Self priming discrete or sequential infusion system

Abstract

Two different fluid flow paths for use in delivery of one or multiple vials of drug product are described. Each fluid flow path is adapted and configured to be self-priming while also mitigating if not eliminating air bubbles in the fluid delivery path. Each fluid flow path may be used for discrete, sequential or combined drug product delivery. Alternatives include direct to patient needle set via a filled syringe or via an infusion pump.

Description

SG Docket No.: 14962-700.600 SELF PRIMING DISCRETE OR SEQUENTIAL INFUSION SYSTEM PRIORITY CLAIM

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 701,297 entitled, “SELF PRIMING DISCRETE OR SEQUENTIAL INFUSION SYSTEM” filed on September 30, 2024, incorporated herein by reference for all purposes. INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. BACKGROUND

[0003] At home infusion therapies have become more common over time to manage cost and for patient convenience. Patients that self-administer intravenous or subcutaneous therapies that are supplied in vials will benefit from improved delivery devices to help manage the complexity of at home administration. Whether delivered at home or in a clinic, complexity is naturally higher when therapies require delivery of multiple sequential drug products from multiple vials. Sequential delivery of drug products may be beneficial in many situations. The discrete drugs may not be appropriate to co-formulate or to mix within the same container due to chemical incompatibility. The drugs may also require a specific delivery order and timing of infusion to achieve the desired therapeutic effect.

[0004] As a result, there is a need for improved sequential infusion methods and systems to meet the aforementioned shortcomings. SUMMARY OF THE DISCLOSURE

[0005] In one aspect, there is a Fluid Path with multiple spikes connected inline that is terminated by a preconnected syringe to close the fluid path and provide manual control over air and fluid movement.

[0006] In yet another aspect, Fluid Path with multiple spikes connected inline that is terminated by a male luer activated device (LAD) and vented luer cap, which work together to facilitate automatic priming and prevents fluid leaks.SG Docket No.: 14962-700.600

[0007] In another aspect, a Fluid Path with multiple spikes connected inline, where the distal spike has an integrated check valve and vent filter assembled directly into the outlet side of spike component.

[0008] In a further aspect, pierceable sheath component to cover a spike, where a groove at the base of the mating spike facilitates radial compression and robust seal at both the ID and OD of a ring-shaped seal feature near the base of the sheath.

[0009] In yet another aspect, a one-piece housing that fixes the position of Fluid Path subassemblies and locates and orients multiple vials relative to those subassemblies.

[0010] In a further aspect, a method of a creating a stable array of spikes by directly joining the compatible female and male ends of the spike’s T-shaped ports components by permanent adhesive or solvent bond. As an alternative to direct connection of adjacent integral spike ports, the array could be joined by short straight tubular rigid or flexible components that extend axially from the spike ports.

[0011] In a further aspect. an array of spikes where spike-to-spike spacing is not more than 2 cm larger than diameter of vials docked to the system, to achieve the most compact form factor.

[0012] In another aspect, a modular platform that re-uses the same Fluid Path components to achieve a larger or smaller array of up to 6 in-line spikes per Fluid Path, by mounting those components to an appropriately sized housing.

[0013] In yet another aspect. a method of locking an array of spikes by inserting all spikes through the housing and then horizontally along a channel to lock the spike array into a final assembled position.

[0014] In another aspect. an overall system that facilitates sequential pump delivery of two drug products from multiple vials. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0016] FIG.1 is an isometric view of an exemplary Fluid Path A for two vials directly connected to a syringe.

[0017] FIG 2 is an isometric view of an exemplary Fluid Path B for two vials directly connected to a Male Luer Activated Device (LAD).SG Docket No.: 14962-700.600

[0018] FIG.3 are cross section views of the fluid paths in FIG.1 (upper) and 2 (lower) illustrating priming differences visible in cross-sectional views of both Fluid Paths, shortly after vials are fully pierced by spikes.

[0019] FIG.4 is an enlarged detailed view of a terminal end portion of a fluid path showing two adjacent spikes along with the compact design spike, check valve and plug with filter at the terminal end (right side in this view).

[0020] FIG.5 is a cross-section view of Fluid Path A with Drug Product aspirated into the syringe.

[0021] FIG.6 is a cross section of Fluid Path A of FIG.5 with empty vials and with air purged from the disconnected syringe.

[0022] FIG.7 shows the filled and purged syringe of FIG.6 containing Drug Product A connected to a pump that pulls Drug Product A directly from the syringe to prime and then deliver through the connected administration set and needle set.

[0023] FIG.8 is the arrangement of components in FIG.7 showing an “End of Infusion for Drug Product A” event is signaled by a pump occlusion alarm.

[0024] FIG.9 is a cross-section view of how Drug Product B is pulled by the pump through the connected LAD of Fluid Path B (i.e. Drug Product B is pumped direct from vial(s) that are connected in series with one distal vent see FIG.4).

[0025] FIG.10 is the arrangement of components in FIG.9 showing an “End of Infusion for Drug Product B” event is signaled when all Drug Product B is pulled by the pump through the connected LAD of Fluid Path B, the pump signals end of infusion via an air in line detection alarm, which occurs because all available Drug Product B has been aspirated from the vented Fluid Path B.

