Patent Description:
It is common practice in the administration of drugs by intravenous infusion for the drugs to be compounded within a pharmacy environment. Such drugs are typically supplied sterile in glass vials and may be supplied in solid or aqueous solution form. When supplied in solid form the drugs must be reconstituted with a sterile aqueous diluent prior to transfer to the infusion bag. The person skilled in the art will appreciate that such drug formulations will typically include several excipients for example buffers, pH modifiers, tonicity modifiers, stabilizers and so on. Typically liquid drugs for intra-venous infusion are compounded in an infusion bag in a pharmacy environment prior to transfer to the patient for infusion. Because of the need to maintain sterility of the drugs while compounding the compounding procedure is typically performed in an aseptic pharmacy hood. Typically the pharmacist or pharmacy technician (practitioner) will prepare the drugs in accordance with an individual patient prescription.

After ensuring the hood is clear of all materials the practitioner will retrieve vials of the drugs required per the prescription from the pharmacy stocks and will verify their identity and strength. The verification process may be assisted by use of a bar code scanner or other identification technology. The practitioner will also pick from stock all of the other necessary equipment required to safely prepare the drugs for infusion including the infusion bag itself, syringes, needles, transfer sets, gloves, sharps disposal containers and so on. Once all of the necessary equipment has been assembled the practitioner will follow a protocol for the preparation of the drugs which may include the reconstitution of solid drugs by addition of diluents, the ordered withdrawal of liquid drugs from their individual vials into the IV bag via the transfer port. Typically this procedure is performed manually and involves the use of multiple needles. The risk of needle-stick injuries to the practitioner is increased by each needle required to effect the compounding of the drugs. With high potency or toxicity drugs, e.g. cytotoxic agents for chemotherapy, this presents a considerable exposure risk for the practitioner.

To eliminate some of the risks associated with manual preparation including exposure to dangerous drugs and the risk of medication errors, pharmacy compounding machines are known to the person skilled in the art which automate many of the steps involved in the preparation and compounding of drugs. Typically such machines are complex electromechanical systems which implement sophisticated precision dispensing mechanisms for the accurate reconstitution of liquid drugs. Aside from their cost, size and complexity, many of the designs for such machines described in the art draw liquid drugs from a stock reservoir and so only use a fraction of the drug in the container. Because of the need to maintain sterility, unused drug solutions must typically be discarded and so are wasted. With the very high cost of some drugs, especially biologic drugs, this waste is a significant undesirable cost. When the wasted drugs are cytotoxic agents, their disposal creates a significant environmental and safety hazard.

Recent advances in medicine, particularly in the treatment of cancer, have demonstrated that therapeutically beneficial effects can be achieved by the synergistic combination of two or more drugs. For example, recent clinical research has demonstrated that the combination of an anti-PD-<NUM> checkpoint inhibitor drug with a CTLA-<NUM> checkpoint inhibitor can have beneficial synergistic effects in some tumor types which can lead to better clinical outcomes than could be achieved by the individual administration of either drug alone. Typically such checkpoint inhibitor drugs are biotechnology derived monoclonal antibodies or fragments thereof of the immunoglobulin type. In some situations it may be beneficial to combine such biologic drugs with conventional chemotherapy agents such as cytotoxic drugs.

Applicant has now realized that the combinatorial principles described in <CIT>, to the same assignee as herein, can address several of the challenges encountered in the preparation and compounding of drugs for intra-venous infusion and can provide several advantages including but not limited to simplification of pharmacy procedures, reduction in the risk of medication errors, containment and protection for the practitioner from highly potent or highly toxic agents, reduction in the risk of needle-stick injuries, reduction or elimination of drug waste, avoidance of the need for complex and expensive pharmacy compounding machines. As a consequence of these advantages in embodiments the present invention may further enable the preparation and compounding of drugs for IV infusion and direct administration to a patient at locations remote from the pharmacy, and by a non-specialist practitioner, for example by a suitably trained technician or nurse at the patient's home. This possibility is enhanced by the intrinsic portability of the system described herein.

<CIT> describes a device for pooling a fluid from a container unit having at least one container, and includes an inlet port having at least one inlet channel configured for receiving the fluid or ambient air, and an outlet port having at least one outlet channel configured for delivering the fluid to an attachment.

<CIT> describes a device for delivering a liquid drug to a user. The device comprises a reservoir adapted to contain a liquid, an outlet opening for delivering liquid drug from the device, and means for connecting the device to at least one other at least substantially identical device.

<CIT> describes a spike for facilitating the introduction of liquid under pressure into a container containing a substance which includes an elongate spike shaft having a spike side wall, a longitudinal axis, a distal end and a proximally located end portion, where the distal end has a sharp, pointed tip.

<CIT> describes a containment assembly for enclosing a medication vial that may comprise a first housing portion or interface portion having a proximal end and a distal end.

<CIT> describes a multi-vial dispensing cassette that provides serial dispensement into a plurality of dispense vials.

According to the present disclosure, there are provided drug modules each defining a chamber for the receipt of a drug filled vial. In embodiments, spacing adapters may be provided, or vial-retaining dimensions may be altered, to enable the receipt of different sized vials. The modules may further comprise a displaceable vial retainer to allow access to the vial septum for disinfection, a cannula arranged to breach the vial septum on displacement of the vial retainer, sterile tubing defining a sterile fluid path from the cannula to the inlet and outlet ports which connect the sterile fluid paths on adjacent modules. The modules also may comprise male and female mating features such that any number of modules of identical design can attach to each other in a 'stack'. Further the mating features and ports may be arranged so that the fluidic connections between the modules are made automatically when modules are serially connected together via their respective mating features. Each module may be also provided with a vent, including a vent terminated by an aseptic particulate filter that enables the equalization of pressure within the vial during removal of liquid drug from the vial whilst preventing the entrainment of contaminants into the fluid path. The vents may be arranged such that when another module is mated adjacent to the vent side of the module, a seal is formed which blocks that vent. In this way, only the terminal module on a stack may be vented to atmosphere.

