Medication error detection system

Abstract

To prevent the occurrence of medication errors.SOLUTION: Various embodiments are provided herein for checking proper inclusion and sequencing of drug modules in a combinatorial drug delivery device.SELECTED DRAWING: Figure 6

Description

[Background technology]

[0001] Drug combination systems are disclosed and described in U.S. Provisional Patent Application 62 / 670,266 (filed May 11, 2018), International Application PCT / US2019 / 031727 (filed May 10, 2019), International Application PCT / US2019 / 031762 (filed May 10, 2019), and International Application PCT / US2019 / 031791 (filed May 10, 2019). All of the above patent applications are by the same assignee as the present case. As shown in the above patent applications, multiple drug modules of different liquid drugs can be provided in various combinations to provide different (personalized) drug combinations. Multiple drug modules can be housed, i.e., connected, in series or in parallel on a tray or other base structure. Alternatively, multiple drug modules can be directly connected in series (vertically and / or horizontally) to each other. U.S. Provisional Patent Application No. 62 / 670,266, International Application No. PCT / US2019 / 031727, International Application No. PCT / US2019 / 031762, and International Application No. PCT / US2019 / 031791 are hereby incorporated by reference in their entireties.

[0002] A serial combination system, such as that shown diagrammatically for intravenous injection in FIG. 1, has the advantage over the housed designs shown in FIGS. 2 and 3 that it is more efficient in parts and therefore in the supply chain because it does not require a separate tray part to make the fluid connections.

[0003] In a container-based system, the tray design can "carry" information regarding the configuration of multiple modules through the inherent design and layout of the tray design. For example, the tray may provide features (e.g., mechanically cooperating mechanisms such as "lock" mechanisms) that ensure that only the correct drug modules can be inserted into the tray's receptacles and that the correct drug modules are in the correct order. This acts as a security check when preparing the drug modules for use. In contrast, a serial connection system does not have a tray-type element and therefore does not have the ability to perform a security check based on this.

[0004] A required feature of modules in both serial and housed systems is that they should be as universal in design as possible so that a minimum number of component parts are required to use them as a system. A limitation of housed systems is that their use of mechanical features to identify all possible drugs and strengths to be used requires molding and stocking different components for different configurations. This introduces distribution complexities in the supply chain and requires the manufacture of multiple mold tools per configuration (e.g., per lock configuration). In a portfolio where many drugs of different strengths are intended to be used in combination with each other, the number of mold components that must be manufactured and stocked becomes excessively large.

[0005] A serial design does not have a configuration tray and all modules must fit together, so it must be mechanically universal by design. The universality of this design means that it allows modules to be installed in the wrong order, unlike a stowed design.

[0006] Because in-line connections do not provide a tray-based mechanical means of error prevention, it would be desirable to implement an alternative means of detecting configuration errors in in-line connections, thereby preventing medication errors from occurring. [Brief description of the drawings]

[0007] [Figure 1] Schematic of a serially connected, module-based, intravenous (IV) combination delivery system showing pump housing and infusion bag. [Diagram 2] Schematic of a tray-type intravenous (IV) combination delivery system [Diagram 3] Schematic of a combined intravenous (IV) delivery system in a receiving tray format showing an integrated syringe pump and infusion bag. [Figure 4] Schematic diagram of the 5-gang plug integrated into the module to code the module type. [Diagram 5] FIG. 5 is a schematic diagram of a circuit that can be used to interrogate the coding of the module from FIG. [Figure 6] FIG. 1 is a schematic diagram of a circuit that can be used to interrogate the status of all the modules in an assembly; [Figure 7] 7 is a schematic diagram of the circuit of FIG. 6 adapted so that the address and data buses are integrated into a modular design; [Figure 8] FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 9] FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 10] FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 11] FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 12]FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 13] FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 14] FIG. 1 illustrates different configurations that allow automatic mechanical addressing of modules on appropriate address lines in an address bus based on the location of the module in the assembly. [Figure 15] FIG. 7 is a schematic diagram of the circuit of FIG. 6 with a termination block component including a termination resistor that provides electronic termination of the address data bus. [Figure 16] Schematic diagram of the circuit in Figure 7 with bus termination resistors integrated into the module [Figure 17] FIG. 1 illustrates various additional features that can be used with the subject invention. [Figure 18A] FIG. 1 illustrates various additional features that can be used with the subject invention. [Figure 18B] FIG. 1 illustrates various additional features that can be used with the subject invention. [Figure 19] 17 is a schematic diagram of the circuit of FIG. 16 with two additional auxiliary switches per module and additional data bus lines for status indicators showing the connection status of, for example, microswitches, etc. [Figure 20A] FIG. 1 illustrates various additional features that can be used with the subject invention. [Figure 20B] FIG. 1 illustrates various additional features that can be used with the subject invention. [Figure 21] Diagram showing the use of an optoelectronic addressing system instead of an address bus. [Figure 22] Diagram showing the use of an optoelectronic addressing system instead of an address bus. [Diagram 23] Diagram showing lane-moving electronic connections between modules [Figure 24]Diagram showing lane-moving electronic connections with an error detection system made up of resistors and MOSFETs. [Diagram 25] Diagram showing lane-moving electronic connections between modules [Figure 26] FIG. 1 illustrates a substrate (e.g., PCB) configuration for lane-moving electronic connections. [Figure 27] Schematic diagram of an electrical circuit that can be used with any of the lane-moving electronic connections [Figure 28] Schematic diagram showing the use of persistent memory with each of the modules. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] According to the invention, configuration for a series-connected system is feasible to verify the correctness of assembled modules by realizing that information regarding the correct configuration is required from two different levels within the system: The first level is the level of the individual modules: modules must store and provide access to information about their contents.

[0009] The second level at which information about the correct configuration is required is the system configuration level, i.e., information about the order in which the individual modules are assembled in the overall system.

[0010] Identifying the system level configuration requires that the type (what) and status of each module at each location be identified.

[0011] Information regarding the type of module may be coded or programmed into each individual module at the factory at the time of manufacture. However, due to the desire for universality in module design, the modules are preferably manufactured identically. System configuration information (i.e., the type and order of modules in assembly) is defined only when the system is prescribed for use (i.e., the actual drugs and order of the modules are determined). This information is stored so that it is available for interrogation during field assembly and use (i.e., when the drugs to be used are actually determined).

[0012] As will be appreciated by those skilled in the art, the serial system can be used with a vast number of drugs and drug concentrations. As a result, the number of permutations in the system can be in the millions, if not millions. For example, consider a portfolio of 10 drugs, each available in three different strengths, for a total of 30 different drug containers to be combined with each other in a combination therapy using the serial system. In addition, there can be diluent modules that can be combined with any drug module in any order. Each type of 31 containers must be identifiable while maintaining the universality of the module design.

[0013] To illustrate a possible example, assume that the number of modules in the series-connected system is limited to six, but the order of their assembly is not restricted, and further assume that the most different drugs that may be combined with one another are three (combinations of one, two, and three are allowed), then for each of the three combinations of drugs there are 1092 possible configurations of modules in the assembly, giving a number of possible drug-module configurations of 1092. Now assume that for each particular drug, different strengths are available such that there are three options for the strength of each module in the series-connected system, then the number of unique configurations of modules that can be achieved is 597870. The number of configurations increases exponentially by including changes in strength.

[0014] Without any controls, the risk of a medication error occurring is proportional to the number of possible ways the system can be configured. If the total number of possible configurations is CT, then the probability that a randomly selected assembly of modules will result in the correct configuration is 1 / CT. This can be used to define the probability of a medication error as 1-1 / CT. In the first example of 1092 possible combinations, the probability of error is 0.9991. In the second example of 597870 possible combinations, the probability of error is 0.999998. Therefore, there is a high probability of error in their use.