[0026] FIG.11 is a top-down isometric view of an exemplary Docking System showing one configuration of self-priming Fluid Paths A and B for sequential infusion.

[0027] FIG.12A is a bottom-up isometric view of the Docking System of FIG.11 with a friction-fit channel to receive one or more spike hubs.

[0028] FIG.12B is a bottom-up isometric view of the Docking System of FIG.11 with a channel with sidewall locking features to receive one or more spike hubs.

[0029] FIG.13 is an exemplary sequential infusion method.

[0030] FIG.14A is an isometric view of a spike hub in an universal configuration.

[0031] FIG.14B is an isometric view of the spike hub of FIG.14A with a sheath of FIG.20 in position above the spike shaft prior to compression fit assembly into the spike base recess.SG Docket No.: 14962-700.600

[0032] FIG.15 is a cross-section view of the spike hub and sheath of FIG.14B after compression fit assembly of the sheath seal into the spike base recess. Also shown in this view are a check valve and a filter within the hub inlet port and a length of tubing within the hub outlet port.

[0033] FIG.16A is an isometric view of the sheath of FIGs.1, 14B and 15.

[0034] FIG.16B is a side view of the sheath of FIG.16A.

[0035] FIG.16C is a top-down view of the sheath of FIG.16A.

[0036] FIG.16D is a cross-section view A-A of the sheath of FIG.16A. DETAILED DESCRIPTION

[0037] Embodiments of the present invention provide a simple system to achieve primed fluid paths when delivering two discrete fluids sequentially using one infusion pump, such that air is not inadvertently delivered to the infusion site or causing pump alarms due to air detection.

[0038] The nature of this invention describes a single-use disposable drug delivery manifold system that provides an improved method of sequential drug delivery via an infusion pump. During infusions of liquid drug products, care must be taken not to inadvertently infuse air. Infused air could result in undesirable effects ranging from air embolism to discomfort. Drug delivery pumps typically include air sensors and algorithms that alarm upon detecting a quantity of air passing through pump fluid paths. Experiencing and resolving pump alarms is often a stressful and confusing event for patients that self-administer drug product at home.

[0039] The invention described in this document applies to therapies where two drug products initially supplied in vials are administered sequentially. The device’s fluid path dedicated to Drug Product “A” (2) will be referred to as Fluid Path A (12). The device’s fluid path dedicated to Drug Product “B” (4) will be referred to as Fluid Path B (14). Ideally, single vials would be sufficiently sized to contain a patient’s desired dose volume, i.e. a single vial of Drug Product A and a single vial of Drug Product B. However, another common case is that a patient must extract and deliver the contents of multiple vials of Drug Product A (2), followed by sequential extraction and delivery from multiple vials of Drug Product B (4). Complexity of managing air 6 during such a scenario increases substantially.

[0040] Specific scenarios and objectives further increase the utility of the invention. Utility increases when the total volume of Drug Product A is small enough to fit in a syringe (typically <50 mL) while the total volume of Drug Product B would not fit into a single syringe (typically >50 mL). The preferred approach for that situation is to deliver Drug Product B direct from vials rather than via intermediate transfer to other containers such as multiple syringes or to a pooling bag.SG Docket No.: 14962-700.600 Utility increases when the objective is to deliver the entire contents of all vials, rather than a fixed target amount that is below the total volume contained within the vials.

[0041] By way of introduction, turning briefly to FIG.14A, there is a perspective view of a spike hub 100. The spike hub 100 has a base 102 with an inlet wall 104, an outlet wall 106 and sidewalls 108. There is also a spike 125 within a recess 120. Advantageously, the base components of the spike hub 100 may be adapted and configured into two different spike hub configurations having different components at the hub inlet port 116 and the hub outlet port 118. The spike hub 100 may be provided in an universal configuration 160 or in a pre-selected length configuration 162. Embodiments of the universal configuration 160 have a dual-purpose inlet and a universal outlet. The dual-purpose inlet is sized and configured to receive tubing 30 or components such as a filter and check valve. The universal outlet is sized and configured to couple to tubing 32. (see FIG.15). Embodiments of the spike hub 100 in a pre-selected length configuration are provided in a middle spike hub configuration 165, a first spike hub configuration 167 and a last spike hub configuration 168. Details of the spike hub in the pre-selected length configuration will be appreciated with reference to the various views of FIGs.1-6. that differ based on what type of inlet and outlet are as will be in a base configuration has an inlet side and port and an outlet side and port s shown in two different configurations. central to the advantageous configurations of shown and described in two different configurations. The spike hub 100

