Patent Description:
Closed systems for handling drugs and closed system drug-transfer devices are well known in the art. They are typically used to reduce potential human exposure to drugs, particularly when transferring hazardous drugs from one receptacle to another. These types of systems and devices are generally designed to conform to the definitions provided by the American National Institute for Occupation Safety and Health (NIOSH) which is as follows:
"A closed system drug-transfer device (CSTD) is a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system.

Exposure to hazardous drugs may cause serious health complications for those who are exposed to them, particularly when the exposure is over time. These complications may range from skin irritation, to birth defects, and even to development of various forms of cancer. For example, to prepare and administer chemotherapy drugs, which contain hazardous antineoplastic agents, the drugs need to be transferred from the original vial to a syringe and from a syringe to an IV infusion bag. Each transfer creates the possibility for exposure to the hazardous drugs.

Without using a CSTD, studies have shown hazardous drug residue on surfaces in the workplace, including on counters, and doorknobs, and even in unlikely places like a secretary's desk. This is due to the adhesive properties of the drugs. Using a CSTD, the rates of residue, as well as exposure to harmful vapors from the drugs, may be substantially reduced. Additional background art is described in <CIT> which describes "A medicament transport system includes a syringe adapter assembly; and a vial adapter assembly including a base defining an opening having a seal member disposed therewithin, a stem extending from the base and defining a lumen therethrough and an opening through a wall thereof, a needle shuttle valve slidably disposed within the lumen of the stem and supporting a transfer needle and a vacuum needle; and a vacuum cup slidably supported on the stem, wherein a vacuum chamber is defined in the space between the base, the stem and the vacuum cup. The medicament transport system includes a condition where the transfer needle and the vacuum needles penetrate the seal member of the vial adapter assembly, and the vacuum cup is moved to draw a vacuum through the vacuum needle. An automation system is provided that utilizes a medicament transport system for forming a medicament solution from a liquid/non-liquid solution".

There is provided, according to an embodiment of the present invention, a closed liquid transfer system including a transfer device including a multi-port manifold and a connector suitable to be attached to a drug container. The transfer device includes a first conduit to transfer a liquid entering an inlet port of the manifold through the connector and into the drug container, and a second conduit to transfer a gaseous fluid through the connector and the manifold to an outlet port of the manifold. The system additionally includes a tube connectable to the inlet port for transporting a liquid to the transfer device, and a tube connectable to the outlet port for transporting the gaseous fluid away from the transfer device.

According to an embodiment of the present invention, the system additionally includes a gas collection container to collect the gaseous fluid in the gas transporting tube.

According to an embodiment of the present invention, the manifold includes a hermetic seal in the outlet port to prevent liquid flow into the gas transporting tube.

According to an embodiment of the present invention, the system additionally includes a valve with three ports operable to allow unidirectional liquid flow from a first port to a second port, and from the second port to a third port.

According to an embodiment of the present invention, the system additionally includes a liquid supply tube connectable to the first port to transport the liquid into the first port.

According to an embodiment of the present invention, the liquid transporting tube is connectable to the third port of the valve.

According to an embodiment of the present invention, the system additionally includes a liquid container connectable to the liquid supply tube for supplying the liquid.

According to an embodiment of the present invention, the second port is connectable to any one of a manually operable syringe, an automatic syringe device, and a repeater pump.

According to an embodiment of the present invention, the second port includes a luer connector.

According to an embodiment of the present invention, the system additionally includes a unidirectional valve connected to the gaseous fluid transporting tube to allow unidirectional flow of the gaseous fluid towards the gas collection container.

According to an embodiment of the present invention, the drug container is any one of a drug vial or a drug bag.

According to an embodiment of the present invention, the liquid is a diluent.

There is provided, according to an embodiment of the present invention, a method of reconstituting a dry drug or diluting a liquid drug in a plurality of drug containers. The method includes: (<NUM>) attaching to a drug container a transfer device including a multi-port manifold and a connector suitable to be attached to the drug container, transfer device including a first conduit to transfer a liquid entering an inlet port of the manifold through the connector and into the drug container, and a second conduit to transfer a gaseous fluid through the connector and the manifold to an outlet port of the manifold; (<NUM>) administering a measured amount of a diluent into a tube connected to the inlet port of the manifold; (<NUM>) collecting in a gas collection container through a tube connected to the outlet port gaseous fluid expelled from the drug container; and (<NUM>) repeating the above steps for the plurality of drug containers.

According to an embodiment of the present invention, the method additionally includes administering the measured amount of diluent using any one of a syringe, an automatic syringe device, and a repeater pump.

According to an embodiment of the present invention, the method additionally includes supplying the diluent from a diluent container.