[0015] Applicant has realized that module level type information for a serially connected system can be encoded as a binary code, possibly through the use of configurable switches at assembly time. Enough switches are needed to provide enough switch states to encode all of the drug types and concentrations. In the example above of 10 drugs in three strengths plus one diluent module with a possible "empty" or "vacant" state, 32 switch states can be used (i.e., a switch state for each drug at a specified concentration (30 switch states), one switch state for the diluent, and one switch state for the empty, bypass module). The 32 switch states can be achieved by using five switches connected in parallel (those skilled in the art will know that this is commonly known as a "5-gang" switch). If an open switch represents a binary "0" and a closed switch represents a binary "1", then the state of each switch in the gang for the module represents one bit of a 5-bit binary number. The number of possible binary states in a parallel array of n switches is 2 n When n=5, the number of possible switch states is 2 5= 32, which is sufficient for the range of modules. For example, a module for drug 3, strength 1 may be coded by the 5-bit binary number 00110 (decimal 6). The switch states of this module are shown diagrammatically in Figure 4.

[0016] For simplicity of design and to keep module size to a minimum, the actual switches need not be switches in the traditional sense. Instead, they may simply be multiple electrical conductors, e.g., five electrical conductors, connected in parallel with one another in the module. Setting the switches for encoding for a particular module type may be accomplished by cutting or otherwise destroying the desired conductors to interrupt the conductive path so that they are "switched off." For example, to set the example switch of FIG. 4, the first, fourth, and fifth conductors would be cut, leaving the second and third wires intact, to encode the binary number 00110 (the first, fourth, and fifth conductors being "off" would be considered a "0" in binary, and the second and third conductors being intact and "on" would be considered a "1" in binary). The electrical conductors are preferably breakable, and breaking the conductors may be accomplished by any means including, but not limited to, mechanical, electrical, such as, for example, applying an electrical current to melt the desired wiring, and / or other suitable means that can be automated and integrated into a rapid assembly operation, such as, for example, a laser beam. Such irreversibility of the switch setting is preferred in this case, since the switch state should not be changed once it is set correctly, e.g., at the factory.

[0017] To minimize tampering, the electrical conductors are preferably configured so that they are not easily accessible within the module when the module is in commerce, and the conductors are preferably covered, especially once they have been coded (and, if necessary, destroyed). For example, the conductors may be overmolded or covered by a lid or other covering that is preferably secured (e.g., melted, glued, etc.) to the module so that it is preferably not removable.

[0018] After manufacture, destruction of the electrical contacts is possible, for example at the pharmacy where the module is filled with drugs. For example, non-conductive push-down spikes or the like may be formed in the module to line up with the electrical conductors. Deflection of the spikes inside the body of the module may destroy the corresponding electrical conductors. The non-conductive nature of the spikes (e.g., thermoplastic material) prevents electrical flow through the individual conductors. To limit inadvertent movement of the spikes, the spikes may be overmolded or otherwise equipped with restraints that must be removed to allow deflection. If overmolded, a threshold force is required to overcome the inherent stiffness of the overmolding, which must be exceeded to allow the spikes to deflect. Additionally or alternatively, a panel or other covering may be provided that covers and spans all the spikes, rendering them inaccessible. To make the spikes accessible, the panel must be removed. After the target spikes have been deflected to encode the corresponding drug designation, the panel is reattached to the module. The refastening may be configured to resist further removal of the panel, for example, by providing detents or other features that snap into a locked position upon refastening of the panel.

[0019] The modules may be loaded with the target drug before and / or after encoding the modules with the binary number of the drug type. This may be performed at the manufacturing stage or at a later stage, including at the point of use. As shown in FIG. 1, once all modules 12 intended for the system 10 are prepared (encoded and loaded), the modules 12 may be serially connected to each other and to a controller housing 104 to form the system or assembly 10. The system 10 (including any aspect thereof) may be formed according to any of the embodiments disclosed in any of U.S. Provisional Patent Application 62 / 670,266, International Application PCT / US2019 / 031727, International Application PCT / US2019 / 031762, and International Application PCT / US2019 / 031791. For purposes of illustration, exemplary features of the system 10 are described herein. As will be recognized by one of ordinary skill in the art, the subject invention may be used with any of the combination drug delivery devices, including with any of their components (e.g., module 12, the manner in which multiple modules 12 are connected, controller housing 104, etc.) disclosed in any of the above-mentioned patent applications.

[0020] As shown in FIG. 1, a plurality of modules 12 (12A-12F) may be connected in series to define a single flow path extending from a reservoir in the most distant module, through the reservoirs in each succeeding module, and to the controller housing 104. The flow path need not be continuous, and may, for example, have lengths (e.g., tubes) extending between adjacent reservoirs. As shown in FIG. 2, the flow path may be configured such that the outlet of one module leads to the inlet of an adjacent module, such that the drug in the first-mentioned module must pass through the next-mentioned module, and so on, to proceed down the fluid path toward the controller housing 104. The fluid path may traverse one or more reservoirs of the plurality of modules 12 connected in series. One or more of the plurality of modules 12 may be bypassed and may not have liquid drug, such as module 12A in FIG. 2. As shown in FIG. 1, the outlet of the flow path from a first module, e.g., module 12A, leads to an inlet of the controller housing 104 (the first module, e.g., module 12A, is considered to be the closest to the controller housing and the furthest or last module, e.g., module 12F, is considered to be the most distant module). Although it is preferred that only one flow path is utilized, it is possible to have multiple fluid paths (e.g., multiple rows of serially connected modules are provided in parallel and connected by a manifold or common outlet diversion). To best facilitate emptying of the reservoir, the flow path may be open in the most distant module, e.g., at the end of the flow path.

[0021] In a preferred embodiment, the controller housing 104 includes a pump 20 having an inlet that communicates with an inlet passage. The pump 20 is preferably driven by an electric motor 22, which is controlled by a computer processing unit (CPU) 24 located in the controller housing 104. The pump 20 is sized to provide sufficient negative pressure (e.g., suction) to empty all of the reservoirs of the multiple serially connected modules 12. A variety of pumps, such as positive displacement pumps, capable of drawing a drug through a flow path can be utilized. An outlet passage is provided in the controller housing 104 in communication with the outlet of the pump 20. The outlet passage leads to the exterior of the controller housing 104 to allow connection to additional tubing or other equipment to direct the flow of the drug being expelled. The expelled drug is directed to a collection container, such as an IV bag, or to a drug delivery device, such as a delivery needle (e.g., a butterfly needle), which is inserted into the patient.

[0022] In another embodiment, the controller housing 104 is not provided with a pump. For example, an external pump may be utilized to draw fluid through the fluid paths, as shown in FIG. 3 (a manual syringe pump). If the controller housing 104 does not have a pump, then a valve is preferably located inside the controller housing 104 in series between the inlet and outlet paths. The valve is preferably controlled by an electronic actuator, which in turn is controlled by the CPU 24. The CPU 24 is configured to selectively open and close the actuator, thereby selectively permitting flow of drug through the outlet path. The inlet path may be connected to the inlet of the valve, and the outlet path may be connected to the outlet of the valve.

[0023] A valve may be provided in combination with the pump 20 contained in the controller housing 104. As described above, the valve may be controlled by the CPU 24. One or more check valves may also be used along the flow path (e.g., in the module 12) or within the controller housing 104 to restrict flow through the flow path to one direction.

[0024] The CPU 24 preferably has an associated memory in which an authentication code can be stored. The authentication code can be placed in the memory when the modules 12 are encoded. In this manner, a kit of encoded modules 12 and the controller housing 104 are packaged together for shipping and subsequent assembly. As will be described below, the system allows for the generation of codes based on the encoding of the individual modules and the order of the modules. For purposes of non-limiting example, FIG. 4 shows a configurable switch gang, e.g., five switchable electrical conductors, that may be provided on each module 12. The generated code is compared to the authentication code for comparison. A match indicates that the correct modules and the correct order of modules are in place. This causes the CPU 24 to activate any valves to an open position and / or activate the pump 20 so that the pump 20 is activated or can be activated by a user operated switch. The system can be equipped with a transmitter / receiver that transmits the generated code to a remote server, mobile device, etc., which performs the comparison with the authentication code. An electronic message is sent back, either allowing or denying the drug discharge. In this configuration, the controller housing is not customized for a particular system (i.e., authentication codes based on the actual drug modules and their sequence do not need to be stored on the device). Additionally, the receiver may be used to receive authentication codes from an external source (remote server, mobile device, etc.), also eliminating the need to pre-store authentication codes on the CPU 24.

