Combination drug delivery device

Abstract

The present invention relates to a combination drug delivery device, in particular to a combination drug delivery device for delivering a predetermined selected drug ingredient, comprising a plurality of modules, each module comprising: a body having an internal volume; a tip plate is movably disposed in the interior volume and has a protruding cannula and first and second ports. The apparatus also includes a base tray comprising: a frame defining a plurality of grooves, each groove formed to receive one of the modules in an insertion manner; a first inlet port and a second inlet port, the first inlet port and the second inlet port being formed, for each groove, to interface with the first port and the second port of the module received in the corresponding groove; a channel connects some of the grooves with adjacent grooves to permit fluid flow therebetween. For each groove, the tip plate of the respective module is maintained in a fixed position by inserting the module into the groove.

Description

[0001] This invention application is a divisional application based on an invention patent application with an application date of May 10, 2019, application number 201980031352.4 (international application number PCT / US2019 / 031791) and name “Combined drug delivery device”. Technical Field

[0002] The field of the invention is the formulation and preparation of liquid medications, particularly for intravenous infusion and direct patient administration. More specifically, the invention relates to devices for the formulation and preparation of combinations of two or more medications. Background Art

[0003] In the administration of drugs by intravenous infusion, it is common practice to prepare drugs in a pharmaceutical environment. Such drugs are usually provided aseptically in glass bottles, and can be provided in solid form or aqueous solution form. When provided in solid form, before being transferred to the infusion bag, the drug must be reconstructed with a sterile aqueous diluent. It will be appreciated by those skilled in the art that such drug preparations will usually include several excipients, such as buffers, pH modifiers, tension regulators, stabilizers, etc. Usually, before being transferred to the patient for infusion, liquid drugs for intravenous infusion are prepared in the infusion bag in a pharmaceutical environment. Due to the need to maintain the sterility of the drug when preparing, the preparation procedure is usually performed in a sterile pharmacy cover. Usually, a pharmacist or a pharmaceutical technician (practitioner) will prepare the drug according to individual patient prescriptions.

[0004] After ensuring that all materials are cleared from the cover, the practitioner will retrieve the required drug bottles from the drug library according to the prescription and verify their identity and strength. The verification process can be assisted by using a barcode scanner or other identification technology. The practitioner will also pick out all other necessary equipment required for the safe preparation of drugs for infusion from the inventory, including the infusion bag itself, syringe, needle, transfer kit, gloves, sharp object disposal container, etc. Once all necessary equipment is assembled, the practitioner will follow the regulations for preparing the drug, which may include reconstructing solid drugs by adding diluents, and orderly extracting liquid drugs from their respective vials into IV bags via transfer ports. Typically, this procedure is performed manually and involves the use of multiple needles. Each needle required for drug preparation increases the risk of needlestick injuries to practitioners. In the case of highly potent or highly toxic drugs (e.g., cytotoxic agents for chemotherapy), this presents a considerable exposure risk to practitioners.

[0005] In order to eliminate some risks associated with manual preparation (some of which include exposure to hazardous drugs) and the risk of medication negligence, pharmaceutical preparation machines are known to those skilled in the art, which automate many steps involved in drug preparation and preparation. Typically, such machines are complex electromechanical systems that implement complex precision dispensing mechanisms for accurately reconstructing liquid drugs. In addition to their cost, size, and complexity, many designs for such machines described in the art extract liquid drugs from library storage, and therefore only use a small portion of the drug in the container. Due to the need to maintain sterility, unused drug solutions must usually be discarded, and therefore waste is caused. Due to the high cost of some drugs, particularly biopharmaceuticals, this waste is an obviously undesirable cost. When the wasted drug is a cytotoxic agent, their disposal produces significant environmental hazards and safety hazards.

[0006] Recent advances in medicine, especially in the treatment of cancer, have demonstrated that therapeutic benefits can be obtained by synergistic combinations of two or more drugs. For example, recent clinical studies have demonstrated that the combination of anti-PD-1 checkpoint inhibitor drugs and CTLA-4 checkpoint inhibitors can have a beneficial synergistic effect on some tumor types, which can lead to better clinical results than can be obtained by administering either drug separately. Typically, such checkpoint inhibitor drugs are monoclonal antibodies or fragments thereof of the immunoglobulin type derived from biotechnology. In some cases, it can be beneficial to use such biological drugs in combination with conventional chemotherapy drugs such as cytotoxic drugs.

[0007] Applicants have now realized that the combined principles described in U.S. Provisional Patent Application No. 62 / 670,266, filed on May 11, 2018 to the same assignee as herein, can solve several challenges encountered in preparing and formulating drugs for intravenous infusion and can provide several advantages, including but not limited to simplifying pharmaceutical procedures, reducing the risk of medication negligence, curbing and protecting practitioners from potent or highly toxic drugs, reducing the risk of needlestick injuries, reducing or eliminating drug waste, and avoiding the need for complex and expensive pharmaceutical compounding machines, and the U.S. Provisional Patent Application is incorporated herein by reference in its entirety. Due to these advantages in the embodiments, the present invention can further enable the preparation and formulation of drugs for IV infusion and direct administration to patients at locations away from pharmacies and by non-professional practitioners (e.g., by appropriately trained technicians or nurses in patients' homes). The inherent portability of the system described herein enhances this possibility. Summary of the invention

[0008] According to the present invention, medication modules are provided which are inserted into and mechanically locked into a provided common base tray which fluidly connects all inserted modules and delivers the contents of all modules.