There is provided, according to an embodiment of the present invention, a transfer device for use in reconstituting dry drugs and for diluting liquid drugs in drug containers, the transfer device including a multi-port manifold and a connector suitable to be attached to a drug container, a first conduit to transfer a liquid entering an inlet port of the manifold through the connector and into the drug container; and a second conduit to transfer a gaseous fluid through the connector to an outlet port of the manifold.

Details shown are for exemplary purposes and serve to provide a discussion of embodiments of the invention. The description and the drawings may be apparent to those skilled in the art how embodiments of the invention may be practiced.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings.

Drug reconstitution or dilution processes which use known CSTDs frequently involve many steps. A typical CSTD reconstitution or dilution process may include (a) connecting an adapter to a container holding a diluent (e.g. Saline, Dextrose, distilled water) , for example a spike adapter connected to a Saline bag; (b) connecting a syringe to the adapter; (c) drawing an amount of diluent into the syringe; (d) removing the syringe from the diluent container and connecting it to an adaptor on a drug container (e.g. vial adaptor on a vial, or a spike adaptor on a bag); (e) injecting the diluent into the drug container holding a dry drug to be reconstituted or a fluid drug to be diluted; and (f) following injection of the diluent, depending on the CSTD, the syringe may be removed and steps b - e repeated for a new drug container using the same syringe, or alternatively, the syringe is discarded and a new syringe is used. The syringe may be fitted with a special connector which may fit onto a special adaptor on the drug container, both the connector and the adapter designed to prevent gases from escaping from the drug container (and the attached syringe) into the surrounding, and to prevent contaminated air from flowing into the drug container (and the attached syringe) from the surrounding.

The Applicant has realized, as may be appreciated from the above description, that drug reconstitution and drug dilution using known CSTDs may be tedious, time consuming, and potentially expensive processes, particularly when many drug containers have to be prepared. Known CSTDs may be practical for preparation of small quantities of drug containers, for example, a few containers per day as may be required by small size medical facilities, but may prove to be impractical for medium size and large size facilities where daily preparation requirements may exceed the tens, and something the hundreds, or even more.

The Applicant has further realized that reducing the number of steps in a typical CSTD reconstitution or dilution process may potentially overcome some, if not all of these drawbacks, and that a possible solution may be provided by a closed system liquid transfer system which may allow transferring of diluent from the diluent container to a plurality of drug containers without having to physically connect and disconnect a syringe to and from the diluent container and the drug container every time a new drug container is used.

In <CIT>, <CIT>, Israel Patent Application <CIT>, and <CIT>, all commonly owned by the assignee of the present invention disclosed are embodiments of closed system liquid transfer devices suitable to provide contamination-free transfer of hazardous drugs. The Applicant has realized that some of these liquid transfer devices include connectors and adapters (e.g. spike adapters and vial adapters) which may be used with the closed system liquid transfer system of the present invention (hereinafter referred to as "liquid transfer system" for convenience) to allow economically preparing, with relative ease, measured quantities of contamination-free reconstituted or diluted drugs in a plurality of containers.

The Applicant has further realized that safety issues and potential hazards associated with reconstituting and diluting hazardous drugs may be remedied by using the liquid transfer system. For example, to reconstitute widely used hazardous drugs for chemotherapy such as Cyclophosphamide from their powder form to their injectable liquid form, a diluent such as a solution of sodium chloride (Saline) may be injected into a glass vial. Saline solution is typically available in infusion bags and generally needs to be drawn from the bag into a syringe. A <NUM> gram Cyclophosphamide vial typically requires the injection of <NUM> of solution. Since it may take a long time until the Cyclophosphamide powder dissolves in practice, many pharmacies may reconstitute a large number of such vials at once and use them throughout a work week to avoid long preparation times. The addition of the <NUM> of liquid into the vial may pose a safety issue and a potential safety hazard as the pressure in the glass vial increases (due to the addition of the diluent), possibly resulting in the reconstituted drug leaking out of the pressurized vial while stored for use. The liquid transfer system provides a solution to eliminate such overpressure conditions inside the vials and may provide leak-free transfer of fluids in a closed system.

The following figures illustrate exemplary embodiments of the liquid transfer system of the present invention, and an exemplary method of using the system for drug reconstitution and drug dilution. These figures and their associated description are not intended to be exhaustive or to limit the present invention to the disclosed embodiment.

The ordinary person skilled in the art may readily realize that the present invention may be practiced with modifications, substitutions, changes, and equivalents which are not disclosed herein yet are within the constraints of the teachings of the present invention. Furthermore, the skilled person may readily realize that the present invention may be used in other applications other than drug reconstitution and dilution as disclosed herein, for example, for contamination-free transferring of a measured amount of a liquid from a first container to a second container. In some cases the liquid may include a drug or combination of drugs being transferred from a first container to a second container, although any liquid which may be transferrable by means of a syringe may be suitable.