[0042] As shown in FIG.1, Fluid Path A (12) is comprised of a series of spike hubs 100 each one having a dual-lumen spike 15. The spike hubs 100 are connected in series. Each of the spike hubs 100 in FIGs.1-6 are of the pre-configured length configuration. The syringe 70 has a barrel 72 and a hub or tip 74. The plunger 76 is at the distal end of the barrel 72. The syringe outlet 74 is coupled to a female Luer fitting 34 and tubing 30. The tubing 30 is coupled to the spike hub 100 of drug flow path A (12) for drug 2. Spike hub 100 is configured as a first hub 167. A first hub 167 has an outlet sized to receive tubing 32 from the syringe. The inlet of the spike hub 100 in this configuration includes tubing 30 ending with a male Luer 30. Additional details of a spike hub configured as a first spike hub 167 may be appreciated with reference to FIG.3. The next spike hub 100 in flow path A (12) is a spike hub 100 configured as a middle spike hub 165. The details of the middle spike hub 165 configuration are further detailed in the view of FIG.3. The middle hub 165 configuration of the spike hub 100 includes a length of tubing 30 and a male Luer fitting 32 on the inlet port 116 and a length of tubing 30 and a female Luer fitting 34 on the outlet port 118. The spike hub configured as a middle hub 165 does not contain a drug vial 50 and the sheath 20 remains in place over the spike. A spike hub 100 configured as an end hub or last hub 168 is included in flow path 12. Additional details of the spike hub 100 configured as a last hub 168 may beSG Docket No.: 14962-700.600 appreciated with reference to FIG 3. The spike hub 100 configured as a last hub 168 has a hub inlet port 116 configured to receive flow control components such as a check valve 38 and a filter 40.

[0043] The optimal number of spike hubs 100 for a manufacturer to assemble would be influenced by the expected range of dose sizes for a population of patients and economic and supply chain constraints on vial fill volume configuration. In some embodiments described herein, there is shown three spike hubs 100 in series, with vials 50 docked to 2 of the 3 available positions. However, it is understood that the number of in-line spike hubs 100 could be more or less, such as 1 spike hub to 6 spike hubs per fluid path. In one specific implementation, vials 50 are assembled onto spike hubs by the end-user, immediately before drug delivery. While possible, vials 50 are not typically pre-docked onto spikes at time of manufacture.

[0044] Each spike 125 of a spike hub 100 is covered by a pierceable and collapsable elastomeric sheath 20. The specifics of the sheath 20 are illustrated and described further in FIGs. 16A-16D. The sheath 20 has a ring seal 26 that creates a compression seal in the spike hub 100 at the base of the spike shaft 126, where it nests into a defined groove or recess 120 of the molded spike hub 100 component. In one specific aspect, the quality of the seal achieved by this integrated groove design geometry advantageously maintains from 10% to 40% compression across the inside and outside diameters of the sheath’s ring-shaped seal feature. The closed space formed by the upper portion 24 of the sheath 20 creates a connecting bridge for flow between the adjacent proximal and distal lumens of that spike, such that flow may pass from any spike inlet to outlet even without a vial 50 docked at that spike hub 100. Additional details of the cooperation of the spike hub, spike and sheaths will be appreciated by reference to the various views in FIGs.4, 14A, 14B and 15.

[0045] The distal most spike hub 100 of the in-line chain has the last hub configuration 168. This spike hub has an integrated normally closed check valve 38 and hydrophobic vent filter 40 at its inlet 116. (see cross section view of FIG.4). These spike hubs 100 of the pre-selected length configuration 162 are illustrated as separate components that are press-fit directly into each successive spike hub component 165, 167, 168 depending upon the desired configuration. However, a vent filter membrane 40could also be welded, staked or bonded directly to the distal spike inlet. A length of flexible tubing connects the proximal spike outlet to a female luer fitting and pre-assembled syringe. The syringe serves as a cap or closure for Fluid Path A.

[0046] As shown in FIG.2, Fluid Path B (14) is also comprised of a series of spike hubs 100 with dual-lumen spikes 125 that are connected in series. The spike hubs 100 in flow path B (14) are also of the pre-selected length configuration 162. The first hub 167 has a vial 50 of drug B (4) connected to the hub. Tubing 30 connects the outlet of first hub 167 to a male LAD 36. The maleSG Docket No.: 14962-700.600 LAD 36 has a vented luer cap 37 with a hydrophobic membrane. As with flow path A, the spike hub 100 configured as a middle hub 165 does not have a drug vial but is covered by sheath 20. Fluid Path B’s distal spike hub 100 is also configured as a last hub 168. The last spike hub 168 integrates a normally closed check valve 38 and hydrophobic vent filter 40 at its inlet 116. Fluid Path B’s flexible tubing 30 connects the proximal spike 167 outlet to a male Luer Activated Device (LAD) 36 with pre-connected vented luer cap with hydrophobic filter membrane 37. The LAD 36 contains an integral valve that is automatically opened by the cap or any other connected luer fitting. The cap’s hydrophobic vent filter membrane is capable of allowing air to exit while blocking liquid leaks from the system. Upon separating the vented cap 37 from the LAD 36, the integral valve of the LAD automatically recloses.