[0009] Each module defines a chamber for receiving a vial filled with medication, and in an embodiment, a spacer bushing may be provided to enable receiving vials of different sizes. The module further comprises a hinged cap to allow access to the vial septum for sterilization. Within the hinged cap, a floating vial spike plate having a protruding spike having an inlet port and an outlet port is captured, the spike plate allowing only axial travel, thereby permitting the spike to create a notch in the vial septum when the module is inserted into the base tray.

[0010] The base tray consists of several pre-arranged grooves designed to receive the hinged cap geometry of the module. Within each groove are two check valve type fluid connection ports that interface with the input and output ports of the module bottle tip plate. By fully pressing the bottle tip plate into the valves of the base tray, a fluid connection can be established between the base tray valves through the bottle tip plate. Internally, sterile tubing is used to connect a single check valve fluid to an adjacent groove to create a fluid circuit that is only complete when all the grooves of the base tray have been filled with a specified module. The base tray will contain an air filter and / or vent that will terminate one end of the internal fluid circuit. The fluid circuit of the base tray will allow the drug product from the module to flow out of the sterile main output line from the base tray. The one-way valve in the main output line will prevent the drug product from backwashing into the base tray.

[0011] Cooperating mechanical keying features present on both the inner wall of the base tray recess and the outer surface of the hinged cap of the module create a poka yoke mechanism that ensures that the module can only be inserted into the specified recess of the base tray. In an embodiment, module placement within the base tray can be controlled and monitored by electronic means.

[0012] The main output line from the base tray may be terminated by a sterile hollow needle that may be used to breach a sterile port on an infusion bag or other container for pumping transfer of liquid medication into the container, or may be used to administer medication directly into a patient. Further, a pump may be provided so that when fully connected, liquid medications in bottles may be pumped into a bag, container, or patient as one collective output from their respective bottles.

[0013] The pump may be integrated into the base tray or may be externally connected to the base tray. The pump may be sterile and form a component of the fluid path, or may be a contactless type (such as a peristaltic pump). Those skilled in the art will be familiar with several pumping technologies that are suitable for pumping transfer liquid drugs in the manner described.

[0014] Specifically, the present invention includes the following items:

[0015] 1. A combination drug delivery device for delivering a predetermined selection of drug ingredients, each drug ingredient being contained in a vial, the device comprising:

[0016] A plurality of modules, wherein each module comprises:

[0017] a body having an interior volume formed to receive a vial;

[0018] a spike plate movably disposed in the interior volume, the spike plate having a protruding cannula and first and second ports, first and second openings, the protruding cannula terminating at a free end, the first and second openings being formed in the free end, and first and second lumens extending therefrom through the cannula and terminating at the first and second ports, respectively; and

[0019] A base tray, the base tray comprising:

[0020] a frame defining a plurality of recesses, each recess being formed to insertably receive one of the modules;

[0021] a first inlet port and a second inlet port, for each recess, the first inlet port and the second inlet port being formed to interface with the first port and the second port of a module received in the corresponding recess;

[0022] a channel connecting the second inlet port of some of the grooves with the first inlet port of grooves adjacent to the some of the grooves to permit fluid flow therebetween,

[0023] Wherein, for each groove, the first inlet port and the second inlet port are configured to maintain a spike plate of a corresponding module in a fixed position when the module is inserted into the groove.

[0024] 2. The drug delivery device as described in claim 1 further comprises a negative pressure source to draw the drug component from the module.

[0025] 3. A drug delivery device as described in claim 2, wherein the base tray includes a shell and the negative pressure source is located in the shell.

[0026] 4. A combination drug delivery device for delivering a predetermined selection of drug ingredients, each drug ingredient being contained in a vial, the device comprising:

[0027] a plurality of modules, wherein each module comprises a body having an interior volume formed to receive a vial, a plurality of keying features defined on the body; and,

[0028] a base tray comprising a frame defining a plurality of recesses bounded by upstanding walls, each recess being formed to insertably receive one of the modules, wherein a tray keying feature is defined on an interior portion of the upstanding walls,

[0029] Wherein, the keying features and the tray keying features are configured to allow the modules to be inserted into predetermined grooves so as to arrange the modules in a predetermined order along the base tray, while the keying features and the tray keying features restrict the insertion of the modules into predetermined grooves that are not intended for the modules.

[0030] 5. A drug delivery device as described in claim 4, wherein the keying feature includes one or more ridges and guide grooves.