[0025] The code may be generated by the system using the circuitry shown in FIG. 5. Wires from the switch gangs in the module 12 are connected to a number of data transmission lines of the data bus 101. The data bus 101 has one transmission line for each switch in the gang, in this example there are five, forming a 5-bit data bus. For the type of module numbered 6 in binary notation described above, the binary number 00110 appears in parallel at the input pins of the encoder integrated circuit. The binary number read from the module array may be used to display further information about the module by using standard digital electronic components such as, but not limited to, decoders, encoders, multiplexers, demultiplexers, logic gates, read-only memories, programmable logic arrays, microprocessors, and displays. For example, the programmable logic array or read-only memory may be used as a look-up table that stores further information about the module corresponding to 00110, such as the identity and strength of the drug.

[0026] However, interrogation of individual modules does not provide information about the system level configuration in which the modules were assembled, e.g., the order in which the modules were assembled. To accomplish this, a means of uniquely addressing each module in the assembly is required.

[0027] Addressing of an array of modules, ie an assembly, can be achieved by a circuit shown diagrammatically in FIG.

[0028] The modules 12 of the assembly 10 are connected in parallel to a data bus 101 and an address bus 102. Typically the address bus has N transmission lines, where N is equal to the maximum number of modules allowed in the assembly. There is one transmission line for each module in the assembly, six in this example. Various numbers can be used.

[0029] The data and address buses 101, 102 are connected to an electronic controller 103 integrated in a controller housing 104 through a data selector / decoder integrated circuit 105 and an encoder integrated circuit 106, respectively. The controller 103 allows the data selector / decoder 105 to address and supply current to each conductor in each module in the row. The controller 103 allows the identity of each module 12 (12A, 12B, 12C, 12D, 12E, 12F, ...) of the assembly 10 to be read in sequence by synchronizing the addressing sequence of the decoder 105 with the binary module type read on the output lines of the data bus 101. Thus, system level type and configuration data can be established, which is required to verify the correct identity of the modules in the assembly and their configuration. The switch line for the least significant bit is labeled LSB and the switch line for the most significant bit is labeled MSB. The identities of the modules in the assembly shown in FIG.

[0030] [Table 1]

[0031] It will be understood by those skilled in the art that the functionality required for the controller 103 may be constructed from standard electronic components and integrated circuits, including, but not limited to, memory elements (RAM, ROM), microprocessors, timers / clocks, logic gates, multiplexers, demultiplexers, programmable logic arrays, shift registers, etc.

[0032] In an embodiment, the digital electronics of the controller 103 may be programmed to store the specific configuration required for a particular prescription and may automatically perform a logical comparison between the expected binary code of each module 12 and that read from the output from the data bus 101. In an embodiment, this expected configuration may be programmed into the memory elements by any suitable input means, such as, for example, keypad input, optically based such as a bar or quick response (QR) code, or radio frequency means (e.g., radio frequency identification (RFID), near field communication (NFC), or personal area network (PAN) technology using Bluetooth, Zigbee, Ant, or other personal area network protocols). Alternatively, the determined binary code may be transmitted to a remote server or the like where the expected binary code is stored to perform the comparison. If a match is determined, an activation code may be transmitted to the assembly to indicate the correctness of the assembly. To enable the comparison, the expected activation code may be stored in the controller 103.

[0033] In an embodiment, it may be beneficial to concatenate the binary numbers received from the output of each module into a single binary number. For example, the 6×5 bit binary numbers in the previous example may be concatenated into a single 30 bit binary number. For example, when concatenating from the last module 12F to the first module 12A in FIG. 6, the resulting number is 111111001110011101101011011010. Similarly, the numbers may be combined in the direction from the first module 12A towards the last module 12F, the resulting number being 110101011010110100111001111111.

[0034] Therefore, verification of the correct configuration of the correct module is a comparison of this 30-bit binary number with the expected 30-bit binary number for the prescription combination. 30 =32 6= 1,073,741,824, which represents the total number of ways that the 32 objects can be arranged into compositions of 6, i.e., the number of states that can be coded in this example (note that most of these states overlap, so the actual number of unique states will be substantially less).

[0035] Verification of the correct configuration acts as a key for the CPU 24 to activate the pump 22 and / or valves. The CPU 24 may be part of the controller 103 or may be operatively coupled to the controller 103.

[0036] As will be appreciated by those skilled in the art, a variety of numbers of modules 12 may be utilized and the address and data buses 101, 102 may be adapted accordingly.

[0037] While the circuitry of FIG. 6 can authenticate the type of each module in each location and compare the stored configuration for the intended prescription, thereby verifying the correct configuration of the correct module, the physical implementation of the data and address buses 101, 102 remains a technical challenge.

[0038] In a preferred embodiment, the address and data buses 101, 102 are ideally integrated into the modules 12 themselves and not separate from them. Otherwise, the modules would need to connect to a separate bus, which would require a board that could be the electronic equivalent of a tray in a housed design. The need for a separate bus board would defeat the purpose and advantages of the serially connected design.

[0039] In a preferred embodiment, buses 101, 102 are configured so that modules may be assembled together by connection of electronic conductive paths integral to the modules. In practice, modules must provide and assemble their own data and address buses, so that a complete circuit is provided regardless of the number of modules 12 utilized. This modification to the circuit of FIG. 6 is shown diagrammatically in FIG. 7.

[0040] In the case of data bus 101, the construction of data bus 101 is simple because modules 12 are connected such that data transmission lines 101' are connected in series between modules 12 in the data bus regardless of the position of the modules in the assembly. Data bus 101 should include at least as many data transmission lines 101' as there are switches used for each of the modules 12. Switch lines 101" are provided in each module 12 to connect each of the switches in a one-to-one correspondence to the data transmission lines 101', as shown, for example, with module 12F in FIG. 6.

[0041] Physically, data bus 101 may be fabricated by wiring embedded or glued into the module housing, by conductive paint or film embedded on or within the surface of the module housing, by a label, or by other suitable means of forming conductive paths in a molding known to those skilled in the art.

[0042] In the case of the address bus 102, address lines 102' are provided to each of the modules 12 in a number at least equal to the number of modules 12 in the assembly 10. The address lines 102' are connected axially and in series to the modules 12 to which they are connected.

[0043] It is preferred that each of the modules 12 be independently addressable. This may be accomplished by electrically connecting each of the modules 12 to different address lines 102' such that each module 12 is in unique electrical contact with one of the address lines 102'. In this manner, the address lines 102' provide a unique address for the module 12. In other words, the address lines 102' correlate to the position of the module 12 in the assembly 10. The address lines 102' to which a given module 12 is attached depends on the position of the module 12 in the assembly.

[0044] In one variation, each of the modules 12 may include manually adjustable electrical contacts that allow for variable connection with each of the address lines 102'. The manually adjustable contacts may be slide contacts, dial contacts, or other repositionable contacts that can be individually altered in position to make electrical contact with each of the address lines 102'. The manually adjustable contacts are adjusted to make electrical connection with the address lines 102' that correspond to the position of the associated module 12 in the assembly 10.

[0045] Preferably, modules 12 are passive and automatically electrically connected to the correct address lines 102' without the user having to do anything more than connect modules 12. Any configuration that allows for automatic electrical connection to the correct address lines 102' may be utilized.

[0046] If universality is used in the module design such that all modules are mechanically equivalent so that any module can in principle be mounted anywhere, then the predictability of the module's location cannot be stored in the module itself. For example, external mechanical features of the module cannot be used to control the connection to an address bus. Instead, module connections to the address bus must be made locally at the point of use.