[0047] Cross-sectional views in FIGs.3 and 4 further illustrate both Fluid Paths of the system, shortly after drug product vials have been pierced by spikes. Note that inner volume of these two Fluid Paths have been differentiated by using light grey to represent air 6 in the system and darker grey / hatched pattern to represent a liquid drug product 2,4. A key difference between Fluid Path A (12) and Fluid Path B (14) is that drug product in Fluid Path B has filled the flexible tubing segment 30, LAD 36, and vent cap up to the hydrophobic filter membrane 37. Advantageously, this automatic “priming” of the line is uniquely achieved by the counter-intuitive method of assembling a vented cap to a normally closed Luer Activated Device 36. As a result, priming flow is driven by the head height of fluid in the vial and / or slight positive pressure present in the vial head space due to shipping or inward tenting of the vial’s elastomeric closure during piercing by a spike. Little to no drug product fills the volume of Fluid Path B that is distal to the first pierced vial. That is because the check valve remains closed and does not allow air to escape. Similarly, little to no drug product fills the volume of Fluid Path A because air can not exit the closed check valve at its inlet nor exit at the female luer joint that is closed by the syringe. Pressure in the vials and fluid head height for Fluid Path B are too weak to move the syringe plunger, i.e. to overcome friction between syringe plunger and syringe barrel.

[0048] FIG.3 illustrates the priming differences by comparing the cross-sectional views of the Fluid Paths A,B, shortly after vials 50 are fully pierced by spikes 125. Fluid Path A in the upper portion of the figure and Fluid Path B in the lower portion of the figure. In the upper view, air 6 is trapped above the fluid 2 in vials 50 and blocked from exiting Fluid Path A by the syringe and distal spike hub check valve. Fluid Path B in the lower portion of FIG.3 shows how drug 4 from the first vial 50 automatically primes from the outlet lumen of the first spiked vial to the vent filter that caps the LAD component 36.SG Docket No.: 14962-700.600

[0049] FIG.4 is an enlarged detailed view of a terminal end portion of a fluid path of hubs 100 in the pre-selected length configuration 162. The left side spike hub 100 is configured as a middle hub 165. The right side spike hub 100 is configured as a last hub 168. The spike hubs 100 are adjacent showing a compact design between spikes. The last spike hub 168 has a check valve 38 and plug with filter 40 at the terminal end (right side in this view). The drug vial 50 has a bottom 52, body 51, neck 53 and flange 54. The vial 50 is sealed with a stopper 55. In the view of FIG.4, the drug vial 50 is shown empty with the spike tip 130, outlet bevel 132 and inlet bevel 134 piercing through stopper 55. The sheath 20 is shown in a compressed state as a result of compressing the neck 53 and stopper 55 against the spike 125.

[0050] Turning now to FIG.5. Next, a patient aspirates Drug Product A into the syringe 70 by pulling the syringe plunger 76 and plunger rod back. Both air from the line and drug product from the closer vial (Vial #1) flows into the syringe, which in turn generates a vacuum pressure that pulls air and fluid from upstream lumens and vial(s) toward Vial #1. Note that air 6 quickly rises above liquid drug 2 product in a vial 50 due to the lower density of air 6. Therefore, the spike lumen openings 140, 142 positioned near the bottom of an inverted vial, i.e. near the well of the elastomeric closure of the vial, remain submerged in drug product until the vial 50 is emptied down to the level of those lumen openings. The forward vial may always re-supplied by vial(s) further upstream. Environmental air does enter the vent filter of Fluid Path A and pass through the nearby check valve to limit vacuum pressure buildup within the Fluid Path. The check valve 38 prevents unwanted backflow through the fluid path.

[0051] When drug product is fully aspirated into the syringe (except for minor residual drug product losses in the stopper well, below the spike lumen openings), the syringe will contain a mixture of air and liquid as shown in FIG.5. The patient disconnects the syringe at Fluid Path A’s female luer fitting, inverts the syringe, and manually purges air from the syringe, as shown in FIG. 6. Also shown in FIG.6 is an Empty Fluid Path A with air purged from the disconnected syringe.

[0052] As shown in FIG.7, the filled syringe 70 may now be connected directly to the inlet 62 of an infusion pump 60. The infusion pump 60 has an inlet 62, an outlet 64 with a display 66 and function buttons 68. The pump outlet 64 is connected to administration set tubing 80. The pump’s prime function is used to prime the pump administration set 80 tubing and any downstream needle infusion set 82 tubing. Once connected, the pump 60 pulls Drug Product A directly from the syringe 70 to prime the connected administration set 80 and needle set 82 connected to the patient injection site 84.

[0053] The patient inserts the needle (or needles in the case of a bifurcated, trifurcated, etc. needle set) into the desired injection site 84. Thereafter, the patient proceeds to run the pump 60 toSG Docket No.: 14962-700.600 deliver all of Drug Product A (2) directly from the syringe 70. Advantageously, because air 6 was manually purged from the syringe, there is no source of air 6 to trigger a pump air alarm or to be inadvertently infused into the patient.

[0054] FIG.8 shows how the pump 60 may signal an end of infusion of Drug Product A via an upstream occlusion alarm such as “occlusion detected” as shown on display 66. The upstream occlusion alarm occurs because the Drug Product A’s syringe plunger 76 is bottomed out in the syringe barrel 72. In this illustrative embodiment, the End of Infusion for Drug Product A is signaled by a pump occlusion alarm as shown.