[0031] 6. A drug delivery device as described in claim 5, wherein the tray keying feature includes one or more ridges and guide grooves. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figures 1 to 5 A module formed in accordance with the subject invention is shown;

[0033] Figure 6 to Figure 7 A spike plate that may be used with the subject invention is shown;

[0034] Figure 8 is along Figure 1 A cross-sectional view taken along line 8-8;

[0035] Fig. 9 is with Figure 8 A similar view showing the spike piercing the septum of a medicine bottle;

[0036] Figures 10 to 13 A base tray that may be used with the subject invention is shown;

[0037] Fig.14 , Fig.15 and Fig.16 Along Fig.13A cross-sectional view taken along line 14-14, line 15-15 and line 16-16;

[0038] Figures 17 to 19 The module is shown inserted into the groove of the base tray;

[0039] Figures 20 to 27 shows different assemblies of modules and base trays; and

[0040] Fig.28A and Fig.28B Matching keying features and non-matching keying features are schematically shown. DETAILED DESCRIPTION

[0041] Referring to the drawings, there is shown a module 12 and a base tray 14 formed in accordance with the subject invention, the module 12 once installed into the base tray 14 being connected in series to form a combination drug delivery device 10. In order to minimize the number of parts required in the inventory, the modules 12 are preferably formed similarly. The modules 12 can be formed with adjustable features to allow verification of accuracy of use, the adjustable features corresponding to any contained medications.

[0042] like Figures 1 to 5 As shown, each module 12 is generally box-shaped having a body 16 and a lid 18, which together enclose an internal volume 20. The lid 18 can be hingedly attached to the body 16 so as to be selectively opened to enter the internal volume 20. The shape and size of the internal volume 20 are designed to accommodate a medicine bottle or container 22. In order to accommodate medicine bottles 22 of various sizes, (multiple) liners or (multiple) spacers can be provided to be placed in the internal volume 20 to accommodate medicine bottles of various sizes. The internal volume 20 can be configured to accommodate the maximum medicine bottle size without any liner or spacer. The outer surface 24 of the lid 18 can have a protruding keying feature 26, which is formed to connect with a corresponding tray keying feature 28 to control the placement of a particular module in the fluid serial connection of the base tray 14, and the tray keying feature is formed on the inner surface 30 of any groove 32 of the base tray 14. The keying features 26 may be ridges and / or grooves, with the ridges and / or grooves of the tray keying features 28 being patterned (sized and arranged) to allow only modules 12 having the same pattern of keying features 26 to be inserted therein. Fig.28A and Fig.28B Schematically shown in FIG, a possible arrangement of keying features 26, 28 is shown. As will be appreciated by those skilled in the art, such as Fig.28B The non-matching keying features 26, 28 shown in FIG. 1 prevent the module 12 from being inserted into the recess 32. In contrast, a Fig.28A The mating keying features 26 , 28 shown in FIG. 1 allow the module 12 to be inserted into the recess 32 .

[0043] As in Figures 8 to 9 As shown in FIG. 1 , each module 12 includes a vial spike plate 34 captured within a hinged lid 18. When the lid 18 is closed, the vial spike plate 34 has the ability to slide vertically within the module 12, thereby extending a spike 36 into the interior volume 20, the spike being positioned to pierce a septum 38 ( 40 ) of the contained vial 22 upon entering the interior volume 40 of the vial 22. Fig. 9 ). The bottle tip 36 can be sharp to facilitate piercing the septum 38. The tip 36 must be provided with sufficient length to completely pierce the septum 38 when entering the interior volume 40 of the vial 22. The tip 36 preferably includes a plurality of lumens 42, such as a primary lumen 42a and a secondary lumen 42b, extending from a distal opening 43. In this arrangement, in the event that the tip 36 pierces the septum 38, all of the lumens 42 are in communication with the interior volume 40 of the vial 22 via the distal opening 43. The lumens 42 extend through the tip 36 away from the distal end 44 and extend into the tip plate 34, terminating at two fluid ports 46 (46a, 46b) proximal to the tip 36. The fluid ports 46 are formed to connect to the inlet ports 48 (48a, 48b) of the base tray 14 through an opening 50 in the lid 18. In this arrangement, liquid can flow into and out of the interior volume 40, for example, in a one-way flow that travels from one inlet port 48a through the primary lumen 42a into the interior volume 40, through the secondary lumen 42b, and into the second inlet port 48b. This allows both the introduction of liquid into and the removal of liquid from the vial 22. A seal may be provided to seal the interface between the port 46 and the inlet port 48.

[0044] In order to limit the entry of contaminants through the inlet port 48, a check valve 52, preferably a one-way check valve, may be provided to normally seal the closed inlet port 48. The port 46 may be formed to be inserted into the inlet port 48, thereby pushing the check valve 52 open to allow open communication between the port 46 and the inlet port 48. As will be appreciated by those skilled in the art, any form of one-way check valve may be utilized, including but not limited to a spring-based check valve ball configured to be seated in a normally closed state. A passage 54, which may be in the form of a tubing, communicates with each inlet port 48 to deliver a liquid flow to the port 48 and receive a liquid flow from the port 48.

[0045] like Figures 13 to 16As shown in , the base tray 14 is composed of a frame of grooves 32, each groove being formed to accommodate a module 12. It is preferred to provide multiple grooves 32 to allow multiple medicine bottles 32, which will be used to mix their contents into combined medication. A pair of inlet ports 48 are located in each groove 48, and the inlet ports particularly protrude upward from the base 53. Upright walls 56 limit each base 53 in a manner that partially closes the grooves 32. The inner surface 30 including the tray keying feature 28 can be defined on the inner portion of the wall 56. The wall 56 needs to define the occupied area that allows the module 12 to be inserted into the groove 32, while the keying features 26, 28 limit access to a specific position (if used). In this way, the module 12 including the corresponding medicine bottle 22 can be arranged in an orderly and specific manner. This can allow combined drug preparation by indicating the drug component to be used (i.e., the medicine bottle), while also arranging the components at a higher level in a specific order. This provides a fail-safe check for the end user to prevent improper inclusion of components and / or improper order.