The first module in the stack may be connected to a housing which comprises a male port similar to that provided on the modules. The housing comprises further sterile tubing, which may extend from the housing and be terminated by a sterile hollow needle which may be used to breach the sterile port on an infusion bag or other container for the pumped transfer of liquid drugs into the bag or other container, or may be used for drug administration directly into a patient. Further pumping means may be provided so that when fully connected the liquid drugs in the vials may be pumped as one from their respective vials to the needle.

In embodiments such pumping means may be integral to the housing or may be external to the housing. The pumping means may be sterile and form a component of the fluid path or may be of the non-contacting variety such as peristaltic pumps. The person skilled in the art will be familiar with several pumping technologies suitable for use in the pumped transfer of liquid drugs in the manner described.

With reference to the Figures, modules <NUM> formed in accordance with the subject invention are shown which are serially connectable to form a combinatorial drug delivery device <NUM>. To minimize the number of components needed in inventory, the modules <NUM> are similarly formed. The modules <NUM> may be formed with adjustable features to correspond to any contained drugs.

As shown in the Figures, each of the modules <NUM> is generally box shaped with a body <NUM> and a vial retainer <NUM>, with the body <NUM> enclosing an interior volume <NUM>. The vial retainer <NUM> is displaceable relative to the body <NUM>, including possibly being hingedly attached to the body <NUM>. The vial retainer <NUM> is shaped and dimensioned to accommodate a drug vial or container <NUM>. To accommodate drug vials <NUM> of various sizes, adapter(s) or spacer(s) may be provided for placement into the vial retainer <NUM> to accommodate various sized drug vials <NUM>. Typically, the size (i.e., volume) of the drug vials <NUM> will be varied by altering the length thereof. With this arrangement, the vial retainer <NUM> may be configured to accommodate a largest drug vial size without any adapters or spacers, as shown in <FIG>. In this manner, the modules <NUM> may be coupled as described below with the modules <NUM> accommodating drug vials <NUM> of different volumes.

As shown in <FIG>, each of the modules <NUM> includes a cannula <NUM> extending into the interior volume <NUM> positioned to pierce a septum <NUM> of an accommodated drug vial <NUM> in accessing interior volume <NUM> of the drug vial <NUM>. A distal end <NUM> of the cannula <NUM> may be sharpened to facilitate piercing of the septum <NUM>. The cannula <NUM> must be provided with sufficient length to fully pierce the septum <NUM> in accessing the interior volume <NUM>.

The cannula <NUM> preferably includes multiple inner lumens <NUM>, such as primary inner lumen 30A and secondary inner lumen 30B. With this arrangement, with the cannula <NUM> piercing the septum <NUM>, all of the inner lumens <NUM> are in communication with the interior volume <NUM> of the drug vial <NUM>. The inner lumens <NUM> extend through the cannula <NUM> away from the distal end <NUM> and into the body <NUM>. A primary passageway <NUM> is provided in communication with the primary inner lumen 30A, and a secondary passageway <NUM> is provided in communication with the secondary inner lumen 30B. With this arrangement, liquid may flow in and out of the interior volume <NUM>, e.g., with one-way flow travelling from the primary passageway <NUM>, through the primary inner lumen 30A, into the interior volume <NUM>, through the secondary inner lumen 30B, and through the secondary passageway <NUM>. This allows for both introduction of liquid into the drug vial <NUM> and removal of liquid therefrom. The primary and secondary passageways <NUM>, <NUM> may be formed by portions of the body <NUM>, e.g., the passageways being etched into the body <NUM> or formed by other material removal processes. In addition, the primary and secondary passageways <NUM>, <NUM> may be defined by tubing which passes through channels formed in the body <NUM>.

The modules <NUM> are formed to be serially connected so that the primary and secondary passageways <NUM>, <NUM> of adjacent modules <NUM> are in communication, as shown in <FIG> and <FIG>. In particular, the modules <NUM> are serially connected so that, with the exception of the ultimate module (marked as 10F in <FIG>), the primary passageway <NUM> of each module <NUM> is in communication with the secondary passageway <NUM> of the adjacent module. For the ultimate module 10F, the primary passageway <NUM> is left open as not being connected to a further module. The primary passageway <NUM> of the ultimate module 10F may be plugged or otherwise closed off.

As shown in <FIG>, liquid may be drawn from the drug vials <NUM> to be delivered through a single discharge in the form of the secondary passageway <NUM> of the first located module (marked as 10A in <FIG>). This allows for different liquid drugs to be accommodated by the drug vials <NUM> of the modules 10A-10F with the liquid drugs being combined by the device <NUM>. As will be appreciated by those skilled in the art, any quantity of the modules <NUM> may be utilized, possibly limited by the fluidic resistance of the assembly and/or strength of negative pressure utilized with the assembly.

A source of negative pressure is used to draw the liquid drugs through the modules <NUM>. In an example not part of the invention, negative pressure may be provided by an external pump or syringe <NUM> in communication (directly or indirectly) with the secondary passageway <NUM> of the first module 10A. A housing <NUM> is provided with the device <NUM> which may contain a pump <NUM>, e.g., electrically powered, along with The internal pump <NUM> may be provided in the housing <NUM>, along with any motor, power source, controller, etc., useable to operate and/or control the pump <NUM>. The housing <NUM> may be provided with discharge passageway <NUM> in communication with the secondary passageway <NUM> of the first module 10A. The discharge passageway <NUM> may be subjected to negative pressure by the external pump or syringe <NUM> and/or the pump <NUM>. Discharge tubing <NUM> may be provided in communication with the discharge passageway <NUM> to convey discharged liquid drug to a target delivery site, such as an IV bag, drug container, or directly into a patient. A cannula, as known in the art, may be provided on the discharge tubing <NUM> as needed for injection or other accessing. Sufficient negative pressure needs to be generated to draw fully the contents of all of the drug vials <NUM>. Check valving may be provided along the discharge passageway <NUM> and/or the discharge tubing <NUM> to limit back flow. The external pump <NUM> and/or the pump <NUM> may be non-contact pumps, e.g., peristaltic pumps, which may act on the discharge passageway <NUM> or the discharge tubing <NUM> without contacting liquid flow therethrough.