[0055] Before proceeding to an illustrative use case for Flow Path B, it is to be appreciated that Flow Path A may be used for direct injection into the patient needle set alone or in combination with other Drug Products. Direct injection is accomplished after the filling and venting actions of FIG.6. Instead of connecting the filled and vented syringe to the pump as in FIG.7, the syringe is connected directly an appropriate fitting on the user needle set.

[0056] Turning now to an exemplary use case for Fluid Path B. The initial situation is as shown in the lower portion of FIG.3. First, the patient disconnects the LAD of Fluid Path B from its vented cap. Fluid Path B is automatically and immediately closed by the integrated valve within the LAD, such that Fluid Path B remains primed throughout the flexible tubing segment and LAD. The patient disconnects Drug Product A syringe from the pump administration set (FIG.8) and connects Fluid Path B’s LAD to the pump administration set (FIG.9). Advantageously, the steps described above combined with the choice of these specific components did not present any source of air to the pump administration set during the transition from Drug Product A to Drug Product B.

[0057] FIG.9 also illustrates Drug Product B being pulled by the pump 60 through the connected LAD 36 of Fluid Path B (i.e. Drug Product B (4) is pumped direct from vial(s) that are connected in series with one distal vent).

[0058] Thereafter, the patient proceeds to run the pump 60 to deliver all of Drug Product B directly from the vials 50. Similar to aspiration of Drug Product A via syringe 70 and through Fluid Path A, drug product from the closer vial (Vial #1) is pulled through the LAD via pump, which in turn generates a vacuum pressure that pulls air and fluid from upstream lumens and vial(s) toward Drug Product B Vial #1. Air quickly rises above Drug Product B in a vial due to the lower density of air, such that spike lumen openings positioned near the bottom of an inverted vial remain covered by Drug Product B. Environmental air does enter the vent filter integrated into the distal spike of Fluid Path B and pass through the nearby check valve to limit vacuum pressure buildup within the Fluid Path B. Because air had been automatically purged from the flexible tubing and LAD of Fluid Path B, there is no source of air to trigger a pump air alarm until the end of infusion. At thatSG Docket No.: 14962-700.600 point as shown in FIG.10, Drug Product B has been aspirated from all vials such that fluid no longer covers the spike lumen openings. The pump 60 would typically signal this end of infusion of Drug Product B via an air in line detection alarm, such as “Air Detected” as shown on the display 66. The air detected alarm occurs because all available Drug Product B has been aspirated from the vented Fluid Path B.

[0059] Optionally, a user could flush the line with saline or other appropriate fluid if delivery of remaining drug product downstream of the pump (for example, residual fluid in the needle set) was critical to therapeutic outcome.

[0060] These discrete fluid paths may be integrated into a vial holding apparatus (housing), to maintain the position and orientation of all vials throughout the procedure. Size of the housing docking system can be minimized by ensuring that rigid integrated ports or short tubular port segments that extend horizontally from the spikes create spike-to-spike spacing that is slightly larger than vial diameter. For example, vials with 66mm outside glass diameter may be most compactly aligned with 67 to 80 mm spacing between spikes.

[0061] A representative image of a 4-spike configuration of Fluid Path A and B assembled into a vial docking housing will be described with regard to FIGs.11, 12A and 12B. FIG.11 is a top- down isometric view of an exemplary Docking System showing one configuration of self-priming Fluid Paths A and B for sequential infusion. FIGs.11, 12A and 12B are top down and two alternative bottom-up isometric views respectively of dual 4 vial self-priming Fluid Paths A and B in a compact form factor with the syringe alongside the base and a Male LAD 36 with vented Luer cap within hydrophobic membrane 36 on the upper surface 172 of the housing 170. Four vial sockets 174 and associated spikes (under membrane 20) are provided for fluid path A (12). Four vial sockets 176 and associated spikes (under membrane 20) are provided for fluid path B (14).

[0062] FIG.12A is a bottom-up isometric view of the Docking System housing 170 of FIG.11 showing lower surface 180. In this embodiment, the channel 182 and walls 184 are adapted and configured for a friction-fit to receive one or more spike hubs 100. Different lengths of tubing 30 are shown connecting each of the spike hubs 100 configured with universal configuration 160.

[0063] FIG.12B is an enlarged, partial bottom-up isometric view of an alternative configuration of the Docking System housing 170 of FIG.11. In this embodiment, the channel 182 has sidewalls 184 with a series of channel sidewall locking features 186. In use, a spike hub 100 is positioned into the channel 182. Movement of the spike hub 100 along the channel 182 will engage a spike hub sidewall feature 110 (see FIG.14A) with sidewall locking feature 186 to secure the spike hub into the channel 182 in the desired location. It is to be appreciated that engagement of one or more spike hubs 100 along the channel 182 may be reversible to allow for reuse of the housing 170 orSG Docket No.: 14962-700.600 allow for separate disposal of contaminated materials (i.e., spike hubs and tubing) from uncontaminated materials. While shown with a spike hub 100 of the universal configuration 160, the spike hubs 165, 167, 168 of the pre-selected length configuration may also be adapted for use with locking sidewall features 186.