[0046] To allow liquid flow between the grooves 32, the channels 54 are arranged in series between the inlet ports 48 to define a continuous fluid path through the base tray 14 when the module 12 is engaged in the groove 32. Fig.12 , the channel 54 is connected to one inlet port 48b of one groove 32 and extends to one inlet port 48a of an adjacent groove 32, thus serving as an outlet for the first mentioned groove 32 and serving as an inlet for the second mentioned groove 32. The grooves 32 at the ends of the base tray 14 may include a common outlet 58 and a vent 60 if necessary.

[0047] The vent 60 can be terminated by a sterile particle filter embedded in the base tray 14. The filter can be configured to allow atmospheric air to enter the base tray fluid path (which limits the entry of microorganisms and other contaminants) to replace the fluid volume loss during the discharge of the drug product from the module 12 from the sterile main output line from the base tray 14. The vent 60 can be located at the end away from the common outlet 58 to provide ventilation for the full length of the fluid path. A one-way valve can be provided with the common outlet 58 to prevent the drug product from backwashing into the base tray 14. In the case where the medicine bottle 22 has a rigid structure (e.g., a polymer structure or a glass structure), the vent 60 may be necessary. In the case where the medicine bottle 22 is foldable (such as a flexible bag structure), ventilation may not be necessary.

[0048] like Figures 8 to 9 and Figures 17 to 19 As shown in FIG, when the module 12 is installed in the correct groove 32, the inlet port 48 will contact the bottle tip plate 34 in the module 12 through the opening 50. Figure 8As best shown in FIG. 1 , the bottle tip plate 34 is releasably retained in an initial state adjacent the opening 50 by cooperating retention elements (e.g., biased detents 51a) formed on the bottle tip plate 34 and the cap 18 (e.g., retention ridges or guide grooves 51b). In the initial state, the port 46 is axially aligned with the opening 50 so as to be accessible therethrough. Figures 17 to 19 As shown in , when the module 12 is inserted into the groove 32, the inlet port 48 engages the port 46 to form a sealed fluid flow path therebetween, and the port 46 opens the check valve 52. Further insertion of the module 12 causes the cap 12 to move relative to the bottle tip plate 34, which is held fixed by the inlet port 48. Due to the relative movement, the retaining force of the mating retention element can be overcome by the movement of the body 16 toward the bottle tip plate 34, wherein the tip 36 pierces the septum 38 when fully moved. The module 12 can be locked in the groove hole 32 to ensure the connection with the tip 36 and to limit the reusability of the module 12. The movement of the bottle tip plate 34 through the cap 18 can be guided by a guide groove or other structure. Once all modules 12 are installed, the fluid circuit can be completed, allowing the vial contents of the module to be discharged, and the fluid circuit starts from the main line, passes through all the vials 22 and ends at the vent 60.

[0049] Liquid can be drawn from the vials 22 for delivery into the outlet conduit 62 through the common outlet 58. This allows different liquid medications to be contained by the vials 22 of the modules 12 and combined by the device 10. As will be appreciated by those skilled in the art, any number of modules 12 may be utilized, which may be limited by the fluid resistance of the assembly and / or the strength of the negative pressure used with the assembly.

[0050] A negative pressure source (e.g., a pump) is required to draw the liquid medication through the module 12. Negative pressure may be provided by an external pump 100 (e.g., a syringe) or an internal pump 102 that communicates (directly or indirectly) with the common outlet 58 and / or outlet conduit 62 to deliver the expelled liquid medication to a target delivery site (such as an IV bag, medication container) or directly into the patient. Fig.10As shown in , the base tray 10 can be optionally provided with a housing 104, and the outlet conduit 62 is at least partially located therein. The internal pump 102 can be provided in the housing 102 together with any motor, power supply, controller, etc. that can be used to operate and / or control the internal pump 102. As known in the art, the cannula 106 can be provided on the outlet conduit 62 as needed for injection or other access. It is necessary to generate sufficient negative pressure to completely aspirate the contents of all medicine bottles 22. Check valves can be provided along the common outlet 58 and / or the outlet conduit 62 to limit backflow. The external pump 100 and / or the internal pump 102 can be a non-contact pump (e.g., a peristaltic pump) that can act on the outlet conduit 62 without contacting the liquid flowing therethrough.

[0051] One or more vials 22 may contain a lyophilized drug that may be reconstituted with the introduction of a diluent. The diluent may be located upstream of the lyophilized drug so that the diluent is drawn into the vial with the lyophilized drug and the reconstituted drug is drawn out of it. A variety of drugs may be included in the vial. A diluent or other additive may also be included to increase the efficacy of the drug combination to be delivered.

[0052] In one embodiment, the drug delivery device 10 is capable of delivering two or more drugs to benefit patients suffering from any of a wide range of diseases or health conditions (eg, cancer, autoimmune disorders, inflammatory disorders, cardiovascular disease, fibrotic conditions).

