^ − ^M − ^O^. ^( − 2^^M + ^O^. ^^] ≥ −^TM + TO^. ^(which gives a relationship between H^, %^and ^^as follows:

[0078] When employing the syringe 100 to inject the first fluid F1 out through the needle 118, an injection force is driven by the gliding of the plunger stopper 124 and sequential stopper 10 within the syringe barrel 106, plus the Hagen Poiseuille flow law through the needle (HPn). During this injection of the first fluid F1, the sequential stopper 10 is maintained watertight (i.e., the first fluid F1 and / or second fluid F2 do not flow through the capillary channels 30) thanks to an equilibrated capillary rise from the first fluid F1 and second fluid F2 on the distal face 22 and proximal face 20 of the membrane 12, i.e., CR1 and CR2, see FIG. 12.

[0079] When transitioning from the first injection of the first fluid F1 and preparing for the second injection of the second fluid F2, an activation of the second fluid F2 through the capillary channels 30 must be achieved by overcoming the Laplace pressure resistance. It isthus desired that the force exerted by the capillary rise, FCRc, be: |^^^^| < 30%, preferably <20%, more preferably < 10%, and even more preferably < 5%.6407943.DOCX Page 18 of 28Attorney Docket No.04606-2502111 (P-30019.WO01)

[0080] Upon the first fluid F1 having been fully ejected from the syringe 100, the sequential stopper 10 abuts the end wall 114 at the distal end 110 of the syringe barrel 106 and fluid pressure is exerted on the sequential stopper 10 (i.e., on the proximal face 20 of membrane 12) via pressing of the plunger rod 120, so as to cause the second fluid F2 to flow through the capillary channels 30. As previously described, the injection force is driven by the capillary rise force (positive or negative depending on the sequential stopper material water contact angle) and Hagen Poiseuille flow law (HPc) of the second fluid F2 through the capillary channels 30, with it further recognized that the injection force for forcing the second fluid F2 through capillary channels 30 must be low enough to enable a manual injection. Thus,according to embodiments, the injection force should be: FDE^ < 30%, preferably < 20%,more preferably < 10%, and even more preferably < 5%. The injection force for forcing thesecond fluid F2 through capillary channels 30 should also be low enough in comparison to theflow out from the needle 118, according to: FDE^ < 3F>?^, preferably < 2F>?^, morepreferably < F>?^, even more preferably < F>?^ / 5. In general, it is desired that the injectionforce for forcing the second fluid F2 through capillary channels 30 be no less than 1 N and no more than 30 N, as an injection force lower than 1 N may result in mixing of the first and second fluids F1, F2 during an injection of the first fluid F1 (i.e., second fluid F2 may be forced through capillary channels 30 rather than the sequential stopper 10 being advanced within syringe barrel 106 during the first injection) and an injection force higher than 30 N may increase the difficulty of a manual injection.

[0081] Referring now to FIGS. 13A-13D, functioning of an injection device including a sequential 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, sequential stopper 10 and a plunger assembly 120 (including plunger rod 122 and plunger stopper 124), with the syringe 100 being manually actuated by a user. In other embodiments, the injection device may be a pre-filled cartridge (stand-alone cartridge or integrated in an auto-injector or safety device), with the cartridge including barrel 106, sequential stopper 10, and a plunger stopper 124.

[0082] As previously described, the injection device 100 enables the sequential delivery of an initial fluid F1 and a second fluid F2 through a single continuous advancement of a plunger rod 122 of the injection device 100. The first fluid F1 and second fluid F2 may have similar or dissimilar properties, including a concentration, viscosity, and / or pressure of the fluids, as 6407943.DOCX Page 19 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) non-limiting 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 F1 and / or the secondary fluid F2. Additionally, the structure of the sequential stopper 10 - in particular membrane 12 - may be specifically configured based on properties of the fluids F1, F2 contained within the syringe. That is, the pressure and / or viscosity of the fluids F1, F2 may dictate the thickness of the membrane 12 and / or a number and sizing of the capillary channels 30.

[0083] According to aspects of the disclosure, the first fluid F1 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.

[0084] One exemplary embodiment of a liquid-liquid combination of a first fluid F1 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 F1 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.

[0085] In one exemplary embodiment, the injection device 100 enables a delivery / injection of CagriSema to a patient, with the first fluid F1 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.