[0064] In one configuration, the assembled spike array for a fluid flow path is inserted through the lower surface 180 of the housing, and then slides horizontally (i.e. in the axial direction of the spike ports) until locking into a fully assembled position.

[0065] In various embodiments, a dual-lumen spike with rigid straight port lengths extended into the range of 2 to 7 cm for a predetermined spacing between adjacent spikes.

[0066] FIG.13 is an exemplary sequential infusion method 1300 of a self-priming sequential two drug infusion process according to one aspect of the present invention. First, at step 1305, insert (i.e. spike) the desired number of Drug Product A vials to available spikes of Device Fluid Path A.

[0067] Next, at step 1310, withdraw the syringe plunger of Device Fluid Path A to sequentially aspirate all Drug Product A from each Drug Product A vial connected in series. (Air enters the proximal vent filter and one-way check valve to prevent vacuum pressure from building in Device Fluid Path A.)

[0068] Next, at step 1315, disconnect the syringe filled with Drug Product A from Device Fluid Path A.

[0069] Next, at step 1320, with the syringe tip pointed up, manually advance the syringe plunger until air is visibly purged from the syringe.

[0070] Next, at step 1325, connect the inlet of a needle set (ex. subcutaneous needle set) to the outlet of the administration tubing set for an infusion pump (ex. peristaltic infusion pump).

[0071] Next, at step 1330, use the pump’s prime function to move fluid from the Drug Product A syringe until Drug Product A nearly reaches the needle.

[0072] Next, at step 1335, insert the needle through the skin to the desired infusion site.

[0073] Next, at step 1340, use the pump to infuse all Drug Product A, until the pump’s occlusion alarm signals that the syringe plunger has fully travelled to the end of the syringe barrel.

[0074] Next, at step 1345, insert (i.e. spike) desired number of Drug Product B vials to available spikes of Device Fluid Path B.

[0075] Next, at step 1350, Drug Product B automatically flows (by gravity) to the outlet at the Luer Access Device cap with hydrophobic membrane at the distal outlet of Device Fluid Path B, while air is vented through the membrane. (Device Fluid Path B is automatically primed.)SG Docket No.: 14962-700.600

[0076] Next, at step 1355, remove the cap from the outlet of Fluid Path B. (The LAD valve automatically seals to prevent fluid loss.)

[0077] Next, at step 1360, disconnect the empty Drug Product A syringe from the pump administration set inlet.

[0078] Next, at step 1365, connect the Fluid Path B outlet to the pump administration set inlet.

[0079] Next, at step 1370, use the pump to infuse all Drug Product B, until the pump’s air detection alarm signals that fluid has been aspirated from each Drug Product B vial connected in series. (Air enters the proximal vent filter and check valve to prevent vacuum pressure from building in Device Fluid Path B.)

[0080] Next, at step 1375, disconnect the needle set inlet from the pump administration set outlet.

[0081] Next, at step 1380, Optional: Flush remaining Drug Product B from the needle set, for example by manual push of a saline-filled syringe.

[0082] FIG.14A is an isometric view of a spike hub 100. This spike hub is adapted to be in an universal configuration 160. The spike hub 100 has a base 102 with an inlet wall 104 and an outlet wall 106 connected by sidewalls 108. Sidewalls 108 may include one or more sidewall features 110 used to couple a spike hub to the housing 170 as described herein. The inlet wall 104 is coupled to the hub inlet port 116. The outlet wall 106 is coupled to the hub outlet port 118. The hub outlet port 118 and hub inlet port 116 are adapted and configured to accept tubing or components depending upon configuration (universal configuration 160 or pre-selected length configuration 162). The views of FIGs.14A, 14B and 15 are of a spike hub 100 in universal configuration 160.

[0083] FIG.14A also shows the spike 125 on the base 102 within the recess 120. The recess 120 has a bottom wall 122 and a sidewall 124. The spike outer wall 138 along with the recess bottom wall 122 and the recess sidewall 124 are dimensioned for a compression fit for sheath o-ring 26 (see FIG.15).

[0084] FIG.14A and 14B also provide additional details of the spike 125. The spike tip 130 is part of wall 136 that separated the spike interior into a spike inlet lumen 140 and a spike outlet lumen 142. The spike inlet lumen 140 opens into spike inlet bevel 134. The spike outlet lumen 142 opens into the spike outlet bevel 132. As described herein, the spike inlet and outlet lumens 140, 142 become spike flow path 145 a sheath 20 is sealed over a spike 125 or a drug vial 50 is sealed over a spike 125.

[0085] FIG.14B is an isometric view of the spike hub of FIG.14A with a sheath 20 (see FIG. 16A) in position above the spike shaft 125 prior to compression fit assembly into the spike base recess 120.SG Docket No.: 14962-700.600

[0086] FIG.15 is a cross-section view of the spike hub and sheath of FIG.14B after compression fit assembly of the sheath 20 to seal into the spike base recess 120. Also shown in this view are a check valve 38 and a filter 40 within the hub inlet port 116. In the universal configuration, the hub inlet port 116 is adapted and configured to accept (a) components such as a check valve 38 and a filter 40 or (b) tubing 30 within the tube bond interface. As such, there is a universal inlet for in the universal spike hub configuration 160. Depending upon position in the chain of spike hubs, the inlet may be configured to receive tubing via interface 144 or components as shown in FIG.15. The hub outlet port 118 includes a tube bond interface 144. The tube bond interface 144 allows for a desired length of tubing 30 to be provided between adjacent spike hubs 100.