[0053] In one embodiment, one or more drugs of the drug delivery device 10 are immune checkpoint inhibitors. In certain embodiments, the immune checkpoint inhibitors are programmed death-1 ("PD-1") pathway inhibitors, cytotoxic T lymphocyte-associated antigen 4 ("CTLA-4") antagonists, lymphocyte activation gene 3 ("LAG3") antagonists, CD80 antagonists, CD86 antagonists, T cell immunoglobulin mucin ("Tim-3") antagonists, T cell immunoreceptor with Ig and ITIM domains ("TIGIT") antagonists, CD20 antagonists, CD96 antagonists, indoleamine 2,3-dioxygenase ("IDO1") antagonists, ”) antagonists, stimulator of interferon genes (“STING”) antagonists, GARP antagonists, CD40 antagonists, adenosine A2A receptor (“A2aR”) antagonists, CEACAM1 (CD66a) antagonists, CEA antagonists, CD47 antagonists, receptor-associated immunoglobulin domain protein (“PVRIG”) antagonists, tryptophan 2,3-dioxygenase (“TDO”) antagonists, T cell activation V-domain Ig inhibitor (“VISTA”) antagonists, or killer cell immunoglobulin-like receptor (“KIR”) antagonists.

[0054] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-1 antibody is pembrolizumab (KEYTRUDA; MK-3475), pidilizumab (CT-011), nivolumab (OPDIVO; BMS-936558), PDR001, MEDI0680 (AMP-514), TSR-042, REGN2810, JS001, AMP-224 (GSK-2661380), PF-06801591, BGB-A317, BI 754091 or SHR-1210.

[0055] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-L1 antibody is atezolizumab (TECENTRIQ; RG7446; MPDL3280A; RO5541267), durvalumab (MEDI4736), BMS-936559, avelumab (bavencio), LY3300054, CX-072 (Proclaim-CX-072), FAZ053, KN035 or MDX-1105.

[0056] In one embodiment, the PD-1 pathway inhibitor is a small molecule drug. In certain embodiments, the PD-1 pathway inhibitor is CA-170. In another embodiment, the PD-1 pathway inhibitor is a cell-based therapy. In one embodiment, the cell-based therapy is a PD-L1 / L2-silenced dendritic cell vaccine loaded with MiHA. In other embodiments, the cell-based therapy is an anti-programmed cell death protein 1 antibody expressing multipotent killer T lymphocytes, autologous PD-1 targeted chimeric conversion receptor modified T lymphocytes, or PD-1 knocked-out autologous T lymphocytes.

[0057] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L2 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-PD-L2 antibody is rHIgM12B7.

[0058] In one embodiment, the PD-1 pathway inhibitor is a soluble PD-1 polypeptide. In certain embodiments, the soluble PD-1 polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-1 polypeptide includes a ligand binding fragment of the PD-1 extracellular domain. In other embodiments, the soluble PD-1 polypeptide includes a ligand binding fragment of the PD-1 extracellular domain. In another embodiment, the soluble PD-1 polypeptide further comprises an Fc domain.

[0059] In one embodiment, the immune checkpoint inhibitor is a CTLA-4 antagonist. In certain embodiments, the CTLA-4 antagonist is an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CTLA-4 antibody is ipilimumab (YERVOY), ticilimumab (CP-675,206), AGEN-1884, or ATOR-1015. In one embodiment, the drug delivery device 10 includes a CTLA-4 antagonist (e.g., ipilimumab (YERVOY)), a PD-1 pathway inhibitor (e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA)).

[0060] In one embodiment, the immune checkpoint inhibitor is an antagonist of LAG3. In certain embodiments, the LAG3 antagonist is an anti-LAG3 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-LAG3 antibody is relalizumab (BMS-986016), MK-4280 (28G-10), REGN3767, GSK2831781, IMP731 (H5L7BW), BAP050, IMP-701 (LAG-5250), IMP321, TSR-033, LAG525, BI 754111 or FS-118. In one embodiment, the drug delivery device 10 includes a LAG3 antagonist (e.g., relalizumab or MK-4280) and a PD-1 pathway inhibitor (e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA)). In one embodiment, the drug delivery device 10 includes a LAG3 antagonist (e.g., relalizumab or MK-4280) and a CTLA-4 antagonist (e.g., ipilimumab (YERVOY)). In one embodiment, the drug delivery device 10 includes a LAG3 antagonist (e.g., relalizumab or MK-4280), a CTLA-4 antagonist (e.g., ipilimumab (YERVOY)), and a PD-1 pathway inhibitor (e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA)).

[0061] In one embodiment, the CTLA-4 antagonist is a soluble CTLA-4 polypeptide. In one embodiment, the soluble CTLA-4 polypeptide is abatacept (ORENCIA), belatacept (NULOJIX), RG2077 or RG-1046. In another embodiment, the CTLA-4 antagonist is a cell-based therapy. In some embodiments, the CTLA-4 antagonist is an anti-CTLA4mAb RNA / GITRL RNA transfected autologous dendritic cell vaccine or an anti-CTLA-4mAb RNA transfected autologous dendritic cell vaccine.