[0086] 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 F1 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 6407943.DOCX Page 20 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) be utilized for sequential injections of other liquid-liquid combination of pharmaceuticals, including analgesics, vitamins, vaccines (and boosters), monoclonal antibodies, and the like.

[0087] FIG. 13A corresponds to the configuration of the injection device 100 in an at rest configuration - before injection of the first fluid F1. In this configuration, the plunger stopper 124 is in a proximal position and the sequential stopper 10 is in a rest position, with the capillary channels 30 being configured – i.e., with a capillary channel length Lc and capillary channel diameter Dc– to prevent a flow of the first and second fluids F1, F2 through the fluid path 32 provided by the capillary channels 30. That is, the capillary channel length Lc and capillary channel diameter Dc of the capillary channels 30 are selected to accommodate / control a capillary rise of the first and second fluids F1, F2 into the capillary channels 30 that prevents mixing of the fluids. Additionally, the ribs 26 of the sequential stopper 10 sealingly engage the inner surface 136 of the barrel 106, so that the first and the second fluids F1, F2 cannot pass from a chamber to another via a passage between the sequential stopper 10 and the barrel 106.

[0088] Referring now to FIG. 13B, the injection device 100 is shown being actuated by a user to perform the injection of the first fluid F1. The force applied to the plunger stopper 124 is transmitted to the proximal chamber 104 and then to the sequential stopper 10, which results in a pressure P2exerted by the second fluid F2 onto the proximal face 20 of the membrane 12 of the sequential stopper 10 – which causes the sequential stopper 10 to be advanced / displaced distally within barrel 106. The displacement of the sequential 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.

[0089] In the configuration of FIG. 13B, the sequential stopper 10 is in a sealing configuration, with a flow of the first and second fluids F1, F2 through the fluid path 32 provided by the capillary channels 30 being prevented. That is, during this injection of the first fluid F1, the sequential stopper 10 remains sealed (i.e., the first fluid F1 and / or second fluid F2 do not flow through the capillary channels 30) thanks to an equilibrated capillary rise from the first fluid F1 and second fluid F2 on the distal face 22 and proximal face 20 of the membrane 12. As a consequence, fluid flow through the capillary channels 30 is prevented, and the injection continues until the sequential stopper 10 abuts the end wall 114 at the distal end 110 of the barrel 106, as illustrated in FIG. 13B.

[0090] Referring now to FIG.13C, the user continues to apply a distally directed force to the plunger stopper 124. Since the sequential stopper 10 cannot move further distally, the pressure in the proximal chamber 104 increases as the plunger stopper 124 continues to advance distally, and thus an injection force is exerted on the membrane 12 that activates the second fluid F2 6407943.DOCX Page 21 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) and cause the second fluid F2 to flow through the capillary channels 30. That is, an injection force is exerted on the membrane 12 that overcomes the Laplace pressure resistance, as well as the capillary rise force (positive or negative depending on the sequential stopper material water contact angle) and Hagen Poiseuille flow law (HPc) of the second fluid F2 through the capillary channels 30. As a result, the second fluid F2 passes through the fluid path(s) 32 provided by capillary channels 30 and to / through the channel 118 in tip 116 of syringe 100 for the injection. As previously described, the injection force is desirably less than 30 N, with the injection force preferably less than 20 N, more preferably less than 10 N, and even more preferably less than 5 N.

[0091] As shown in FIG. 13D, at the end of the injection of the second fluid F2, the plunger stopper 124 abuts the sequential stopper 10. In some embodiments, a fraction of the second fluid F2 may remain in a “dead volume” of the proximal chamber 104 – i.e., within the cavity 16 of sequential stopper 10. This fraction of the second fluid F2 may be forced out by collapsing the sequential 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.

[0092] Beneficially, embodiments of the invention thus are directed to a sequential stopper and associated injection device. The sequential stopper includes a membrane having a proximal face and a distal face, with the membrane including one or more capillary channels formed therein through a thickness of the membrane that selectively provide 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. The number of capillary channels, along with a channel length and channel diameter of each of the channels, may be selected / controlled in order to prevent mixing of the fluids and set the injection force (needed to cause fluid to flow through the capillary channels) at an acceptable level. The construction of the sequential stopper also provides desirable isostatic properties and sliding / gliding of the sequential stopper within the syringe barrel.