[0087] FIG.15 shows the estimated compression of the sheath seal 26 within the recess 120. Once the compression fit is completed, the spike flow path 145 is complete. The spike hub flow path 145 travels along the spike inlet lumen 140 along the interior of the sheath 20 interior around the spike tip 130 and then down the spike outlet lumen 142 and out into the hub outlet port 118 to connected tubing 30. It is to be appreciated that the recess 120 within a spike hub base facilitates radial compression and sealing of an inner diameter and an outer diameter of a ring-shaped seal 26 feature along the base of the sheath 20.

[0088] In still another aspect, there may be provided in any of the various fluid path devices described herein, a pierceable sheath 20 molded from a visually identifiable color relative to the housing or other system component. The sheath may be molded from colors to help alert the user to the presence of sharp spikes 125 and corresponding injury risk. In one aspect, the sheath is made from the visually identifiable color of red. Optionally, the sheath 20 may be transparent with all or part of the spike 125 formed from a visually identifiable color. Colors may include any suitable color to draw attention and may include, red, orange or yellow or stripes.

[0089] FIG.16A is an isometric view of the sheath 20 of FIGs.1, 14B and 15. The sheath 20 has a body 22 with a top 24 and a seal ring 26 around the base. The seal ring is an annular or o-ring type seal adapted and configured for a compression fit into the base recess 120 as described above. As a result of the compression fit, the sheath seal 26 exerts sealing pressure along the spike outer wall 138, the recess side wall 124 and the recess bottom wall 122. It is believed that a compression fit along these three surfaces provides a superior seal and pressure performance for the drug delivery systems described herein.

[0090] FIG.16B is a side view of the sheath 20 of FIG.16A.

[0091] FIG.16C is a top-down view of the sheath of FIG.16A indicating section A-A. FIG. 16D is a cross-section view A-A of the sheath of FIG.16A. The body 22 sidewall thickness may beSG Docket No.: 14962-700.600 between 0.5 mm to about 1mm thick. In some embodiments, the sidewall thickness may range between 0.65 mm to 0.80 mm. In other embodiments, the sidewall thickness may be one of 0.70 mm, 0.71 mm, 0.72 mm, 0.73 mm, 0.74 mm or 0.75 mm.

[0092] Additional details of multiple vial systems may be appreciated with reference to International Patent Application Publication WO 2016 / 205687 entitled “Pooling Device for Single or Multiple Containers” published on December 22, 2016 and incorporated herein by reference for all purposes.

[0093] As appreciated by the above description, the various embodiment of the invention simplifies both discrete delivery alone or in combination with sequential delivery of drug products from multiple vials by providing intuitive air management features and flow strategy, such that one drug in the case of discrete delivery or two or more drugs in the case of sequential delivery may be administered via one pump, pump administration set and needle set. Without the priming methodology facilitated by Fluid Path device features, unintended air could inadvertently enter the pump administration line causing pump alarms and difficult steps to resolve the issue.

[0094] Additionally, the sheath-to-spike sealing features described herein improves seal reliability over other conventional sheath configurations.

[0095] Advantageously, the various alternative configurations envisioned for the Housing and Fluid Path subassemblies result in a compact form factor.

[0096] The advantages of Fluid Paths A and B to dramatically improve discrete or sequential infusion described herein may find broad applicability as there is significant clinical research and applications emerging involving sequential drug delivery. Examples of ongoing research that would potentially benefit from the improved flow paths described herein include:

[0097] In one aspect, sequential or concurrent drug deliveries with Hyaluronidase are known to enhance a variety of injectable medications. Examples include Hyaluronidase with insulin in diabetes, with beta interferons in multiple sclerosis, with biotherapeutics in rheumatoid arthritis, with immunoglobulin replacement therapy in primary immunodeficiencies, and with monoclonal antibodies in cancer treatment. (See Hyaluronidase - StatPearls - NCBI Bookshelf (see nih.gov) Murray RL, Zafar Gondal A. Hyaluronidase. [Updated 2023 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK545163 / )

[0098] In still other applications, various antibiotic therapies have been delivered in sequence to treat infection. (See Sequential and Concomitant Therapy with 4 drugs are Equally Effective for Eradication of H. pylori Infection - PMC (see nih.gov) Wu DC, Hsu PI, Wu JY, Opekun AR, Kuo CH, Wu IC, Wang SS, Chen A, Hung WC, Graham DY. Sequential and concomitant therapy withSG Docket No.: 14962-700.600 four drugs is equally effective for eradication of H pylori infection. Clin Gastroenterol Hepatol. 2010 Jan;8(1):36-41.e1. doi: 10.1016 / j.cgh.2009.09.030. Epub 2009 Oct 3. PMID: 19804842; PMCID: PMC2838430.