[0062] In one embodiment, the immune checkpoint inhibitor is a KIR antagonist. In certain embodiments, the KIR antagonist is an anti-KIR antibody or an antigen-binding fragment thereof. In some embodiments, the anti-KIR antibody is lirelumab (1-7F9, BMS-986015, IPH 2101) or IPH4102.

[0063] In one embodiment, the immune checkpoint inhibitor is a TIGIT antagonist. In one embodiment, the TIGIT antagonist is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-TIGIT antibody is BMS-986207, AB 154, COM902 (CGEN-15137), or OMP-313M32.

[0064] In one embodiment, the immune checkpoint inhibitor is a Tim-3 antagonist. In certain embodiments, the Tim-3 antagonist is an anti-Tim-3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-Tim-3 antibody is TSR-022 or LY3321367.

[0065] In one embodiment, the immune checkpoint inhibitor is an IDO1 antagonist. In another embodiment, the IDO1 antagonist is indomod (NLG8189; 1-methyl- D -TRP), edostat (INCB-024360, INBC-24360), KHK2455, PF-06840003, navromod (RG6078, GDC-0919, NLG919), BMS-986205 (F001287), or pyrroline-2,5-dione derivatives.

[0066] In one embodiment, the immune checkpoint inhibitor is a STING antagonist. In certain embodiments, the STING antagonist is a 2' or 3'-monofluoro-substituted cyclic dinucleotide; a 2'3'-difluoro-substituted mixed-bond 2',5'-3',5' cyclic dinucleotide; a 2'-fluoro-substituted bis-3',5' cyclic dinucleotide; a 2',2"-di-f-Rp,Rp,bis-3',5' cyclic dinucleotide; or a fluorinated cyclic dinucleotide.

[0067] In one embodiment, the immune checkpoint inhibitor is a CD20 antagonist. In some embodiments, the CD20 antagonist is an anti-CD20 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD20 antibody is rituximab (RITUXAN; IDEC-102; IDEC-C2B8), ABP 798, ofatumumab or obinutuzumab.

[0068] In one embodiment, the immune checkpoint inhibitor is a CD80 antagonist. In certain embodiments, the CD80 antagonist is an anti-CD80 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD80 antibody is galiximab or AV1142742.

[0069] In one embodiment, the immune checkpoint inhibitor is a GARP antagonist. In some embodiments, the GARP antagonist is an anti-GARP antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-GARP antibody is ARGX-115.

[0070] In one embodiment, the immune checkpoint inhibitor is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an anti-CD40 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CD40 antibody is BMS3h-56, lucatumumab (lucatumumab) (HCD122 and CHIR-12.12), CHIR-5.9 or dacetuzumab (dacetuzumab) (huS2C6, PRO 64553, RG 3636, SGN 14, SGN-40). In another embodiment, the CD40 antagonist is a soluble CD40 ligand (CD40-L). In one embodiment, the soluble CD40 ligand is a fusion polypeptide. In one embodiment, the soluble CD40 ligand is CD40-L / FC2 or a monomeric CD40-L.

[0071] In one embodiment, the immune checkpoint inhibitor is an A2aR antagonist. In some embodiments, the A2aR antagonist is a small molecule. In certain embodiments, the A2aR antagonist is CPI-444, PBF-509, istradefylline (KW-6002), preladenant (SCH420814), tozadenant (SYN115), vipadenant (BIIB014), HTL-1071, ST1535, SCH412348, SCH442416, SCH58261 ZM241385 or AZD4635.

[0072] In one embodiment, the immune checkpoint inhibitor is a CEACAM1 antagonist. In some embodiments, the CEACAM1 antagonist is an anti-CEACAM1 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CEACAM1 antibody is CM-24 (MK-6018).

[0073] In one embodiment, the immune checkpoint inhibitor is a CEA antagonist. In one embodiment, the CEA antagonist is an anti-CEA antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CEA antibody is cergutuzumab amunaleukin (RG7813, RO-6895882) or RG7802 (RO6958688).

[0074] In one embodiment, the immune checkpoint inhibitor is a CD47 antagonist. In some embodiments, the CD47 antagonist is an anti-CD47 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CD47 antibody is HuF9-G4, CC-90002, TTI-621, ALX148, NI-1701, NI-1801, SRF231, or Effi-DEM.

[0075] In one embodiment, the immune checkpoint inhibitor is a PVRIG antagonist. In certain embodiments, the PVRIG antagonist is an anti-PVRIG antibody or an antigen-binding fragment thereof. In one embodiment, the anti-PVRIG antibody is COM701 (CGEN-15029).

[0076] In one embodiment, the immune checkpoint inhibitor is a TDO antagonist. In one embodiment, the TDO antagonist is a 4- (indol-3-yl) -pyrazole derivative, a 3- indole substituted derivative or a 3- (indol-3-yl) -pyridine derivative. In another embodiment, the immune checkpoint inhibitor is an IDO and TDO dual antagonist. In one embodiment, IDO and TDO dual antagonists are small molecules.

[0077] In one embodiment, the immune checkpoint inhibitor is a VISTA antagonist. In some embodiments, the VISTA antagonist is CA-170 or JNJ-61610588.

[0078] In one embodiment, one or more drugs of drug delivery device 10 are immune checkpoint enhancers or stimulators.