With the drug vials <NUM> being rigid (e.g., glass or polymeric construction), the device <NUM> may require venting to facilitate acceptable liquid flow throughout the device <NUM>. Preferably, each of the modules <NUM> is provided with a venting passageway <NUM> in communication with the primary passageway <NUM>. The venting passageway <NUM> extends through exterior surface <NUM> of the body <NUM> to terminate at vent opening <NUM>. The vent opening <NUM> is positioned so as to be covered fully by an adjacent module with the module being serially connected to a further module (e.g., the vent opening <NUM> of the first module 10A is fully covered by the body <NUM> of the second module 10B with the vent opening <NUM> of the second module 10B being covered by the body <NUM> of the third module 10C, and so forth). The vent opening <NUM> of the ultimate module 10F is exposed without being covered. This allows for venting for the device <NUM> from the end of the series of connected modules <NUM>. To limit ingress of contaminants, each of the vent openings <NUM> may be provided with an aseptic particulate filter <NUM>, which allows transmission therethrough of air, but resists passage of microbes or other contaminants.

The primary and secondary passageways <NUM>, <NUM> may be provided with male and female configurations to provide for fitted connections. The Figures show each of the secondary passageways <NUM> terminating as a protruding boss <NUM> formed to be insertingly received in a socket <NUM> defined at the opening to the primary passageways <NUM>. These components may be reversed with the bosses <NUM> protruding from the primary passageways <NUM> and the sockets <NUM> being formed in the openings of the secondary passageways <NUM>. In either configuration, elastomeric seals or other components (such as o-rings) may be provided on the bosses <NUM> and/or the sockets <NUM> to enhance the frictional connection and the liquid-tight connection at the interface therebetween. Friction may be relied upon for maintaining connections between the modules <NUM>. As shown in <FIG>, the boss and the socket may be configured as mating male and female luer components. Check valving may be utilized to seal the primary and secondary passageways <NUM>, <NUM> prior to use. Connection of the modules <NUM> may cause the opening of the check valving.

To limit reusability of the modules <NUM>, the bosses <NUM> and the sockets <NUM> may be formed to lock together when assembled. For example, as shown in <FIG>, the bosses <NUM> may be each formed with a protruding ridge <NUM> formed to snap engage corresponding channel <NUM> formed in each of the sockets <NUM>. The ridges <NUM> and the channels <NUM> may be ramped to restrict reverse movement of the bosses <NUM>, relative to the sockets <NUM>, once sufficiently inserted therein. In addition, or alternatively, cooperating locking elements may be provided on the modules <NUM>, outside of the bosses <NUM> and the sockets <NUM> which lock together with assembly of the modules <NUM>. It is preferred that the locking occur along the flow path, such as locking between the bosses <NUM> and the sockets <NUM>, so that attempts to un-do the locked engagement results in damage along the flow path, thereby rendering the modules <NUM> unuseable.

The housing <NUM> may be provided with a feature to cooperate with the secondary passageway <NUM> of the first module 10A, such as the socket <NUM> (<FIG>).

As shown in <FIG>, in an alternative arrangement, the venting passageway <NUM> may not be provided. To allow for venting, a venting module <NUM> may be provided formed to be mounted to the primary passageway <NUM> of the ultimate module. The venting module <NUM> includes an aseptic particulate filter to allow for air flow therethrough with limiting ingress of contaminants.

To best preserve the sterility of the module <NUM> and the contents of the drug vial <NUM> during shipping and storage, the drug vial <NUM> may be provided intact, not breached by the cannula <NUM>. As such, it is preferred that the drug vial <NUM> be maintained in a spaced relationship from the cannula <NUM>, until use. To provide for this arrangement, the vial retainer <NUM> may be formed to snap engage or otherwise retain the drug vial <NUM> such that the drug vial <NUM> is displaceable with the vial retainer <NUM> (e.g., the vial retainer <NUM> may include grippers <NUM> or a collar <NUM> formed to retentively engage a portion of the drug vial <NUM>, such as about a neck N of the drug vial <NUM>). Displacement of the vial retainer <NUM>, with the drug vial <NUM>, relative to the cannula <NUM> may be utilized to cause the cannula <NUM> to breach the septum <NUM> when ready for use. In addition, the septum <NUM> of the drug vial <NUM> may be covered with a removable barrier <NUM> formed to limit contamination of the septum <NUM>, e.g., the removable barrier <NUM> being a microbial barrier as is known in the art. In this manner, the drug vial <NUM> may be better maintained in a sterile state.

For example, as shown in <FIG>, to achieve displacement of the vial retainer <NUM> relative the body <NUM>, a sliding hinge <NUM> may be provided connecting the vial retainer <NUM> to the body <NUM> for each module <NUM>. As shown in <FIG>, the sliding hinge <NUM> has first end <NUM> hingedly connected to top edge <NUM> of the body <NUM>. It is preferred that the vial retainer <NUM> be formed to accommodate the drug vial <NUM> in an initial state (<FIG>). The grippers <NUM> may be provided with the vial retainer <NUM> to hold the drug vial <NUM> during loading. Initially, the module <NUM> may be in an open state as shown in <FIG> with a sterile barrier <NUM> covering the cannula <NUM> within the body <NUM>. In a first step, with the drug vial <NUM> loaded in the grippers <NUM> of the vial retainer <NUM>, the sterile barrier <NUM> is removed. If the removable barrier <NUM> is not provided with the drug vial <NUM>, the septum <NUM> is preferably wiped with an antiseptic wipe to provide sterilization of the outer surface of the septum <NUM>. The vial retainer <NUM>, with the contained drug vial <NUM>, is caused to be displaced by rotation with the sliding hinge <NUM> about the top edge <NUM> (<FIG>) to the position shown in <FIG>. The sliding hinge <NUM> has an elongated plate shape which extends from the first end <NUM>. Once in the up position as shown in <FIG>, the sliding hinge <NUM> is caused to translate into recessed channel <NUM> formed in the body <NUM>. This straight-line motion causes the vial retainer <NUM> to be lowered into the body <NUM>, with the drug vial <NUM>, sufficiently such that the cannula <NUM> fully pierces the septum <NUM> (<FIG>). Locking elements may be provided to lock the vial retainer <NUM> to the body <NUM> once the septum <NUM> has been breached.