Reference is now made to <FIG> which schematically illustrates an exemplary liquid transfer system <NUM>, according to an embodiment of the present invention. Liquid transfer system <NUM> may include a liquid supply tube <NUM>, a dual check valve <NUM> or functionally similar device, a liquid transport tube <NUM>, a transfer device <NUM> including a multi-port manifold <NUM> and a CSTD connector <NUM>, a gas transport tube <NUM>, and a check valve <NUM> or functionally similar device. Additionally, liquid transfer system <NUM> may include a gas collection container <NUM>. For convenience hereinafter, devices which are functionally similar to dual check valve <NUM> and to check valve <NUM> may also be referred to as "dual check valve <NUM>" and "check valve <NUM>", respectively.

In an embodiment of the present invention, liquid transfer system <NUM> may be used for contamination-free transfer of fluids, for example, a diluent <NUM>, from a diluent container <NUM> to a drug container <NUM> which may be connected to CSTD connector <NUM>, and to conduct gases <NUM> (which may include air mixed with drug-emitted vapors) from the drug container to gas collection container <NUM> in the closed system. Drug containers <NUM> may include a vial <NUM> or a bag drug container <NUM> containing a drug <NUM> which may be in dry form (for reconstitution) or liquid form (for dilution). These gases may be naturally pushed out of drug container 131during the process of adding diluent <NUM> to drug <NUM> as the diluent takes up the space previously occupied by gases <NUM> in the drug container and there is no room for both.

Liquid supply tube <NUM> may connect at a distal end to diluent container <NUM> which may include one or more diluent bags containing diluent <NUM> ,which may for example, Saline, Dextrose, distilled water, or other type of fluids used to reconstitute dry drugs and/or to dilute fluid drugs. At a proximal end the liquid supply tube <NUM> may connect to dual check valve <NUM>.

Dual check valve <NUM> may include three ports, a first port <NUM> which connects to liquid supply tube <NUM> and through which diluent <NUM> flows into the valve from diluent container <NUM>, a second port <NUM> to which may be connected to a manually operated syringe, an automatically operated syringe, or a pump such as, for example a repeater pump, or any other source capable of injecting a measured amount of a fluid into the system, and a third port <NUM> to which may be connected a proximal end of liquid transport tube <NUM> and into which may flow diluent <NUM> from the dual check valve. Dual check valve <NUM> may allow unidirectional diluent flow from port <NUM> to port <NUM>, and may further allow unidirectional flow from port <NUM> to port <NUM>, as is described further on below with reference to <FIG>. Second port <NUM> may include a standard female luer lock port <NUM> or any other suitable connection means.

Liquid transport tube <NUM> may fluidly connect third port <NUM> in dual check valve <NUM> with multi-port manifold <NUM> to allow diluent flow from the dual check valve to the manifold. Multi-port manifold <NUM> may include a T-connector or a Y-connector and may include a first port <NUM> connecting to a distal end of liquid transport tube <NUM>, a second port <NUM> which may connect to CSTD connector <NUM>, and a third port <NUM> which may connect to a proximal end of gas transport tube <NUM> leading to gas container <NUM>.

Reference is now also made to <FIG> which schematically illustrates a detailed view of transfer device <NUM> including multi-port manifold <NUM> (T-connector) and CSTD connector <NUM> connected to second port <NUM>, according to an embodiment of the present invention. Third port <NUM> in manifold <NUM> may include a seal <NUM> to prevent diluent <NUM> flowing into the manifold through first port <NUM> from flowing into gas transport tube <NUM>.

CSTD connector <NUM> may include one of the connectors described in the aforementioned patents and patent applications commonly owned by the assignee of the present invention. The connectors described therein are suitable for use in CSTDs and attachable to adapters connectable to drug containers <NUM>. The adapters may also include one of the adapters described in the aforementioned patents and patent applications commonly owned by the assignee of the present invention. For example, the CSTD connector <NUM> may be a syringe connector and the adapter a vial adapter for attaching to vial (drug container) <NUM>, both as described in <CIT>, the syringe connector appropriately modified to connect to second port <NUM> in manifold <NUM>. Alternatively, the adapter may be a bag adapter for attaching to bag drug container <NUM> to which the modified syringe connector may be connected.

CSTD connector <NUM> may include a diluent conduit <NUM> through which diluent <NUM> entering first port <NUM> in manifold <NUM> may flow through the manifold and through the vial or bag adapter (not shown) into drug container <NUM>. CSTD connector <NUM> may additionally include a gas conduit <NUM> through which gas <NUM> which may include air, which may be mixed with drug vapors, may flow from inside drug container <NUM> through the adapter and through the connector towards gas transport tube <NUM> and onwards to gas container <NUM>. Gas conduit <NUM> may extend through CSTD connector <NUM> into manifold <NUM> and through seal <NUM> in third port <NUM> in a direction of gas transport tube <NUM>.