[0099] In still other applications, opportunities for sequential drug delivery have gained attention in treatment of liver disease and cancer. See Xiaozhong Huang, Fan Lee, Yao Teng, Corey Bryen Lingam, Zijian Chen, Min Sun, Ziwei Song, Gowri M. Balachander, Hwa Liang Leo, Qiongyu Guo, Imran Shah, Hanry Yu. Sequential drug delivery for liver diseases Advanced Drug Delivery Reviews, Volumes 149–150, 2019, Pages 72-84. For Sequential Drug Delivery in Targeted Cancer Therapy see Yu, Han & Ning, Na & Meng, Xi & Chittasupho, Chuda & Jiang, Lingling & Zhao, Yunqi. (2022). Sequential Drug Delivery in Targeted Cancer Therapy. Pharmaceutics.14.573.10.3390 / pharmaceutics14030573.

[0100] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits described herein.

[0101] The process parameters and sequence of steps described and / or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and / or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed. The various example methods described and / or illustrated herein may also omit one or more of the steps described or illustrated herein or include additional steps in addition to those disclosed.

[0102] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and / or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.SG Docket No.: 14962-700.600

[0103] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0104] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0105] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0106] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0107] In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and / or steps may alternatively be exclusive, andSG Docket No.: 14962-700.600 may be expressed as “consisting of” or alternatively “consisting essentially of” the various components, steps, sub-components or sub-steps.

[0108] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub- ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0109] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0110] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned,SG Docket No.: 14962-700.600 other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.SG Docket No.: 14962-700.600 Name Reference Number Drug A 2SG Docket No.: 14962-700.600 Name Reference Number Needle set 82SG Docket No.: 14962-700.600 Name Reference Number

Claims

SG Docket No.: 14962-700.600 CLAIMS What is claimed is:

1. A Fluid Path device comprising multiple spike hubs connected inline that is terminated by a preconnected syringe adapted and configured to close the fluid path and provide manual control over air and fluid movement or a Fluid Path device comprising multiple spike hubs connected inline that is terminated by a male LAD and vented luer cap adapted and configured to work together to facilitate automatic priming and prevention of fluid leaks.

2. A Fluid Path device of claim 1 wherein a distal most spike hub of the multiple spike hubs connected inline comprising an integrated check valve and vent filter assembled directly into the outlet side of spike component.

3. The fluid path device of claim 1 or claim 2 further comprising a pierceable sheath over a spike of a spike hub of the multiple spike hubs, wherein a recess within a spike hub base facilitates radial compression and sealing of an inner diameter and an outer diameter of a ring-shaped seal feature along the base of the sheath.

4. The fluid path device of claim 3 wherein the pierceable sheath molded from a visually identifiable color relative to the housing or other system component colors to help alert the user to the presence of sharp spikes and corresponding injury risk or the visually identifiable color is red.

5. The fluid path device of any of the above claims wherein the pierceable and collapsible sheath has a 0.5 to 1.0 mm cylindrical wall thickness or is adapted and configured to have a thickness selected to balance handling by the manufacturing plant processes with moldability factors and collapsibility characteristics.

6. The fluid path device of any of the above claims further comprising a one-piece housing that fixes the position of Fluid Path subassemblies and locates and orients multiple vials relative to those subassemblies.

7. A method of a creating a stable array of spikes comprising, directly joining the compatible female and male ends of the spike’s T-shaped ports components by permanent adhesive or solvent bond or direct connection of adjacent integral spike ports, wherein the array could be joined by short straight tubular rigid or flexible components that extend axially from the spike ports.

8. A method of creating an adjustable or reconfigurable array of spikes comprising joining the compatible female and male fittings by slip luer, locking luer, or locking luer with spin collar.SG Docket No.: 14962-700.600 9. The device or method of any of the above claims further comprising a dual-lumen spike with rigid straight port lengths extended into the range of 2 to 7 cm for a predetermined spacing between adjacent spikes.

10. The device or method of any of the above claims further comprising an array of spikes where adjacent spike-to-spike spacing is not more than 2 cm larger than a diameter of one or more vials docked to the fluid path device system or wherein the spacing between adjacent vials is adapted and configured to provide a compact form factor based on a diameter of the one or more vials.

11. A modular platform adapted and configured to arrange the elements of any of the above claims to achieve a larger or smaller array of up to 6 in-line spikes per Fluid Path, by mounting those components to an appropriately sized housing.

12. A method of locking an array of spikes comprising inserting all spikes through the housing and then horizontally along a channel to lock the spike array into a final assembled position.

13. The method or device of any of the above claims further comprising one or more spike retaining rib features that can be released from their semi-permanent installed location by deliberate horizontal motion, for purpose of separating fluid-path and non-fluid path system components or wherein components facilitate sustainable approaches such as recycling or re-use of select materials from the system, such as the housing.

14. A drug infusion system further comprising any of the above claims wherein the drug infusion system is adapted and configured to facilitate sequential pump delivery of two drug products from multiple vials.

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