As will be appreciated by those skilled in the art, the vial retainer <NUM> may be displaced in various manners relative to the body <NUM> to allow for the cannula <NUM> to pierce the septum <NUM>. With reference to <FIG>, the vial retainer <NUM> may be slidable relative to the body <NUM>. This allows for a shipping/storage position shown in <FIG>, where the septum <NUM> is separated from the cannula <NUM>. To prepare the module <NUM>, the vial retainer <NUM> is displaced relative to the body <NUM> by being axially slid outwardly from the body <NUM>. The vial retainer <NUM> may be yoke-shaped with arms <NUM> translating along channels formed in the body <NUM>. Stops are preferably provided along the channels to prevent the vial retainer <NUM> from being completely pulled out of the body <NUM>. In addition, a releasable locking arrangement may be provided to initially maintain the vial retainer <NUM> in a fixed position, relative to the body <NUM>, in the shipping/transportation position shown in <FIG>. The releasable locking arrangement may be: a frangible connection between the vial retainer <NUM> and the body <NUM> (e.g., breakable fused or adhesive connection); mechanical fixation (e.g., ramped and/or depressed interengagement which resists movement of the vial retainer <NUM> relative to the body <NUM>); and/or, an external packaging (e.g., tape or shrink-wrap packaging formed to restrict relative movement between the vial retainer <NUM> and the body <NUM>).

The arms <NUM> are preferably provided with sufficient length to allow a user to access to the septum <NUM>, as shown in <FIG>, with the vial retainer <NUM> pulled away from the body <NUM>. As shown in <FIG>, this allows for removal of the removable barrier <NUM>, if present. In addition, this allows for wiping the septum <NUM> with an antiseptic wipe, if necessary. In addition, the body <NUM> may be covered by the sterile barrier <NUM>. Access to the sterile barrier <NUM> is also provided to permit removal thereof with vial retainer <NUM> being in the displaced position as shown in <FIG>. With all barriers <NUM>, <NUM> removed and/or antiseptic wiping completed, the vial retainer <NUM> is displaced by axially sliding the vial retainer <NUM> into the body <NUM> so that the cannula <NUM> pierces the septum <NUM>, as shown in <FIG>. Detents or other locking elements may be provided to retain the vial retainer <NUM> in the state shown in <FIG> to limit outward sliding of the vial retainer <NUM>.

With reference to <FIG>, the vial retainer <NUM> of the prior embodiment may be modified to have the septum <NUM> initially exposed, as shown in <FIG>. This allows for the septum <NUM> to be readied without any adjustment of the drug vial <NUM>. Once readied, the vial retainer <NUM> is provided with a rotatable connection with the drug vial <NUM>, whereby the drug vial <NUM> may be rotated to align the septum <NUM> with the cannula <NUM> (e.g., <NUM> degree rotation). Thereafter, as with the prior embodiment, the vial retainer <NUM> is urged into the body <NUM> to have the cannula <NUM> pierce the septum <NUM>.

In a further possible modification, as shown in <FIG>, the drug vial <NUM> may be provided with the septum <NUM> facing the body <NUM>, in the same manner as in <FIG>. The rotatable connection between the vial retainer <NUM> and the drug vial <NUM> in this embodiment may be used to expose the septum <NUM> (<FIG>) to allow the septum <NUM> to be readied (<FIG>). Thereafter, the drug vial <NUM> is returned to its initial state (<FIG>) and urged into the body <NUM> for engagement with the cannula <NUM>.

With reference to <FIG>, a further manner of displacing the vial retainer <NUM> relative to the body <NUM> is shown. In particular, the body <NUM> may be provided with at least one channel <NUM> in which detent <NUM>, located on the vial retainer <NUM>, axially slides. The interengagement between the channel <NUM> and the detent <NUM> constrains the movement of the vial retainer <NUM> relative to the body <NUM>. The channel <NUM> may be L-shaped, having a horizontal portion 74a, aligned for transverse movement of the vial retainer <NUM> relative to the body <NUM>, and a vertical portion 74b, aligned for coaxial movement of the vial retainer <NUM> relative to the body <NUM>. As shown in <FIG>, the detent <NUM> of the vial retainer <NUM> is initially located in the horizontal portion 74a of the channel <NUM>. The horizontal portion 74a is positioned so that, with the detent <NUM> seated in the horizontal portion 74a, the septum <NUM> is spaced from the cannula <NUM>. This allows for shipping and storage with the septum <NUM> being spaced from the cannula <NUM>. A releasable locking arrangement may be provided to maintain the detent <NUM> in a fixed position in the horizontal portion 74a. The releasable locking arrangement may be: a frangible connection between the detent <NUM> and the channel <NUM> (e.g., breakable fused or adhesive connection); mechanical fixation (e.g., ramped and/or depressed interengagement which resists movement of the detent <NUM> along the channel <NUM>); and/or, an external packaging (e.g., tape or shrink-wrap packaging formed to restrict relative movement between the vial retainer <NUM> and the body <NUM>).