[0079] In one embodiment, the immune checkpoint enhancer or stimulator is a CD28 agonist, a 4-1BB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, an ICOS agonist, a CD70 agonist, or a GITR agonist.

[0080] In one embodiment, the immune checkpoint enhancer or stimulator is an OX40 agonist. In certain embodiments, the OX40 agonist is an anti-OX40 antibody or its antigen-binding fragment. In some embodiments, the anti-OX40 antibody is tavolixizumab (MEDI-0562), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-1015, MEDI-6383, MEDI-6469, BMS 986178, PF-04518600 or RG7888 (MOXR0916). In another embodiment, the OX40 agonist is a cell-based therapy. In certain embodiments, the OX40 agonist is a GINAKIT cell (iC9-GD2-CD28-OX40-expressing T lymphocyte).

[0081] In one embodiment, the immune checkpoint enhancer or stimulator is a CD40 agonist. In some embodiments, the CD40 agonist is an anti-CD40 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CD40 antibody is ADC-1013 (JNJ-64457107), RG7876 (RO-7009789), HuCD40-M2, APX005M (EPI-0050) or Chi Lob 7 / 4. In another embodiment, the CD40 agonist is a soluble CD40 ligand (CD40-L). In one embodiment, the soluble CD40 ligand is a fusion polypeptide. In certain embodiments, the soluble CD40 ligand is a trimeric CD40-L

[0082]

[0083] In one embodiment, the immune checkpoint enhancer or stimulator is a GITR agonist. In certain embodiments, the GITR agonist is an anti-GITR antibody or an antigen-binding fragment thereof. In some embodiments, the anti-GITR antibody is BMS-986156, TRX518, GWN323, INCAGN01876 or MEDI1873. In another embodiment, the GITR agonist is a soluble GITR ligand (GITRL). In some embodiments, the soluble GITR ligand is a fusion polypeptide. In another embodiment, the GITR agonist is a cell-based therapy. In some embodiments, the cell-based therapy is an anti-CTLA4 mAb RNA / GITRL RNA transfected autologous dendritic cell vaccine or a GITRL RNA transfected autologous dendritic cell vaccine.

[0084] In one embodiment, the immune checkpoint enhancer or stimulator is a 4-1BB agonist. In some embodiments, the 4-1BB agonist is an anti-4-1BB antibody or an antigen-binding fragment thereof. In one embodiment, the anti-4-1BB antibody is Urelumab or PF-05082566.

[0085] In one embodiment, the immune checkpoint enhancer or stimulator is a CD80 agonist or a CD86 agonist. In some embodiments, the CD80 agonist or CD86 agonist is a soluble CD80 or CD86 ligand (CTLA-4). In certain embodiments, the soluble CD80 or CD86 ligand is a fusion polypeptide. In one embodiment, the CD80 or CD86 ligand is CTLA4-Ig (CTLA4-IgG4m, RG2077 or RG1046) or abatacept (ORENCIA, BMS-188667). In other embodiments, the CD80 agonist or CD86 agonist is a cell-based therapy. In one embodiment, the cell-based therapy is MGN1601 (allogeneic renal cell carcinoma vaccine).

[0086] In one embodiment, the immune checkpoint enhancer or stimulator is a CD28 agonist. In some embodiments, the CD28 agonist is an anti-CD28 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CD28 antibody is TGN1412.

[0087] In one embodiment, the CD28 agonist is a cell-based therapy. In certain embodiments, the cell-based therapy is JCAR015 (anti-CD19-CD28-ζ modified CAR CD3+ T lymphocytes); CD28CAR / CD137CAR expressing T lymphocytes; allogeneic CD4+ memory Th1-like T cells / microparticle-bound anti-CD3 / anti-CD28; anti-CD19 / CD28 / CD3ζCARγ autologous T lymphocytes transduced by retroviral vectors KTE-C19; anti-CEA IgCD28TCR-transduced autologous T lymphocytes; anti-EGFRvIIICAR-transduced allogeneic T lymphocytes; autologous CD123CAR-CD28-CD3ζ-EGFRt-expressing T lymphocytes; autologous CD171-specific CAR-CD28ζ-4-1-BB-EGFRt-expressing T lymphocytes; autologous CD19CAR-CD28-CD3ζ-EGFRt-expressing Tcm-enriched T cells; autologous PD-1-targeted chimeric switch receptor-modified T lymphocytes (chimeric with CD28); CD19CAR-CD28 -CD3ζ-EGFRt expresses Tcm-enriched T lymphocytes; CD19CAR-CD28-CD3ζ-EGFRt expresses Tn / mem-enriched T lymphocytes; CD19CAR-CD28ζ-4-1BB expresses allogeneic T lymphocytes; CD19CAR-CD3ζ-4-1BB-CD28 expresses autologous T lymphocytes; CD28CAR / CD137CAR expresses T lymphocytes; CD3 / CD28 co-stimulatory vaccine induces autologous T lymphocytes; or iC9-GD2-CD28-OX40 expresses T lymphocytes.

[0088] In one embodiment, the immune checkpoint enhancer or stimulator is a CD27 agonist. In certain embodiments, the CD27 agonist is an anti-CD27 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD27 antibody is varilutumab (CDX-1127).