[0047] In an embodiment, this may be accomplished by providing each module with an identical gang of switches and associated electronic conductors designed to couple the switches and conductors on one module with the switches and conductors of an adjacent module to form an electronic connection between the module and the controller electronics. An important feature of this approach is that the controller housing also has an electronic connector for the first module in the assembly designed to connect the first module in the assembly to the first address bus transmission line by the switching means. An even more important feature is that once the first module has been placed in a position adjacent to the controller housing by the switching means, installation of a second module in the assembly connects the second module to the second address bus transmission line, and so on for all subsequent modules. In an embodiment, such incremental, sequential cascading may be accomplished by pin and spring type electronic connectors designed to increment and shift the active address bus transmission line depending on the current module's position in the assembly. In this manner, by completing the assembly of the modules, the address bus and the module connections thereto are simultaneously completed. In other embodiments, non-mechanical solid state switching means may be used, such as capacitive switches, Hall effect sensors, or other suitable switching means known to those skilled in the art.

[0048] By way of non-limiting example, and with reference to FIGS. 8-14, a configuration is shown that allows identically configured modules to be connected in series and further allows adjustment of the contacts 200 to connect to the appropriate address lines 102′ on the address bus 102. In particular, each of the modules 12 includes an axially shiftable position pin 202 to which the contacts 200 are adjustably coupled. The position pin 202 is formed in length greater than the width of the module 12 such that, in an initial state, a portion extends from the module 12 by a discrete length x. A first module 12 is connected to the controller housing 104 and the position pin 202 is not displaced (i.e., remains in the initial state). All of the modules 12 are configured to position the position pin 202 in the same initial position. In this position, the contacts 200 are aligned to contact the address lines 102′ corresponding to the first module 12A in the first position. When the second module 12B is connected to the first module 12A, the position pin 202 of the first module 12A is caused to protrude into the position channel 204 of the second module 12B. This causes the position pin 202 of the second module 12B to shift axially a distance x. Because the position pin 202 of the second module 12B initially protruded a distance x from the second module 12B, the axial shift causes the position pin 202 to protrude a distance 2x from the second module 12B. The position pin 202 in the second module 12B, as well as all of the modules 12, is coupled to the contact 200 such that axial shifting of the position pin 202 causes movement of the contact 200 between the address lines 102'. As shown in FIGS. 8-10, the position pin 202 may be coupled to a rotatable cam 206. Rotation of the cam 206 causes movement of the contact 200. The cam 206 is configured such that for each positional displacement of a distance x, the cam 206 displaces the contact to the next address line 102'.In the configuration of FIG. 8, the displacement of position pin 202 increases for each subsequently connected module (e.g., 3x for the third module 12C, 4x for the fourth module 12D, etc.), and for each determined displacement of position pin 202, contact 200 lines up with a different address line 102' (e.g., third address line 102" for the third module 12C, fourth address line 102' for the fourth module 12D, etc.). More displacement of position pin 202 causes more rotation of cam 206, resulting in more adjustment of contact 200.

[0049] The position pin 202 may be coupled to the cam 206 by known methods. As shown in Figures 8-10, the position pin 202 is provided with a roller 208 that is arranged for a non-fixed press fit against the cam 206. Axial displacement of the position pin 202 causes the roller 208 to push against the cam 206, causing it to rotate. Other connections, such as a pin connection, with the cam 206 are also possible.

[0050] A spring or other biasing member 210 may be provided within a housing 212 and act on the contact 200. The spring 210 is positioned to bias the contact against the cam 206 to enhance the fit therebetween.

[0051] As will be appreciated by those skilled in the art, various elements and / or arrangements may be used in place of cam 206 to translate axial movement of position pin 202 into displacement of contacts 200. For example, as shown in Figures 13-14, a combination of links 214 configured to displace contacts 200 in response to axial movement of position pin 202 may be used, particularly in a fixed relationship such that each x displacement of position pin 202 causes contacts 200 to adjust to a different address line 102'.

[0052] It is also within the scope of the present invention to couple contact 200 to position pin 202 with rod 216 so that contact 200 moves in unison with (e.g., along a parallel axis with) position pin 202, as shown in Figures 11-12, where contact 200 is displaced the same distance as position pin 202. The distance x of each incremental displacement is equal to the spacing between address lines 102'.

[0053] In another embodiment, as shown in Figures 23-25, the address bus 102 may be defined by a row of parallel conductors provided on each of the modules 12. This allows the modules 12 to be configured in the same way. As shown in Figures 23-25, the electrical conductors are configured such that the ends are not axially aligned. In this format, in each of the modules 12, a first end 300 of the electrical conductor may be disposed along a first face 302 of the module 12, and a second end 304 of the electrical conductor may be disposed along a second face 306 of the module 12. The first ends 300 and second ends 302 are offset by one such that the first ends 300 and second ends 304 of adjacent modules 12 overlap in an n-1 relationship for direct coupling (e.g., for five electrical conductors, four overlap for direct coupling). This allows a continuous path to be defined along the individual conductors from the first face 302 of the first module 12A to the other modules (12B, 12C, ...). This allows the individual modules 12 to be addressed sequentially by addressing each of the conductors individually. So, for example, as shown in Figure 23, a first end 300 of module 12A, labeled 1, provides an addressable connection for module 12A. A first end 300 labeled 2 provides an addressable connection for a second module 12B. A first end 300 labeled 3 provides an addressable connection for a third module 12C, and so on. The number of electrical conductors should be at least equal to the number of modules 12 in the assembly 10. The electrical conductors may be formed to conduct electricity, but may also conduct light if light is used for addressing the modules 12. Additionally, as an alternative, the conductors may be provided, e.g., as traces, on a substrate such as a printed circuit board (PCB) with first end 300 and second end 304 aligned in the same manner as described above, as shown in Figure 26. The conductors may be configured to span the entire length of the printed circuit board or less than the entire length of the printed circuit board. As described below, the printed circuit board may be included in module 12 in any manner, including as an overmolded or other assembly method.In a printed circuit board configuration, jumpers or other connectors may be used to connect the conductors to locations outside of the modules 12 for connection between modules 12, as shown diagrammatically in Figures 25 and 28 where wires extend from the terminal modules 12, 12F. Figure 27 diagrammatically illustrates a possible board (e.g., PCB) circuit configuration that can be used with electrical conductors as arranged in any of Figures 23-26.

[0054] Referring to Fig. 24, the data bus 101 may be formed in a similar manner as described above. Fig. 24 shows a circuit that may be used in each of the modules 12, which includes a MOSFET 308 connected in series with each of the switches. Power may be provided to each of the MOSFETs 308 through one or more resistors 310. This allows for addressing of individual switches in each of the modules 12.

[0055] Like data bus 101, in any embodiment herein, physically, address lines 102' of address bus 102 may be fabricated into module 12 by wires embedded or glued into the module housing, by conductive paint or film embedded on or within the surface of the module housing, by labels, or by any other suitable means of forming conductive paths in a molding known to those skilled in the art. Additionally or alternatively, address lines 102' may be defined by traces and / or conductors on a printed circuit board or other substrate that is incorporated into module 12, for example, by overmolding or other assembly methods.

[0056] As will be appreciated by those skilled in the art, depending on the details of the circuit design, some additional circuit elements may be required on both the address and data bus sides of the circuit, such as pull-up or pull-down resistors to ensure correct logic levels, bus termination resistors, etc. In an embodiment, such additional circuit elements, e.g., bus termination resistors 110, can be provided in a termination component 107 (FIG. 15) that is either integrated into the controller housing 104 or integrated into the module 12 itself. In the latter case, each module 12 can have, for example, an integrated termination resistor 111. The sequential switching cascade connection described above can be designed such that by the last module in the assembly, resistors are connected to automatically terminate the bus lines. This is shown diagrammatically in FIG. 16.

[0057] The electronically serially connected assembly according to the present invention has several advantages. One possible advantage is that the need to make a physical electronic connection can also be used to verify that the mechanical and fluid connections are made correctly. For example, as shown and described in FIG. 17, the system is designed such that the electronic circuit is completed only when the fluid connections are made correctly. For example, as shown in FIG. 17, a conductive pin 500 may be provided on the module 12, which is configured to electrically couple with a spring contact 502 disposed within the recess 504 upon full insertion of the conductive pin 500 into the recess 504. This ensures that the modules 12 are close enough together to ensure proper connection, both fluid and electrical, between them.