To ready the module <NUM>, the vial retainer <NUM> is caused to move transversely along the horizontal portion 74a, as shown in <FIG>. It is preferred that the detent <NUM> is located along one side of the vial retainer <NUM> to allow for the vial retainer <NUM> to be sufficiently shifted out of alignment with the body <NUM> to expose the septum <NUM>. The detent <NUM> may be formed on a downward depending arm protruding from the vial retainer <NUM>. With the septum <NUM> exposed, as shown in <FIG>, the removable barrier <NUM> may be removed and/or the septum <NUM> may be wiped. In addition, the body <NUM> may be readied, e.g., removal of the sterile barrier <NUM>. Once readied, the vial retainer <NUM> is shifted back along the horizontal portion 74a until the detent <NUM> is in alignment with the vertical portion 74b, as shown in <FIG>. Thereafter, the vial retainer <NUM> is urged axially into the body <NUM>, with the detent <NUM> sliding along the vertical portion 74b, and with the cannula <NUM> piercing the septum <NUM>. The vertical portion 74b must be provided with sufficient length to ensure that the cannula <NUM> fully pierces the septum <NUM> in accessing the drug contents of the drug vial <NUM>. Detents or other locking elements may be provided to retain the vial retainer <NUM> in the state shown in <FIG> to limit outward sliding of the vial retainer <NUM>.

With reference to <FIG>, the embodiment of <FIG> may be modified to have the detent <NUM> provide a rotatable connection between the vial retainer <NUM> and the body <NUM>. In this embodiment, the horizontal portion 74a is not required. With reference to <FIG>, the vial retainer <NUM> is positioned relative to the body <NUM> in similar manner to the previous embodiment. A releasable locking arrangement may be likewise provided to restrict pre-use movement of the vial retainer <NUM> relative to the body <NUM>. As shown in <FIG>, the septum <NUM> is exposed by rotating the vial retainer <NUM> relative to the body <NUM> about the detent <NUM>. Once the septum <NUM> and the body <NUM> are readied, as described above, the vial retainer <NUM> is rotated back into alignment with the body <NUM>, as shown in <FIG>. Thereafter, the vial retainer <NUM> is urged axially into the body <NUM>, with the detent <NUM> sliding along the vertical portion 74b, and with the cannula <NUM> piercing the septum <NUM>. As with the prior embodiment, the vertical portion 74b must be provided with sufficient length to ensure that the cannula <NUM> fully pierces the septum <NUM> in accessing the drug contents of the drug vial <NUM>. Detents or other locking elements may be provided to retain the vial retainer <NUM> in the state shown in <FIG> to limit outward sliding of the vial retainer <NUM>.

With reference to <FIG>, in a further embodiment, the vial retainer <NUM> may be connected to the body <NUM> by a living hinge or tether <NUM>. Here, the vial retainer <NUM> may be formed as a block formed for guided sliding within the body <NUM>. The living hinge or tether <NUM> may be integrally formed with the vial retainer <NUM> and/or the body <NUM> (e.g., being made of polymeric material). As shown in <FIG>, in a transportation/shipping state, the vial retainer <NUM> may be removably affixed to the body, such as by a frangible connection (fused and/or adhesive) and/or by external packaging. To ready for use, as shown in <FIG>, the vial retainer <NUM> may be separated from the body <NUM> to allow access to the septum <NUM>. The living hinge or tether <NUM> maintains a connection between the vial retainer <NUM> and the body <NUM>. The living hinge or tether <NUM> may be formed with a length and rigidity which permits supporting the vial retainer <NUM>, with the drug vial <NUM>, in a separated state from the body <NUM>. This permits the vial retainer <NUM> to be maintained in a supported position relative to the body <NUM>.

Once the septum <NUM> and the body <NUM> have been readied, the vial retainer <NUM> may be aligned with the body <NUM>, as shown in <FIG>. Thereafter, the vial retainer <NUM> is urged into the body <NUM> to allow the cannula <NUM> to pierce the septum <NUM>, in similar manner to the embodiments discussed above. The living hinge or tether <NUM> is provided with sufficient flexibility to allow for sufficient displacement of the vial retainer <NUM> relative to the body <NUM> for the cannula <NUM> to fully pierce the septum <NUM>. <FIG> show the cannula <NUM> piercing a portion of the vial retainer <NUM>. These are schematic representations. It is preferred that the cannula <NUM> not pierce a portion of the vial retainer <NUM>. The vial retainer <NUM> may be formed with portions surrounding the septum <NUM>, including downward extending portions to provide rigidity to the vial retainer <NUM> without obscuring the septum <NUM>.

For all embodiments described herein, the cannula <NUM> is sterilized prior to use, along with all liquid flow paths of the module <NUM>. The sterile barrier <NUM> and the removable barrier <NUM> are used to maintain sterility of the module <NUM>, including the drug vial <NUM>, during shipping and storage. As such, the sterile barrier <NUM> and/or the removable barrier <NUM> may be used with any of the embodiments disclosed herein. In addition, other protective packaging, such as being packaged in a pouch, may be utilized.

As will be appreciated by those skilled in the art, the housing <NUM> may be provided with various controls and systems, such as a microprocessor to record use details and a wireless transmitter to transmit such details.

One or more of the drug vials <NUM> may contain lyophilized drug which may be reconstituted with introduction of a diluent. A diluent may be located upstream from the lyophilized drug such that the diluent is drawn into the drug vial with the lyophilized drug with reconstituted drug being drawn therefrom. Various drugs may be contained in the drug vials <NUM>. Diluents or other additives may be contained as well to increase the efficacy of the drug combination to be delivered. For example, as shown in <FIG>, inlet tubing <NUM> from reservoir <NUM> may be connected to the socket <NUM> of the ultimate module 10F. This allows for a reservoir of diluent to be provided for the device <NUM>, particularly to allow for flow through all of the modules <NUM>. The reservoir <NUM> preferably is a flexible bag, which is collapsible with the withdrawal of diluent therefrom. This allows for the device <NUM> to minimize the need for venting, possibly altogether eliminating the need for venting. If venting is required, the particulate filter <NUM> may be provided on the ultimate module 10F. The diluent may be used for reconstitution of drug components in the modules <NUM>. In addition, the diluent may contain drug components to further enhance the combinatorial effect of the device <NUM>. It is also possible to provide the reservoir <NUM> gravitationally higher (e.g., by suspending) than the device <NUM> so that head is generated to assist flow of the diluent through the device <NUM>.