[0089] In one embodiment, the immune checkpoint enhancer or stimulator is a CD70 agonist. In some embodiments, the CD70 agonist is an anti-CD70 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD70 antibody is ARGX-110.

[0090] In one embodiment, the immune checkpoint enhancer or stimulator is an ICOS agonist. In certain embodiments, the ICOS agonist is an anti-ICOS antibody or an antigen-binding fragment thereof. In some embodiments, the anti-ICOS antibody is BMS986226, MEDI-570, GSK3359609 or JTX-2011. In other embodiments, the ICOS agonist is a soluble ICOS ligand. In some embodiments, the soluble ICOS ligand is a fusion polypeptide. In one embodiment, the soluble ICOS ligand is AMG 750.

[0091] In one embodiment, the anti-CD73 antibody or antigen-binding fragment thereof of the drug delivery device 10. In certain embodiments, the anti-CD73 antibody is MEDI9447.

[0092] In one embodiment, the one or more drugs of drug delivery device 10 are TLR9 agonists. In one embodiment, the TLR9 agonist is agatolimod sodium.

[0093] In one embodiment, the one or more drugs of the drug delivery device 10 are cytokines. In certain embodiments, the cytokine is a member of the chemokine, interferon, interleukin, lymphokine, or tumor necrosis factor family. In some embodiments, the cytokine is IL-2 or IL-15 or interferon-γ.

[0094] In one embodiment, one or more drugs of the drug delivery device 10 are TGF-β antagonists. In some embodiments, the TGF-β antagonist is fresolimumab (GC-1008); NIS793:IMC-TR1 (LY3022859); ISTH0036, trabedersen (AP 12009), recombinant transforming growth factor-β-2, autologous HPV-16 / 18E6 / E7 specific TGF-β resistant T lymphocytes or TGF-β resistant LMP specific cytotoxic T lymphocytes.

[0095] In one embodiment, the one or more drugs of drug delivery device 10 are iNOS antagonists. In some embodiments, the iNOS antagonist is N-acetylcysteine ​​(NAC) / aminoguanidine / l-nitroarginine methyl ester or S,S-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea.

[0096] In one embodiment, one or more drugs of drug delivery device 10 is a SHP-1 antagonist.

[0097] In one embodiment, the one or more drugs of drug delivery device 10 are colony stimulating factor 1 receptor ("CSF1R") antagonists. In certain embodiments, the CSF1R antagonist is an anti-CSF1R antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CSF1R antibody is imatinib.

[0098] In one embodiment, the one or more drugs of the drug delivery device 10 are agonists of TNF family members. In one embodiment, the agonist of TNF family members is ATOR 1016, ABBV-621, or adalimumab.

[0099] In one embodiment, the one or more drugs of the drug delivery device 10 are aldesleukin, bempegaldesleukin, tocilizumab, or MEDI5083. In one embodiment, the drug delivery device 10 includes bempegaldesleukin and a PD-1 pathway inhibitor (e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA)). In one embodiment, the drug delivery device 10 includes bempegaldesleukin and a LAG3 antagonist (relalimumab or MK-4280). In one embodiment, the drug delivery device 10 includes bempegaldesleukin, a PD-1 pathway inhibitor (e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA)) and a LAG3 antagonist (relalimumab or MK-4280). In one embodiment, the drug delivery device 10 includes bempegaldesleukin and a CTLA-4 antagonist (e.g., ipilimumab (YERVOY)).

[0100] In one embodiment, the one or more drugs of the drug delivery device 10 are CD160 (NK1) agonists. In certain embodiments, the CD160 (NK1) agonist is an anti-CD160 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD160 antibody is BY55.

Claims

1. A combination drug delivery device for delivering a predetermined selection of drug ingredients, each of which is contained in a vial, the device comprising: a plurality of modules, wherein each of said modules comprises a body, a cover and a plurality of keying features defined on said body, said body and said cover collectively defining an interior volume, said interior volume being formed to receive a vial; and a base tray comprising a frame defining a plurality of recesses bounded by upstanding walls, each of the recesses being formed to insertably receive one of the modules, wherein a tray keying feature is defined on an interior portion of the upstanding walls, The keying features and the tray keying features are configured to permit the module to be inserted into a predetermined recess, while the keying features and the tray keying features restrict the module from being inserted into a recess not intended for the module.

2. The drug delivery device of claim 1, wherein the keying feature comprises one or more ridges and grooves.

3. The drug delivery device of claim 2, wherein the tray keying feature comprises one or more ridges and grooves. The drug delivery device of claim 1 , wherein the keying features are different.

5. The drug delivery device of claim 1, wherein the tray keying features are different.

6. The drug delivery device of claim 1, wherein the keying feature is formed on an outer surface of a cover of each module, the module being insertable into a predetermined groove directed into the cover.

7. A drug delivery device according to claim 6, wherein each of the recesses comprises at least one upstanding inlet port defined by a respective upstanding wall. 8 . The drug delivery device according to claim 7 , wherein the cover comprises an access opening formed to allow passage of the at least one port having each module inserted into the predetermined groove.

9. The drug delivery device of claim 7, wherein the at least one port has a height lower than the respective upright wall such that the at least one port is recessed within the respective recess.

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