[0058] The use of electronics also allows the implementation of additional error prevention and status indication features. For example, by adding additional transmission lines to the data bus, electronic logic circuits can interrogate additional binary status indications of each module. For example, additional microswitches 600 can be included in modules 12 to indicate their connection status to other modules 12. For example, switches 600 can be configured to be open when the module 12 is not connected to another module 12 and closed when the module 12 is installed in an assembly. Similarly, additional status features can indicate whether a module cap 602 is open or closed to allow cleaning of the vial septum. The latter status indicator can be designed to be switchable / resettable or non-openable after the cap 602 has been opened or closed or the peelable seal has been removed, for example as a use or tamper-evident indicator. The latter effect can be achieved, for example, by configuring the opening or closing of the cap to permanently destroy an electronic conductor. In an embodiment, multiple status switches can be implemented with multiple destroyable conductors. That is, as shown and described in FIGS. 18A-18B, the switch 600 can be disabled when the module cap 602 is opened to indicate that the module cap 602 is open. The switch 600 can be formed to extend along the wall of the module 12. A second switch can be disabled when the peelable film is peeled away. A third switch can be fixed by closing the module cap 602. With appropriate logical circuit design, the state of these switches 600 can be interrogated to confirm that the cap 602 has been opened, a vial has been exposed for cleaning of the septum, and the cap 602 has then been closed to penetrate the septum. Additionally, a tamper-evident configuration can be provided, as shown and described in FIGS. 20A-20B, where the switch 600 provides an indication of possible tampering with the contents of the module 12.Here, the switch 600 extends across the vial rather than along the wall of the module 12 as shown in Figures 18A-18B. Figure 19 shows the circuit of Figure 16 with an additional switch 108 in parallel with the 5-gang module ID switch and two additional data bus lines 109 that can be used for purposes such as providing status signals to a controller for assembly verification.

[0059] Referring to FIG. 28, in any of the embodiments described herein, the modules 12 may each include a persistent memory 400, e.g., an EEPROM memory. The memory 400 advantageously allows for the storage of various readable data, including, but not limited to, data related to the associated drug, such as drug name, batch number, serial code, expiration date, etc. Additionally, a security code may be stored in the memory 400 to prevent counterfeiting. The memory 400 of the modules 12 may be interrogated using the address bus 102 in a manner similar to that described above. Additionally, the memory 400 may be erasable / writeable to allow updating of the stored data. The memory 400 may store an identification code for each of the modules 12, which may be read to function similarly to the binary code described above.

[0060] In addition, the modules may be configured to prevent reusability. For example, a fuse may be provided in each of the modules. The fuse is destroyed upon completion of dosing, for example, by a sufficiently large electrical pulse emitted from the controller housing. The fuse may be provided along the electrical conductor (e.g., as an element that can be destroyed) and / or may be provided separately, for example, as a chip that is destroyed, thereby blocking current flow. Additionally or alternatively, the memory 400 of each of the modules 12 may act as a fuse in that it will not pass current if erased. The memories 400 may each include a simple logic scheme that allows current flow, and if the scheme is removed, the current flow is blocked. For example, the memories 400 may include a code indicating "ready for use" and after use, the code may be updated by the controller housing 103 to a code indicating "used". Further use of the associated module 12 may read "used" and prevent reuse.

[0061] In embodiments, an electrically powered transfer pump may be integrated into the pump housing, and in embodiments, the operation of the pump may be configured to be under the control of the controller such that the pump can be switched on to perform drug transfer once the correct module identity, module status, and system configuration have been verified.

[0062] Other status indicators may be envisaged. For example, a simple thermostatic switch may be implemented using a bimetallic plate to provide a temperature dependent signal. Such a thermostatic switch may be set to on or off at a particular threshold temperature. More advanced and complex configurations may be contemplated by the use of other circuit elements to form other status indicators. For example, the temperature status may be more accurately monitored using a thermocouple coupling or a thermistor that provides an analog electronic signal proportional to the temperature. Such circuit features may be integrated into the module using thin or thick film techniques such as pad or silk screen printing of an ink having a positive temperature coefficient of resistance (PTC). Such PTC inks are known to those skilled in the art. Such circuit elements may be applied as labels. Other circuit elements may be used to provide other analog signals proportional to other physical properties of interest. For example, a light-sensitive element such as a light-dependent resistor may be used to confirm that the module has been opened or that a peelable seal has been removed. Sensor readings, particularly those related to the environment (e.g., temperature, humidity, light exposure, etc.), may be stored in memory 400, particularly if sensor readings are taken during storage and transport of the module. A timer may also be used to provide a timestamp of the sensor readings. This allows environmental data to be collected to determine if an associated drug has been exposed to an unsafe condition. Prior to use of the module 12, power may be provided in known manner to allow for such sensor readings, timing, and data storage. Power may be provided from an on-board power source, such as a battery, and / or from an external source, such as exposure to a radio frequency electromagnetic field (with corresponding conversion hardware on the module). Upon assembly, the environmental data may be read out to assess drug stability.

[0063] A disadvantage of using an analog signal is that it needs to be conditioned for interaction with digital electronics, increasing circuit complexity. This may require incorporating an analog-to-digital converter (ADC) integrated circuit into the pump housing. In a simple example, if all that is required is to set a threshold on the signal (i.e., provide a logic high or low value depending on whether the signal is greater than or less than a threshold setting), this may be accomplished simply by using a comparator integrated circuit.

[0064] It should be noted that the control of the controller housing is described in the context of a CPU. As will be appreciated by those skilled in the art, the system may rely on logic that may be implemented in combinatorial and sequential logic circuits having some form of memory but without the need for stored programs (software) running on a microprocessor. That is, the system logic may be built in by design, reducing the risk of logic errors inherent in software design and avoiding the need for verification of the software through, for example, logic gates, etc.

[0065] In another embodiment, as shown in FIGS. 21-22, the address bus 102 may be replaced by an optoelectronic addressing system 700 comprising one or more light sources 702, preferably light emitting diodes (LEDs) or diode lasers, housed in the controller housing 104.

[0066] The controller 103 has connections to the power and ground conductors. The modules 12 may be connected in series to the power and ground conductors. Each module 12 has an internal reflective surface such as a mirror and a light-sensitive element such as a phototransistor or photo-darlington device 704 connected in series with a resistor 206 across the power and ground conductors in a common collector voltage divider circuit and connected to a switch array whose output encodes a binary number representing the module type. The resistance value of resistor 706 is selected so that the common collector circuit is sufficiently saturated so that the phototransistor or photo-darlington (photo sensor) 704 acts as an optical switch. In this configuration, upon illumination from the controller housing 104 by the light source 702, a potential equal to the power line voltage Vcc is applied to the switch array and the binary encoding for the addressed module appears on the data bus 101 on the input line to the encoder 106.

[0067] As shown generally in FIG. 22, by configuring the controller 103 to sequentially illuminate the photosensor 74 with sequentially switched illumination of multiple light sources 702, the drug modules 12 are sequentially addressed and their encodings interrogated.

[0068] In an embodiment, instead of multiple light sources 702, a single light source may be used in conjunction with optical and / or mechanical means to direct a beam of light to each photosensor 204 in turn.

[0069] An advantage of this system is that there are no moving parts or mechanical bus connections in the module 12, and it also utilizes the ability of light to be transmitted without a physical transmission medium.

[0070] System 700 requires a transparent transmission path for the light beam, and for this purpose narrow windows or slits are provided in modules 12 to allow unimpeded passage of light through the module stack. Alternatively, transparent windows may be provided in modules 12, but in this case consideration must also be given to the effects of refraction on the path of the transmitted light beam due to changes in the medium, including allowances for manufacturing tolerances in the window material.