In one embodiment, the drug delivery device <NUM> is able to deliver two or more drugs for the benefit of the patient suffering from any of a wide range of diseases or conditions, e.g., cancer, autoimmune disorder, inflammatory disorder, cardiovascular disease or fibrotic disorder.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is Programmed Death-<NUM> ("PD-<NUM>") pathway inhibitor, a cytotoxic T-lymphocyte-associated antigen <NUM> ("CTLA-<NUM>") antagonist, a Lymphocyte Activation Gene-<NUM> ("LAG3") antagonist, a CD80 antagonist, a CD86 antagonist, a T cell immunoglobulin and mucin domain ("Tim-<NUM>") antagonist, a T cell immunoreceptor with Ig and ITIM domains ("TIGIT") antagonist, a CD20 antagonist, a CD96 antagonist, a Indoleamine <NUM>,<NUM>-dioxygenase ("IDO1") antagonist, a stimulator of interferon genes ("STING") antagonist, a GARP antagonist, a CD40 antagonist, Adenosine A2A receptor ("A2aR") antagonist, a CEACAM1 (CD66a) antagonist, a CEA antagonist, a CD47 antagonist, a Receptor Related Immunoglobulin Domain Containing Protein ("PVRIG") antagonist, a tryptophan <NUM>,<NUM>-dioxygenase ("TDO") antagonist, a V-domain Ig suppressor of T cell activation ("VISTA") antagonist, or a Killer-cell Immunoglobulin-like Receptor ("KIR") antagonist.

In one embodiment, the PD-<NUM> pathway inhibitor is an anti-PD-<NUM> antibody or antigen binding fragment thereof. In certain embodiments, the anti-PD-<NUM> antibody is pembrolizumab (KEYTRUDA; MK-<NUM>), pidilizumab (CT-<NUM>), nivolumab (OPDIVO; BMS-<NUM>), PDR001, MEDI0680 (AMP-<NUM>), TSR-<NUM>, REGN2810, JS001, AMP-<NUM> (GSK-<NUM>), PF-<NUM>, BGB-A317, BI <NUM>, or SHR-<NUM>.

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

In one embodiment, the PD-<NUM> pathway inhibitor is a small molecule drug. In certain embodiments, the PD-<NUM> pathway inhibitor is CA-<NUM>. In another embodiment, the PD-<NUM> pathway inhibitor is a cell based therapy. In one embodiment, the cell based therapy is a MiHA-loaded PD-L1/L2-silenced dendritic cell vaccine. In other embodiments, the cell based therapy is an anti-programmed cell death protein <NUM> antibody expressing pluripotent killer T lymphocyte, an autologous PD-<NUM>-targeted chimeric switch receptor-modified T lymphocyte, or a PD-<NUM> knockout autologous T lymphocyte.

In one embodiment, the PD-<NUM> pathway inhibitor is an anti-PD-L2 antibody or antigen binding fragment thereof. In another embodiment, the anti-PD-L2 antibody is rHIgM12B7.

In one embodiment, the PD-<NUM> pathway inhibitor is a soluble PD-<NUM> polypeptide. In certain embodiments, the soluble PD-<NUM> polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-<NUM> polypeptide comprises a ligand binding fragment of the PD-<NUM> extracellular domain. In other embodiments, the soluble PD-<NUM> polypeptide comprises a ligand binding fragment of the PD-<NUM> extracellular domain. In another embodiment, the soluble PD-<NUM> polypeptide further comprises an Fc domain.

In one embodiment, the immune checkpoint inhibitor is a CTLA-<NUM> antagonist. In certain embodiments, the CTLA-<NUM> antagonist is an anti-CTLA-<NUM> antibody or antigen binding fragment thereof. In some embodiments, the anti-CTLA-<NUM> antibody is ipilimumab (YERVOY), tremelimumab (ticilimumab; CP-<NUM>,<NUM>), AGEN-<NUM>, or ATOR-<NUM>. In one embodiment, the drug delivery device <NUM> includes a CTLA-<NUM> antagonist, e.g., ipilimumab (YERVOY), a PD-<NUM> pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

In one embodiment, the immune checkpoint inhibitor is an antagonist of LAG3. In certain embodiments, the LAG3 antagonist is an anti-LAG3 antibody or antigen binding fragment thereof. In certain embodiments, the anti-LAG3 antibody is relatlimab (BMS-<NUM>), MK-<NUM> (<NUM>-<NUM>), REGN3767, GSK2831781, IMP731 (H5L7BW), BAPO50, IMP-<NUM> (LAG-<NUM>), IMP321, TSR-<NUM>, LAG525, BI <NUM>, or FS-<NUM>. In one embodiment, the drug delivery device <NUM> includes a LAG3 antagonist, e.g., relatlimab or MK-<NUM>, and a PD-<NUM> pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, the drug delivery device <NUM> includes a LAG3 antagonist, e.g., relatlimab or MK-<NUM>, and a CTLA-<NUM> antagonist, e.g., ipilimumab (YERVOY). In one embodiment, the drug delivery device <NUM> includes a LAG3 antagonist, e.g., relatlimab or MK-<NUM>, a CTLA-<NUM> antagonist, e.g., ipilimumab (YERVOY), and a PD-<NUM> pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

In one embodiment, the CTLA-<NUM> antagonist is a soluble CTLA-<NUM> polypeptide. In one embodiment, the soluble CTLA-<NUM> polypeptide is abatacept (ORENCIA), belatacept (NULOJIX), RG2077, or RG-<NUM>. In another embodiment, the CTLA-<NUM> antagonist is a cell based therapy. In some embodiments, the CTLA-<NUM> antagonist is an anti-CTLA4 mAb RNA/GITRL RNA-transfected autologous dendritic cell vaccine or an anti-CTLA-<NUM> mAb RNA-transfected autologous dendritic cell vaccine.

In one embodiment, the immune checkpoint inhibitor is a KIR antagonist. In certain embodiments, the KIR antagonist is an anti-KIR antibody or antigen binding fragment thereof. In some embodiments, the anti-KIR antibody is lirilumab (<NUM>-7F9, BMS-<NUM>, IPH <NUM>) or IPH4102.