[0093] 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 6407943.DOCX Page 22 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 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. 6407943.DOCX Page 23 of 28

Claims

Attorney Docket No.04606-2502111 (P-30019.WO01) THE INVENTION CLAIMED IS 1. A sequential stopper configured to be positioned inside a barrel of a multi-chamber injection device for sequentially injecting a first fluid and a second fluid through a distal end of the barrel, the sequential 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 containing the first fluid from a second, proximal chamber of the barrel containing the second fluid; and a lateral wall joined to the membrane, the lateral wall comprising a circumferential sealing surface configured to sealingly engage the inner surface of the barrel; wherein the membrane includes a channel opening area comprising one or more capillary channels that extend through a thickness of the membrane between the proximal face and the distal face, each of the one or more capillary channels providing a fluid path through the membrane from the proximal face to the distal face for only transferring the second fluid from the second chamber to the first chamber, with a flow of the second fluid through the fluid path being selectively prevented or allowed depending on the strength of an injection force exerted by the second fluid onto the proximal face of the membrane.

2. The sequential stopper of claim 1, wherein each of the one or more capillary channels has a channel length and a channel diameter that: prevent the flow of the second fluid through the fluid path with the multi- chamber injection device at rest or during injection of the first fluid; and allow the flow of the second fluid through the fluid path upon application of an injection force of 1 N or more.

3. The sequential stopper of claim 2, wherein the flow of the second fluid through the fluid path is caused upon application of an injection force preferably less than 30 N.

4. The sequential stopper of claim 2, wherein the channel length is between 0.6 mm and 30 mm.

5. The sequential stopper of claim 2, wherein the channel diameter is between 40µm and 1.8mm. 6407943.DOCX Page 24 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 6. The sequential stopper of claim 2, wherein during injection of the first fluid, the flow of the second fluid through the fluid path is prevented by an equilibrated capillary rise of each of the first fluid and the second fluid into the one or more capillary channels, with the channel length being greater than a total length of the capillary rise of the first fluid and the second fluid.

7. The sequential stopper of claim 6, wherein during injection of the second fluid, the flow of the second fluid through the fluid path is allowed based on the applied injection force being greater than a flow resistance through the one or more capillary channels, as determined by a capillary rise force and a Hagen Poiseuille flow law for the second fluid through the one or more capillary channels.

8. The sequential stopper of claim 1, wherein the membrane is configured to flex between an initial configuration and a deflected configuration, with the membrane flexing in the distal direction.

9. The sequential stopper of claim 8, wherein with the membrane in the initial configuration, each capillary channel has a cylindrical or frustoconical shape; and wherein with the membrane in the deflected configuration, each capillary channel has a frustoconical shape or amplified frustoconical shape, where each capillary channel has a first channel diameter at a proximal opening thereof and a second channel diameter at a distal opening thereof, the second channel diameter greater than the first channel diameter.

10. The sequential stopper of claim 9, wherein the membrane has a convex shape in the initial configuration and a concave shape in the deflected configuration.

11. The sequential stopper of claim 9, wherein the membrane has a flat shape in the initial configuration and a concave shape in the deflected configuration.

12. The sequential stopper of claim 9, wherein the membrane has a concave shape in the initial configuration and a more concave shape in the deflected configuration. 6407943.DOCX Page 25 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 13. The sequential stopper of claim 9, wherein the sequential stopper is formed of an elastomer or a thermoplastic material.

14. The sequential stopper of claim 1, wherein the membrane is positioned at a distal end of the sequential stopper, a proximal end of the stopper, or at a location between the distal end and the proximal end.

15. The sequential stopper of claim 1, wherein the membrane extends between a distal end of the sequential stopper and a proximal end of the sequential stopper, such that no cavity provided in the sequential stopper.

16. 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 sequential 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 sequential 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 sequential stopper and a second chamber is defined within the barrel between the sequential stopper and the plunger stopper.

17. The medical injection device of claim 16, 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 sequential stopper is spaced apart distally from the end wall to separate the first chamber from the second chamber.

18. The medical injection device of claim 16, being one of a syringe or a cartridge.

19. The medical injection device of claim 16, wherein the sequential stopper comprises one of a 1 mL, 1-3 mL, 5mL, 10mL, or 20mL stopper. 6407943.DOCX Page 26 of 28Attorney Docket No.04606-2502111 (P-30019.WO01) 20. The medical injection device of claim 16, wherein the sequential stopper comprises a mono-component, mono-material stopper. 6407943.DOCX Page 27 of 28

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