[0071] As will be appreciated by those skilled in the art, optical components including, but not limited to, optical waveguides ("optical fibers"), lenses, prisms, mirrors, collimators, pinholes, etc., may be implemented in the control unit and / or modules to refract, guide, expand, and focus the light from the LEDs or laser diodes to facilitate optical addressing of the required drug modules. In addition, screens and / or optical filters may be used to prevent unintentional switching due to external light sources. Furthermore, the light source may be any type of solid-state lighting device, including LEDs, OLEDs (organic light-emitting diodes), and PLEDs (polymer light-emitting diodes). Also, due consideration must be given to matching the spectral sensitivity of the photosensor to the spectral emission of the light source.

[0072] In one embodiment, any of the combination drug delivery devices or systems of the present disclosure can deliver two or more drugs for the benefit of patients suffering from any of a wide range of diseases or conditions, such as, for example, cancer, autoimmune disease, inflammatory disease, cardiovascular disease, fibrosis, etc. In one embodiment, one or more of the drug modules 12 can contain a single drug. In one embodiment, one or more of the drug modules 12 can contain two or more combined drugs. In one embodiment, one or more of the drug modules 12 can contain a solid drug (e.g., tablet, capsule, powder, lyophilized, spray dried) that is prepared with the inflow of a diluent to form a liquid drug.

[0073] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is a programmed death 1 ("PD-1") pathway inhibitor, a cytotoxic T-lymphocyte antigen 4 ("CTLA-4") antagonist, a lymphocyte-activation gene 3 ("LAG3") antagonist, a CD80 antagonist, a CD86 antagonist, a T-cell immunoglobulin-mucin domain ("Tim-3") antagonist, a T-cell immunoreceptor with Ig and ITIM domains ("TIGIT") antagonist, a CD20 antagonist, a CD96 antagonist, an indoleamine 2,3-dioxygenase ("IDO1") antagonist, a stimulator of interferon genes ("STING") antagonist, or a combination of these. antagonist, repeat dominant glycoprotein A (GARP) antagonist, CD40 antagonist, adenosine A2A receptor ("A2aR") antagonist, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (CD66a) antagonist, carcinoembryonic antigen (CEA) antagonist, CD47 antagonist, protein receptor-related immunoglobulin domain ("PVRIG") antagonist, tryptophan 2,3-dioxygenase ("TDO") antagonist, V-domain immunoglobulin inhibitor of T-cell activation ("VISTA") antagonist, or killer cell immunoglobulin-like receptor ("KIR") antagonist.

[0074] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In some 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, BI754091, or SHR-1210.

[0075] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some 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.

[0076] In one embodiment, the PD-1 pathway inhibitor is a small molecule drug. In one embodiment, the PD-1 pathway inhibitor is CA-170. In other embodiments, the PD-1 pathway inhibitor is a cell-based therapy. In one embodiment, the cell-based therapy is a MiHA-loaded PD-L1 / L2 expression suppressive dendritic cell vaccine. In other embodiments, the cell-based therapy is anti-programmed cell death protein 1 antibody expressing pluripotent T lymphocytes, autologous PD-1 targeted chimeric switch receptor modified T lymphocytes, or PD-1 knockout autologous T lymphocytes.

[0077] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L2 antibody or antigen-binding fragment thereof, hi another embodiment, the anti-PD-L2 antibody is rHIgM12B7.

[0078] In one embodiment, the PD-1 pathway inhibitor is a soluble PD-1 polypeptide. In some embodiments, the soluble PD-1 polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-1 polypeptide comprises a ligand binding fragment of the PD-1 extracellular domain. In other embodiments, the soluble PD-1 polypeptide comprises a ligand binding fragment of the PD-1 extracellular domain. In other embodiments, the soluble PD-1 polypeptide further comprises an Fc domain.

[0079] 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), tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015. In one embodiment, any of the combination drug delivery devices of the present disclosure includes a CTLA-4 antagonist, such as ipilimumab (Yervoy), or a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda).

[0080] In one embodiment, the immune checkpoint inhibitor is a LAG3 antagonist. In some embodiments, the LAG3 antagonist is an anti-LAG3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-LAG3 antibody is relatlimab (BMS-986016), MK-4280 (28G-10), REGN3767, GSK2831781, IMP731 (H5L7BW), BAP050, IMP-701 (LAG-5250), IMP321, TSR-033, LAG525, BI754111, or FS-118. In one embodiment, any of the combination drug delivery devices of the present disclosure includes a LAG3 antagonist, such as lilatlimab or MK-4280, and a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda). In one embodiment, any of the combination drug delivery devices of the present disclosure includes a LAG3 antagonist, such as lilatlimab or MK-4280, and a CTLA-4 antagonist, such as ipilimumab (Yervoy). In one embodiment, any of the combination drug delivery devices of the present disclosure includes a LAG3 antagonist, such as lilatlimab or MK-4280, a CTLA-4 antagonist, such as ipilimumab (Yervoy), and a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda).

[0081] 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 lirilumab (1-7F9, BMS-986015, IPH2101) or IPH4102.

[0082] 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 some embodiments, the anti-TIGIT antibody is BMS-986207, AB154, COM902 (CGEN-15137), or OMP-313M32.

[0083] In one embodiment, the immune checkpoint inhibitor is a Tim-3 antagonist. In some 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.

[0084] In one embodiment, the immune checkpoint inhibitor is an IDO1 antagonist. In another embodiment, the IDO1 antagonist is indoximod (NLG8189; 1-methyl-D-tryptophan), epacadostat (INCB-024360, INCB-24360), KHK2455, PE-06840003, navoximod (RG6078, GDC-0919, NLG919), BMS-986205 (F001287), or a pyrrolidine-2,5-dione derivative.

[0085] In one embodiment, the immune checkpoint inhibitor is a STING antagonist. In certain embodiments, the STING antagonist is a 2' or 3'-mono-fluoro substituted cyclic-di-nucleotide, a 2'3'-di-fluoro substituted mixed linkage 2',5'-3',5' cyclic-di-nucleotide, a 2'-fluoro substituted, bis-3',5' cyclic-di-nucleotide, a 2',2"-diF-Rp,Rp, bis-3',5' cyclic-di-nucleotide, or a fluorinated cyclic-di-nucleotide.

[0086] 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), ABP798, ofatumumab, or obinutuzumab.

[0087] 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.

[0088] 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 some embodiments, the anti-GARP antibody is ARGX-115.

[0089] In one embodiment, the immune checkpoint inhibitor is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an anti-CD40 antibody for an antigen-binding fragment thereof. In some embodiments, the anti-CD40 antibody is BMS3h-56, lucatumumab (HCD122 and CHIR-12.12), CHIR-5.9, or dacetuzumab (huS2C6, PRO64553, RG3636, SGN14, 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 monomeric CD40-L.

[0090] In one embodiment, the immune checkpoint inhibitor is an A2aR antagonist. In some embodiments, the A2aR antagonist is a small molecule. In some 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.

[0091] 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).

[0092] 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 some embodiments, the anti-CEA antibody is cergutuzumab amunaleukin (RG7813, RO-6895882) or RG7802 (RO6958688).

[0093] 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.

[0094] 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).

[0095] 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 a dual IDO and TDO antagonist. In one embodiment, the dual IDO and TDO antagonist is a small molecule.

[0096] In one embodiment, the immune checkpoint inhibitor is a VISTA antagonist, hi some embodiments, the VISTA antagonist is CA-170 or JNJ-61610588.

[0097] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is an immune checkpoint enhancer or stimulator.

[0098] 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.

[0099] In one embodiment, the immune checkpoint enhancer or stimulator is an OX40 agonist. In some embodiments, the OX40 agonist is an anti-OX40 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-OX40 antibody is tavolixizumab (MEDI-0562), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-1015, MEDI-6383, MEDI-6469, BMS986178, PF-04518600, or RG7888 (MOXR0916). In another embodiment, the OX40 agonist is a cell-based therapy. In some embodiments, the OX40 agonist is a GINAKIT cell (iC9-GD2-CD28-OX40 expressing T lymphocyte).

[0100] 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 one embodiment, 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 some embodiments, the soluble CD40 ligand is trimeric CD40-L (AVREND®).

