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 CTLA4 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.

Through the utilization of serially connectable drug modules as described in applicant's co-pending applications (<CIT>; PCT Appl. No. <CIT>; PCT Appl. No. <CIT>; and, PCT Appl. No. <CIT>) combinations of drugs can be successfully stored, shipped, and administered to patients and a manner that allows for sufficient flexibility while simultaneously minimizing product waste. These drug modules utilize common off-the-shelf vial primary containers, which during administration are pierced with a spike located inside the module, which allows the liquid drug within the vial to enter the internal fluidics of the module. It is critical that a sealing mechanism be present within the fluidics of the module that is not only able to contain the liquid drug product within the module fluidics during the spiking process, but also have the capability to open the fluidic path during use of the product to allow the drug product to flow. As this product is envisioned to be disposable, the ideal sealing mechanism must be low in cost to produce while also being extremely reliable and repeatable.

Applicant has now realized that the combinatorial principles described in <CIT>, PCT Appl. No. <CIT>, PCT Appl. No. <CIT>, and, PCT Appl. No. <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 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 that is provided for pooling a fluid from a container unit having at least one container, and that 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. Both inlet and outlet ports are disposed on the device. A cavity is provided for accommodating insertion of the container unit for pooling the fluid from the at least one container. At least one spike is disposed in the cavity and configured for puncturing a stopper of the at least one container when the container unit transitions from an upper position to a lower position.

Aspects of the invention are as set out in the appended claims. According to the present disclosure, for modules useable with a combinatorial drug delivery device, a moveable piston seal with a bypass chamber put inline of the module's outlet fluidics provides a means of sealing the module's fluidics from atmosphere during vial piercing, while is also able to allow the fluid path to open when vacuum is applied to the outer face of the piston seal.

Two lumen pathways, inlet and outlet, within the spike that enters the vial's drug chamber, divide the module's fluidic pathway. The inlet allows the liquid drug product from the preceding connected module to enter the spiked vial, while the outlet path moves fluid from the vial to the proceeding module. A spring-loaded seal at the entrance of the inlet path is used to interface with preceding modules, this seal ensures the pathway is only opened at the time of connection with a module, therefore, once the vial is spiked, the inlet pathway is closed to the atmosphere and the vial contents cannot escape.

During vial spike, the volume of the spike entering the vial displaces some of the fluid within the vial causing slight pressurization of the vial's contents, which forces it into the spike lumens. On the inlet side this pressure is contained by a spring-loaded seal, on the outlet side the fluid enters the spike lumen and is sealed by a piston seal. Any pressure during the spiking process will slightly push the piston seal allowing the liquid chamber to increase volumetrically, thus reducing the pressure from spiking. On the opposite side of the piston seal is the outlet to the proceeding module's inlet. A small bypass is cut into the module body next to the piston seal connecting the outlet chamber to the outlet fitting. When a source of vacuum is applied to the outlet fitting this will cause the piston to move, exposing the bypass port to the vial's fluidic pathway thus opening up a path way for fluid to travel from the vial to the outlet fitting.

The subject invention is particularly well-suited for use with serially-connected drug modules, particularly in forming fluid paths therebetween. The subject invention is shown in a context of a single module <NUM>, but it is understood that the subject invention operates with a plurality of similarly formed modules <NUM>, serially connected. As depicted in <FIG> and <FIG>, each of the modules <NUM> includes valving having a vial spike <NUM> used to pierce a vial septum S extending into the interior volume V of a liquid filled drug vial DV. A free, distal end <NUM> of the vial spike <NUM> may be sharpened to facilitate piercing of the vial septum S. The vial spike <NUM> must be provided with sufficient length to fully pierce the septum S in accessing the interior volume V.

The vial spike <NUM> includes two lumens dividing the module fluidics into separate circuits, an inlet path <NUM>, and an outlet path <NUM>. With the vial spike <NUM> piercing the septum S, both the inlet path <NUM> and the outlet path <NUM> are open at the free end <NUM> of the vial spike <NUM> and in communication with the interior volume V of the drug vial DV. The inlet path <NUM> extends from the interior volume V of the drug vial DV to an inlet opening <NUM> which is selectively sealed by spring-biased sealing port <NUM>. A vent <NUM> exists on the inlet path <NUM>, preferably between the free end <NUM> and the inlet opening <NUM>, to allow air into the drug vial DV, as needed, to displace fluid during transfer. Preferably, the vent <NUM> is a one-way vent which is normally closed and allows for gas flow into the inlet path <NUM>. The outlet path <NUM> extends from the interior volume V of the drug vial DV down to outlet chamber <NUM>. A piston valve <NUM> is slidably seated inside the outlet chamber <NUM> creating a seal against the chamber inner wall <NUM>. The piston valve <NUM> may include a radial seal <NUM> in sealing contact with the wall <NUM> to define the seal whilst allowing the piston valve <NUM> to slide within the outlet chamber <NUM>.

The piston valve <NUM> forms a seal in the outlet chamber <NUM> to define first and second chamber portions 6a, 6b, which are adjustable in size with movement of the piston valve <NUM> within the outlet chamber <NUM>, with the seal therebetween being maintained. The outlet path <NUM> is in communication with the first chamber portion 6a. An outlet fitting <NUM> is provided which is in communication with the outlet chamber <NUM>, particularly, the second outlet chamber 6b.