In one embodiment, the immune checkpoint inhibitor is TIGIT antagonist. In one embodiment, the TIGIT antagonist is an anti-TIGIT antibody or antigen binding fragment thereof. In certain embodiments, the anti-TIGIT antibody is BMS-<NUM>, AB <NUM>, COM902 (CGEN-<NUM>), or OMP-313M32.

In one embodiment, the immune checkpoint inhibitor is Tim-<NUM> antagonist. In certain embodiments, the Tim-<NUM> antagonist is an anti-Tim-<NUM> antibody or antigen binding fragment thereof. In some embodiments, the anti-Tim-<NUM> antibody is TSR-<NUM> or LY3321367.

In one embodiment, the immune checkpoint inhibitor is an IDO1 antagonist. In another embodiment, the IDO1 antagonist is indoximod (NLG8189; <NUM>-methyl-D-TRP), epacadostat (INCB-<NUM>, INCB-<NUM>), KHK2455, PF-<NUM>, navoximod (RG6078, GDC-<NUM>, NLG919), BMS-<NUM> (F001287), or pyrrolidine-<NUM>,<NUM>-dione derivatives.

In one embodiment, the immune checkpoint inhibitor is a STING antagonist. In certain embodiments, the STING antagonist is <NUM>' or <NUM>'-mono-fluoro substituted cyclic-di-nucleotides; <NUM>'<NUM>'-di-fluoro substituted mixed linkage <NUM>',<NUM>' - <NUM>',<NUM>' cyclic-di-nucleotides; <NUM>'-fluoro substituted, bis-<NUM>',<NUM>' cyclic-di-nucleotides; <NUM>',<NUM>"-diF-Rp,Rp,bis-<NUM>',<NUM>' cyclic-di-nucleotides; or fluorinated cyclic-di-nucleotides.

In one embodiment, the immune checkpoint inhibitor is CD20 antagonist. In some embodiments, the CD20 antagonist is an anti-CD20 antibody or antigen binding fragment thereof. In one embodiment, the anti-CD20 antibody is rituximab (RITUXAN; IDEC-<NUM>; IDEC-C2B8), ABP <NUM>, ofatumumab, or obinutuzumab.

In one embodiment, the immune checkpoint inhibitor is CD80 antagonist. In certain embodiments, the CD80 antagonist is an anti-CD80 antibody or antigen binding fragment thereof. In one embodiment, the anti-CD80 antibody is galiximab or AV <NUM>.

In one embodiment, the immune checkpoint inhibitor is a GARP antagonist. In some embodiments, the GARP antagonist is an anti-GARP antibody or antigen binding fragment thereof. In certain embodiments, the anti-GARP antibody is ARGX-<NUM>.

In one embodiment, the immune checkpoint inhibitor is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an anti-CD40 antibody for antigen binding fragment thereof. In some embodiments, the anti-CD40 antibody is BMS3h-<NUM>, lucatumumab (HCD122 and CHIR-<NUM>), CHIR-<NUM>, or dacetuzumab (huS2C6, PRO <NUM>, RG <NUM>, SGN <NUM>, SGN-<NUM>). 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 a CD40-L/FC2 or a monomeric CD40-L.

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-<NUM>, PBF-<NUM>, istradefylline (KW-<NUM>), preladenant (SCH420814), tozadenant (SYN115), vipadenant (BIIB014), HTL-<NUM>, ST1535, SCH412348, SCH442416, SCH58261, ZM241385, or AZD4635.

In one embodiment, the immune checkpoint inhibitor is a CEACAM1 antagonist. In some embodiments, the CEACAM1 antagonist is an anti-CEACAM1 antibody or antigen binding fragment thereof. In one embodiment, the anti-CEACAM1 antibody is CM-<NUM> (MK-<NUM>).

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

In one embodiment, the immune checkpoint inhibitor is a CD47 antagonist. In some embodiments, the CD47 antagonist is an anti-CD47 antibody or antigen binding fragment thereof. In certain embodiments, the anti-CD47 antibody is HuF9-G4, CC-<NUM>, TTI-<NUM>, ALX148, NI-<NUM>, NI-<NUM>, SRF231, or Effi-DEM.

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

In one embodiment, the immune checkpoint inhibitor is a TDO antagonist. In one embodiment, the TDO antagonist is a <NUM>-(indol-<NUM>-yl)-pyrazole derivative, a <NUM>-indol substituted derivative, or a <NUM>-(indol-<NUM>-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.

In one embodiment, the immune checkpoint inhibitor is a VISTA antagonist. In some embodiments, the VISTA antagonist is CA-<NUM> or JNJ-<NUM>.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is an immune checkpoint enhancer or stimulator.

In one embodiment, the immune checkpoint enhancer or stimulator is a CD28 agonist, a <NUM>-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.

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 antigen binding fragment thereof. In some embodiments, the anti-OX40 antibody is tavolixizumab (MEDI-<NUM>), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-<NUM>, MEDI-<NUM>, MEDI-<NUM>, BMS <NUM>, PF-<NUM>, 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 lymphocytes).

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 antigen binding fragment thereof. In one embodiment, the anti-CD40 antibody is ADC-<NUM> (JNJ-<NUM>), RG7876 (RO-<NUM>), HuCD40-M2, APX005M (EPI-<NUM>), or Chi Lob <NUM>/<NUM>. 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 (AVREND®).

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 antigen binding fragment thereof. In one embodiment, the anti-GITR antibody is BMS-<NUM>, 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.

In one embodiment, the immune checkpoint enhancer or stimulator a <NUM>-1BB agonist. In some embodiments, the <NUM>-1BB agonist is an anti-<NUM>-1BB antibody or antigen binding fragment thereof. In one embodiment, the anti-<NUM>-1BB antibody is urelumab or PF-<NUM>.