[0101] 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 one embodiment, the anti-GITR antibody is BMS-986156, TRX518, GWN323, INCAGN01876, or MEDI1873. In one 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 one embodiment, 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.

[0102] 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.

[0103] 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 (an allogeneic renal cell carcinoma vaccine).

[0104] 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 antigen-binding fragment thereof. In one embodiment, the anti-CD28 antibody is TGN1412.

[0105] In one embodiment, the CD28 agonist is a cell-based therapy. In one embodiment, the cell-based therapy is JCAR015 (anti-CD19-CD28-zeta 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 / CD3 zeta CAR gamma retroviral vector-transduced autologous T lymphocytes KTE-C19, anti-CEA IgCD28TCR transduced autologous T lymphocytes, anti-EGFRvIII CAR-transduced allogeneic T lymphocytes, autologous CD123CAR-CD28-CD3zeta-EGFRt expressing T lymphocytes, autologous CD171-specific CAR-CD28zeta-4-1-BB-EGFRt expressing T lymphocytes, autologous CD19CAR-CD28-CD3zeta-EGFRt expressing Tcm enriched T cells, autologous PD-1 targeted chimeric switch receptor modified T lymphocytes (chimera with CD28), CD19CAR-CD28-CD3zeta-EGFRt expressing T cm-enriched T lymphocytes, CD19CAR-CD28-CD3 zeta-EGFRt-expressing Tn / mem-enriched T lymphocytes, CD19CAR-CD28 zeta-4-1BB-expressing allogeneic T lymphocytes, CD19CAR-CD3 zeta-4-1BB-CD28-expressing autologous T lymphocytes, CD28CAR / CD137CAR-expressing T lymphocytes, CD3 / CD28 costimulatory vaccine-stimulated autologous T lymphocytes, or iC9-GD2-CD28-OX40-expressing T lymphocytes.

[0106] 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 varlilumab (CDX-1127).

[0107] 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 antigen-binding fragment thereof. In one embodiment, the anti-CD70 antibody is ARGX-110.

[0108] 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 AMG750.

[0109] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is an anti-CD73 antibody or antigen-binding fragment thereof, hi one embodiment, the anti-CD73 antibody is MEDI9447.

[0110] In one embodiment, one or more of the drugs in any of the combination drug delivery devices of the present disclosure is a TLR9 agonist, hi one embodiment, the TLR9 agonist is agatolimod sodium.

[0111] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is a cytokine. In certain embodiments, the cytokine is a chemokine, interferon, interleukin, lymphokine, or member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-gamma.

[0112] In one embodiment, one or more of the drugs in any of the combination drug delivery devices of the present disclosure is a TGF-β antagonist. In some embodiments, the TGF-β antagonist is fresolimumab (GC-1008), NIS793, IMC-TR1 (LY3022859), ISTH0036, travedersen (AP12009), recombinant transforming growth factor-beta-2, autologous HPV-16 / 18 E6 / E7-specific TGF-beta resistant T lymphocytes, or TGF-beta resistant LMP-specific cytotoxic T lymphocytes.

[0113] In one embodiment, one or more of the drugs in any of the combination drug delivery devices of the present disclosure is an iNOS antagonist. In some embodiments, the iNOS antagonist is N-acetyl-cysteine ​​(NAC), aminoguanidine, L-nitroarginine methyl ester, or S,S-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea).

[0114] In one embodiment, one or more of the drugs in any of the combination drug delivery devices of the present disclosure is an SHP-1 antagonist.

[0115] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is a colony stimulating factor 1 receptor ("CSF1R") antagonist. 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 emactuzumab.

[0116] In one embodiment, one or more of the drugs in any of the combination drug delivery devices of the present disclosure is an agonist of a member of the TNF family, hi some embodiments, the agonist of a member of the TNF family is ATOR1016, ABBV-621, or adalimumab.

[0117] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is Interleukin-2 (IL-2), such as aldesleukin. Preferably, the IL-2 or conjugated IL-2 (e.g., PEGylated) may be modified to selectively activate effector T cells through regulatory T cells, such as bempegaldesleukin ("T-eff IL-2"). In one embodiment, any of the combination drug delivery devices of the present disclosure includes a modified IL-2, such as bempegaldesleukin, that selectively activates effector T cells through regulatory T cells, and a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda). In one embodiment, any of the combination drug delivery devices of the present disclosure includes a modified IL-2, such as bempegaldesleukin, that selectively activates effector T cells through regulatory T cells, and a LAG3 antagonist, such as lilatolimab or MK-4280. In one embodiment, any of the combination drug delivery devices of the present disclosure includes a modified IL-2, such as bempegaldesleukin, that selectively activates effector T cells through regulatory T cells, and a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda), and a LAG3 antagonist, such as lilatolimab or MK-4280. In one embodiment, any of the combination drug delivery devices of the present disclosure includes a modified IL-2, such as bempegaldesleukin, that selectively activates effector T cells through regulatory T cells, and a CTLA-4 antagonist, such as ipilimumab (Yervoy). In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates effector T cells through regulatory T cells, a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda), and a CTLA-4 antagonist, such as ipilimumab (Yervoy).In one embodiment, any of the combination drug delivery devices of the present disclosure include a modified IL-2, such as bempegaldesleukin, that selectively activates effector T cells through regulatory T cells, a CTLA-4 antagonist, such as ipilimumab (Yervoy), and a LAG3 antagonist, such as lilatlimab or MK-4280. In one embodiment, any of the combination drug delivery devices of the present disclosure include a modified IL-2, such as bempegaldesleukin, that selectively activates effector T cells through regulatory T cells, a PD-1 pathway inhibitor, such as nivolumab (Opdivo) or pembrolizumab (Keytruda), a CTLA-4 antagonist, such as ipilimumab (Yervoy), and a LAG3 antagonist, such as lilatlimab or MK-4280.

[0118] In one embodiment, one or more of the drugs of any of the combination drug delivery devices of the present disclosure is a CD160 (NK1) agonist. 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.

[0119] In one embodiment, one or more of the drug modules 12 may include a soluble CTLA-4 polypeptide. Soluble CTLA-4 polypeptides may be useful in treating, for example, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, graft-versus-host disease, transplant rejection, and other cell-mediated autoimmune diseases. In one embodiment, the soluble CTLA-4 polypeptide is abatacept (Orencia), belatacept (NeuroGics), RG2077, or RG-1046. In certain embodiments, one or more of the drug modules 12 of the combination drug delivery device of the present disclosure include a soluble CTLA-4 polypeptide, for example abatacept (Orencia), and a Bruton's tyrosine kinase inhibitor, for example branebrutinib. In certain embodiments, one or more drug modules 12 of the combination drug delivery device of the present disclosure include a soluble CTLA-4 polypeptide, such as abatacept (Orencia), and a tyrosine kinase 2 inhibitor, such as BMS-986165. In certain embodiments, one or more drug modules 12 of the combination drug delivery device of the present disclosure include a soluble CTLA-4 polypeptide, such as abatacept (Orencia), and interleukin-2 (IL2) or a "T-reg IL-2" that selectively activates regulatory T cells as opposed to effector T cells, such as BMS-986326 and NKTR-358.

Claims

1. a plurality of serially connected drug modules, each of the plurality of drug modules containing a quantity of a liquid drug, the plurality of drug modules being serially connected to define a flow path for delivering the liquid drug from all of the plurality of drug modules through an outlet; a valve and / or pump for selectively controlling flow through said outlet; a controller for selectively controlling the valves; An address bus, A data bus; a data selector electrically coupled to the address bus; an encoder electrically coupled to the data bus; Equipped with each of the plurality of medication modules includes a plurality of frangible electrical conductors; When the drug modules are connected in series, the electrical conductors of each of the drug modules are electrically coupled to the address bus and the data bus; for each of the plurality of medication modules, the plurality of electrical conductors are selectively broken to represent the liquid medication contained therein; the data selector is configured to individually select each of the plurality of electrical conductors in each of the plurality of medication modules; the encoder detects which of the plurality of electrical conductors are broken and which of the plurality of electrical conductors are not broken while applying electrical potentials to the plurality of electrical conductors between the address bus and the data bus to provide a binary representation of the state of each electrical conductor; the controller collects the binary representation of each of the plurality of electrical conductors to determine a data sequence corresponding to all of the plurality of medication modules in sequence; the determined data sequence represents the liquid medication for each of the plurality of medication modules and an order of the plurality of medication modules; the controller having a memory in which an expected sequence of data is stored; the controller is configured to compare the determined data sequence with the expected data sequence; the controller is configured to cause at least one of opening the valve to permit flow through the outlet and / or opening the pump to cause flow through the outlet when the determined data sequence and the expected data sequence match. Combination drug delivery devices.