In an initial state, as shown in <FIG>, the piston valve <NUM> is placed in a first position at the medial end of the outlet chamber <NUM> preventing fluid entering from the outlet lumen <NUM> from accessing the outlet fitting <NUM>. A bypass passageway <NUM> connects the outlet chamber <NUM> to the outlet fitting <NUM>. In particular, the bypass passageway <NUM> terminates at an opening <NUM> in the wall <NUM> of the outlet chamber <NUM>. With the piston valve <NUM> in the first position, the first chamber portion 6a is sealed from the bypass passageway <NUM>.

With this arrangement (the piston valve <NUM> being in the first position), and, as shown in <FIG>, pressurized fluid forced from the drug vial DV, as a result of vial spike <NUM> spiking the septum S, will be contained in the inlet pathway <NUM> by the spring-biased sealing port <NUM>, while any entering the outlet pathway <NUM> will be contained within the first chamber portion 6a behind the piston valve <NUM>. As shown in <FIG>, pressure in the fluid may move the piston valve <NUM> slightly; this movement in position will equilibrate the pressure within the drug vial DV and fluid path to a negligible amount.

As shown in <FIG>, at the time of fluid transfer, a source of negative pressure, e.g., a vacuum, will be provided to the outlet fitting <NUM>, thereby evacuating air from the bypass passageway <NUM> and the outlet chamber <NUM>, particularly, the second chamber portion 6b. This will generate a pressure differential across the piston valve <NUM> which will cause the piston valve <NUM> to slide along the outlet chamber <NUM> towards the outlet fitting <NUM>. This results in an increase in volume of the first chamber portion 6a. Eventually, as the piston valve <NUM> continues moving it will pass over the bypass passageway <NUM>, thereby allowing the first chamber portion 6a, along with the outlet path <NUM>, to come into communication with the bypass passageway <NUM>. As shown in <FIG>, with the bypass passageway <NUM> carrying vacuum, fluid will then be able to move from the vial, through the outlet pathway <NUM>, through the bypass passageway <NUM> circumventing the piston valve <NUM>, and out through the outlet fitting <NUM>.

As shown in <FIG>, a plurality of the modules <NUM> may be coupled in series with the outlet fitting 7a of a secondary module 9a breaching the sealing port <NUM> of an adjacent module <NUM> such that the outlet fitting 7a is in communication with the inlet opening <NUM> thereof. The secondary module 9a is formed similar to the module <NUM> with like parts being similarly numbered, but additionally designated with the letter "a" (except for the outlet chamber of the secondary module which is designated as <NUM>'). The coupled arrangement allows for a fluid path to be defined from a drug vial DV coupled to vial spike 1a of the secondary module 9a to the outlet fitting <NUM> of the module <NUM>, through a drug vial DV coupled to vial spike <NUM>, as shown schematically in <FIG>. This fluid pathway is achieved with sliding movement of piston valve 5a, resulting from negative pressure being applied to the outlet fitting 7a, via the outlet path <NUM> and the inlet path <NUM> of the module <NUM>. In similar manner to that described above, flow bypasses the piston valve 5a with the bypass passageway 8a, upon sufficient sliding displacement of the piston valve 5a. This arrangement allows for a series of modules <NUM> to be coupled, with the respective drug vials DV being in-line to define a single flow path, acted upon by a single source of negative pressure.

Claim 1:
A module (<NUM>) for use in a combinatorial drug delivery device, the module formed to accommodate a drug vial (DV) with a septum, the module comprising:
a vial spike (<NUM>) formed to pierce the septum (S) of the drug vial (DV) with a free end of the vial spike (<NUM>) configured to be located interiorly of the septum (S), the vial spike (<NUM>) including an inlet path (<NUM>) open at the free end (<NUM>) and extending along the vial spike (<NUM>) to an inlet opening (<NUM>), and an outlet path (<NUM>) open at the free end and extending along the vial spike (<NUM>) to an outlet chamber (<NUM>), the outlet path (<NUM>) being separate from the inlet path (<NUM>);
a sealing port (<NUM>) selectively sealing the inlet opening (<NUM>);
a vent (<NUM>) in communication with the inlet path (<NUM>) between the inlet opening (<NUM>) and the free end (<NUM>);
a slidable piston valve (<NUM>) located in the outlet chamber (<NUM>), the piston valve (<NUM>) forming a seal in the outlet chamber (<NUM>) to define first and second chamber portions (6a, 6b), the outlet path (<NUM>) being in communication with the first chamber portion (6a);
an outlet fitting (<NUM>) in communication with the second chamber portion (6b); and,
a bypass passageway (<NUM>) extending between the outlet fitting (<NUM>) and an opening in the outlet chamber (<NUM>),
wherein, in an initial state, the piston valve is located in a first position where the first chamber portion is sealed from the bypass passageway, and,
wherein, with negative pressure introduced through the outlet fitting, the piston valve is caused to move to a second position where the first chamber portion is in communication with the bypass passageway,
wherein the vent (<NUM>) terminates at a vent opening (<NUM>), away from the inlet path (<NUM>), wherein the sealing port (<NUM>) and the vent opening (<NUM>) are located on a common wall of the module (<NUM>).