In one embodiment, the immune checkpoint enhancer or stimulator is a CD80 agonist or a CD86 agonist. In some embodiments, the CD80 agonist or the CD86 agonist is a soluble CD80 or CD86 ligand (CTLA-<NUM>). 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-<NUM>). In other embodiments, the CD80 agonist or the CD86 agonist is a cell based therapy. In one embodiment, the cell based therapy is MGN1601 (an allogeneic renal cell carcinoma vaccine).

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 certain embodiments, the anti-CD28 antibody is TGN1412.

In one embodiment, the CD28 agonist is a cell based therapy. In certain embodiments, the cell based therapy is JCAR015 (anti-CD19-CD28-zeta modified CAR CD3+ T lymphocyte); CD28CAR/CD137CAR-expressing T lymphocyte; allogeneic CD4+ memory Th1-like T cells/microparticle-bound anti-CD3/anti-CD28; anti-CD19/CD28/CD3zeta CAR gammaretroviral 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-CD28 zeta-<NUM>-<NUM>-BB-EGFRt-expressing T lymphocytes; autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells; autologous PD-<NUM>-targeted chimeric switch receptor-modified T lymphocytes (chimera with CD28); CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T lymphocytes; CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T lymphocytes; CD19CAR-CD28zeta-<NUM>-1BB-expressing allogeneic T lymphocytes; CD19CAR-CD3zeta-<NUM>-1BB-CD28-expressing autologous T lymphocytes; CD28CAR/CD137CAR-expressing T lymphocytes; CD3/CD28 costimulated vaccine-primed autologous T lymphocytes; or iC9-GD2-CD28-OX40-expressing T lymphocytes.

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 antigen binding fragment thereof. In one embodiment, the anti-CD27 antibody is varlilumab (CDX-<NUM>).

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-<NUM>.

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 antigen binding fragment thereof. In some embodiments, the anti-ICOS antibody is BMS986226, MEDI-<NUM>, GSK3359609, or JTX-<NUM>. 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 <NUM>.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is an anti-CD73 antibody or antigen binding fragment thereof. In certain embodiments, the anti-CD73 antibody is MEDI9447.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is a TLR9 agonist. In one embodiment, the TLR9 agonist is agatolimod sodium.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is a cytokine. In certain embodiments, the cytokine is a chemokine, an interferon, an interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-<NUM>, IL-<NUM>, or interferon-gamma.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is a TGF-β antagonist. In some embodiments, the TGF-β antagonist is fresolimumab (GC-<NUM>); NIS793; IMC-TR1 (LY3022859); ISTH0036; trabedersen (AP <NUM>); recombinant transforming growth factor-beta-<NUM>; autologous HPV-<NUM>/<NUM> E6/E7-specific TGF-beta-resistant T lymphocytes; or TGF-beta-resistant LMP-specific cytotoxic T-lymphocytes.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is an iNOS antagonist. In some embodiments, the iNOS antagonist is N-Acetyle-cysteine (NAC), aminoguanidine, L-nitroarginine methyl ester, or S,S-<NUM>,<NUM>-phenylene-bis(<NUM>,<NUM>-ethanediyl)bisisothiourea).

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is a SHP-<NUM> antagonist.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is a colony stimulating factor <NUM> receptor ("CSF1R") antagonist. In certain embodiments, the CSF1R antagonist is an anti-CSF1R antibody or antigen binding fragment thereof. In some embodiments, the anti-CSF1R antibody is emactuzumab.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is an agonist of a TNF family member. In some embodiments, the agonist of the TNF family member is ATOR <NUM>, ABBV-<NUM>, or Adalimumab.

In one embodiment, one or more of the drugs of the drug delivery device <NUM> is aldesleukin, bempegaldesleukin, tocilizumab, or MEDI5083. In one embodiment, the delivery device <NUM> includes bempegaldesleukin and a PD-<NUM> pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, the delivery device <NUM> includes bempegaldesleukin and a LAG3 antagonist, e.g., relatlimab or MK-<NUM>. In one embodiment, the delivery device <NUM> includes bempegaldesleukin, a PD-<NUM> pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA), and a LAG3 antagonist, e.g., relatlimab or MK-<NUM>. In one embodiment, the delivery device <NUM> includes bempegaldesleukin and a CTLA-<NUM> antagonist, e.g., ipilimumab (YERVOY).

Claim 1:
A combinatorial drug delivery device (<NUM>) for delivering a predetermined selection of drug components, each of the drug components being contained in a drug vial (<NUM>), the device (<NUM>) comprising:
a plurality of serially-connected modules (<NUM>), wherein each of the modules (<NUM>) is similarly formed and includes:
a body (<NUM>) having an interior volume (<NUM>) formed to accommodate a drug vial (<NUM>);
a cannula (<NUM>) protruding into the interior volume (<NUM>), the cannula (<NUM>) terminating at a free end (<NUM>), first and second openings being formed in the free end with first and second lumens (30A, 30B) extending therefrom and through the cannula (<NUM>);
a socket (<NUM>) located on an exterior portion (<NUM>) of the body (<NUM>);
a first passageway (<NUM>) extending between, and in communication with, the socket (<NUM>) and the first lumen (30A);
a boss (<NUM>) protruding from an exterior portion (<NUM>) of the body (<NUM>); and,
a second passageway (<NUM>) extending from, and in communication with the second lumen (30B), the second passageway (<NUM>) extending through the boss (<NUM>) to terminate at an exit opening formed therein;
a housing (<NUM>) having a discharge passageway (<NUM>), wherein a first of the serially-connected modules (<NUM>) is coupled to the housing (<NUM>) with the second passageway (<NUM>) of the first module being in communication with the discharge passageway (<NUM>), and, wherein a second of the serially-connected modules is coupled to the first module with the second passageway (<NUM>) of the second module being in communication with the first passageway (<NUM>) of the first module, the first module being located between the second module and the housing (<NUM>); and,
a source of negative pressure (<NUM>) for drawing the drug components from the drug vials of the serially-connected modules (<NUM>) and into the discharge passageway (<NUM>), wherein the source of negative pressure (<NUM>) is solely located inside the housing (<NUM>).