2. the memory of the controller is programmable to receive the expected data sequence; The combination drug delivery device of claim 1.

3. each of the plurality of medication modules includes a portion of the address bus; The address bus is formed as a whole by connecting the plurality of drug modules in series. The combination drug delivery device of claim 1.

4. Each of the plurality of medication modules further comprises: a plurality of address line conductors forming respective portions of said address bus; A position pin that can be shifted on the axis; a movable contact movably disposed to be individually electrically connected to each of the plurality of address line conductors; Equipped with the movable contact is coupled to the position pin such that shifting of the position pin on an axis causes the movable contact to move between and selectively electrically connect to the plurality of address line conductors. The combination drug delivery device of claim 3.

5. for each of the plurality of drug modules, the position pin has a length greater than a width of the individual drug module such that in an initial state, the position pin extends from the individual drug module. The combination drug delivery device of claim 4.

6. the plurality of medication modules includes a portion of the data bus; The data bus is formed as a whole by connecting the plurality of drug modules in series. The combination drug delivery device of claim 1.

7. each of said plurality of medication modules comprising a plurality of data transmission lines forming a respective portion of said data bus; The combination drug delivery device of claim 1.

8. For each of the plurality of medication modules, the number of the plurality of data transmission lines is equal to or greater than the number of the plurality of electrical conductors. The combination drug delivery device of claim 7.

9. 13. A drug module for use in a combination drug delivery device according to any one of the preceding claims, comprising: a body having a free volume for containing a quantity of liquid medicament; a plurality of address line conductors; at least one data transmission line conductor; a plurality of frangible electrical conductors electrically connected to the at least one data transmission line conductor; A position pin that can be shifted on the axis; a movable contact movably disposed to be individually electrically connected to each of the plurality of address line conductors; Equipped with the movable contact is coupled to the position pin such that shifting of the position pin on an axis causes the movable contact to move between the plurality of address line conductors. Drug module.

10. the position pin has a length greater than a width of the body such that the position pin extends from the body in an initial state; 10. The drug module of claim 9.

11. 1. A combination drug module for use in a combination drug delivery device, comprising: A first drug module; A second drug module; and Including, The first drug module comprises: a body having a free volume for containing a quantity of liquid medicament; a plurality of address line conductors; at least one data transmission line conductor; a plurality of frangible electrical conductors electrically connected to the at least one data transmission line conductor; an electrical contact electrically connected to a first one of the plurality of address line conductors; A position pin that can be shifted on the axis; Equipped with The second drug module comprises: a second body having a free volume for containing a quantity of liquid medicament; a plurality of second address line conductors; at least one second data transmission line conductor; a plurality of frangible second electrical conductors electrically connected to the at least one second data transmission line conductor; a movable second contact movably disposed to be individually electrically connected to each of the plurality of second address line conductors; a position channel extending through the second body; a second axially shiftable position pin disposed in the position channel so as to be axially shiftable in the position channel; Equipped with the first and second drug modules are connected such that the plurality of address line conductors of the first drug module are connected in series to the plurality of second address line conductors of the second drug module to define a plurality of parallel address lines; a first address line including the first address line conductor; With the first and second drug modules connected, the position pin of the first drug module is inserted into the position channel of the second drug module to cause an axial shift of the second position pin; an axial shift of the second position pin moves the second contact so as to be electrically connected to a second address line conductor of the plurality of second address line conductors corresponding to a second address line that is distant from the first address line; combination.

12. 1. A combination drug module for use in a combination drug delivery device, comprising: A plurality of drug modules are included; Each drug module: The first page and a second surface spaced apart from the first surface; and A plurality of conductors in parallel; Equipped with Each conductor extends from a first end disposed along the first surface to a second end disposed along the second surface; a number of said plurality of conductors is equal to a number of said plurality of drug modules; the first ends of the plurality of conductors are offset relative to the second ends of the plurality of conductors such that the number of conductors is one less than the number of conductors for direct coupling between the first surface of one of the plurality of drug modules and the second surface of another of the plurality of drug modules. combination.

13. 1. A combination drug module for use in a combination drug delivery device, comprising: A plurality of drug modules are included; Each drug module has a substrate therein that includes a plurality of parallel conductors; Each conductor extends from a first end to a second end; a number of said plurality of conductors is equal to a number of said plurality of drug modules; the first ends of the plurality of conductors are offset relative to the second ends of the plurality of conductors such that the number of conductors is one less than the number of conductors for direct coupling between the drug modules. combination.

14. The substrate is a printed circuit board.

14. The combination according to claim 13.

15. a plurality of serially connected drug modules, each of the plurality of drug modules containing a quantity of a liquid drug, the plurality of drug modules being serially connected to define a flow path for delivering the liquid drug from all of the plurality of drug modules through an outlet; a valve and / or pump for selectively controlling flow through said outlet; a controller for selectively controlling the valves; An address bus, A data bus; a data selector electrically coupled to the address bus; an encoder electrically coupled to the data bus; Equipped with each of the plurality of medication modules includes a plurality of conductors electrically coupled to a non-transitory memory storing a unique code; When the drug modules are connected in series, the conductors of each of the drug modules are electrically coupled to the address bus and the data bus; the data selector is configured to individually select each of the plurality of electrical conductors in each of the plurality of medication modules; The encoder sequentially reads each of the unique codes of the plurality of modules; the controller collects the unique codes and determines a sequence of data corresponding to all of the plurality of medication modules in sequence; the determined data sequence represents the liquid medication for each of the plurality of medication modules and an order of the plurality of medication modules; the controller having a memory in which an expected sequence of data is stored; the controller is configured to compare the determined data sequence with the expected data sequence; the controller is configured to cause at least one of opening the valve to permit flow through the outlet and / or opening the pump to cause flow through the outlet when the determined data sequence and the expected data sequence match. Combination drug delivery devices.

16. the memory of the controller is programmable to receive the expected data sequence; 16. The combination drug delivery device of claim 15.

17. each of the plurality of medication modules includes a portion of the address bus; The address bus is formed as a whole by connecting the plurality of drug modules in series.

16. The combination drug delivery device of claim 15.

18. Each of the plurality of medication modules further comprises: a plurality of address line conductors forming respective portions of said address bus; A position pin that can be shifted on the axis; a movable contact movably disposed to be individually electrically connected to each of the plurality of address line conductors; Equipped with the movable contact is coupled to the position pin such that shifting of the position pin on an axis causes the movable contact to move between and selectively electrically connect to the plurality of address line conductors.

18. The combination drug delivery device of claim 17.

19. for each of the plurality of drug modules, the position pin has a length greater than a width of the individual drug module such that in an initial state, the position pin extends from the individual drug module.

20. The combination drug delivery device of claim 18.

20. each of the plurality of drug modules further comprising a plurality of address line conductors forming a respective portion of the address bus; the plurality of address line conductors are offset by one between adjacent ones of the modules; 18. The combination drug delivery device of claim 17.

21. the plurality of medication modules includes a portion of the data bus; The data bus is formed as a whole by connecting the plurality of drug modules in series.

16. The combination drug delivery device of claim 15.

22. each of said plurality of medication modules comprising a plurality of data transmission lines forming a respective portion of said data bus; 22. The combination drug delivery device of claim 21.

23. for each of the plurality of medication modules, a number of the plurality of data transmission lines is equal to or greater than a number of the plurality of conductors; 23. The combination drug delivery device of claim 22.

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