In some embodiments, CSTD connector <NUM> and multi-port manifold <NUM> may be formed as a single component or may be preassembled in factory as a single assembly. Alternatively, CSTD connector <NUM> and multi-port manifold <NUM> may be two separate components which may be connected together as one assembly during in situ assembly of liquid transfer system, with provisions made in seal <NUM> to allow the insertion of gas conduit <NUM> through the seal.

Gas transport tube <NUM> may be connected at a proximal end to third port <NUM> of manifold <NUM> and may transport gas <NUM> flowing through gas conduit <NUM> from drug container <NUM> to gas container <NUM>. Check valve <NUM> in gas transport tube <NUM> may allow unidirectional gas flow into the gas collection bag <NUM> and may prevent gas flow from the gas collection bag in a direction toward manifold <NUM>. Check valve <NUM> may additionally prevent any liquid which may collect in gas collection bag <NUM>, for example as a result of a wash-out procedure, from flowing out of the gas collection bag towards manifold <NUM>.

It may be appreciated by the skilled person that the liquid transfer system of the present invention may be implemented based on the above description using different components or combinations of components and that the practice of the invention may not be limited to using the same exact components or component as shown and described with reference to <FIG>. The following <FIG> illustrate exemplary applications of liquid transfer system <NUM> with different mechanisms for injecting measured amounts of dilation <NUM> (or other fluid) into the system, according to some embodiments of the present invention.

<FIG> schematically illustrates liquid transfer system <NUM> used with a manually-operated syringe <NUM> in a closed system reconstitution or dilation process, or otherwise liquid transfer process, according to an embodiment of the present invention. Syringe <NUM> may be connected to luer connector <NUM> in second port <NUM> of dual check valve <NUM>.

In operation, diluent <NUM> may flow from diluent container <NUM> through liquid supply tube <NUM> into port <NUM> in dual check valve <NUM> responsive to syringe <NUM> drawing of the diluent when the plunger is pulled. Diluent flow from port <NUM> is unidirectional into port <NUM> and diluent <NUM> may be drawn into syringe <NUM>. An amount of diluent <NUM> drawn into syringe <NUM> may be determined by pulling the plunger until the desired position (as visually determined by the position of the plunger in relation to the markings on the syringe). Once filled with the desired amount of diluent <NUM>, the plunger may be pushed forcing the measured amount of diluent <NUM> in syringe <NUM> to flow into port <NUM>. Flow from port <NUM> may be unidirectional to third port <NUM> in dual check valve <NUM>, so that, upon pushing of the plunger, the measured amount of diluent <NUM> flows through dual check valve <NUM> into liquid transport tube <NUM>. From liquid transport tube <NUM>, the measured amount of diluent <NUM> may flow into manifold <NUM> and through CSTD connector <NUM> through diluent conduit <NUM> into drug container <NUM> (vial container <NUM> or bag drug container <NUM>) to produce the reconstituted (or diluted) drug <NUM>. Gases <NUM> displaced from vial <NUM> may flow through gas conduit <NUM> in CSTD connector <NUM> and manifold <NUM> into gas transport tube <NUM> into gas collection bag <NUM>.

<FIG> schematically illustrates liquid transfer system <NUM> used with an automatic syringe device <NUM> in a closed system reconstitution or dilation process, or otherwise liquid transfer process, according to an embodiment of the present invention. Syringe <NUM> may be mounted on automatic syringe device <NUM> (may also be semi-automatic) and may be connected to second port <NUM> in dual check valve <NUM> by means of a transfer tube <NUM> through which diluent <NUM> may flow to and from the syringe. Alternatively, syringe <NUM> may be directly connected to luer connector <NUM> in second port <NUM>. The operation of liquid transfer system <NUM> is substantially similar to that described for <FIG> with the exception that syringe operation is automatic (by means of automatic syringe device <NUM>).

<FIG> schematically illustrates liquid transfer system <NUM> used with a repeater pump <NUM> in a closed system reconstitution or dilation process, or otherwise liquid transfer process, according to an embodiment of the present invention. Repeater pump <NUM>, or other suitable automatic or semi-automatic fluid injection device, may include its own diluent container <NUM> or may be fluidly connected to an external diluent container <NUM> through a supply tube <NUM>, so that diluent container <NUM> and liquid supply tube <NUM> may not be required. Liquid transport tube <NUM> may be directly connected to repeater pump <NUM> so that dual check valve <NUM> previously described may also not be required. Liquid transfer system <NUM> may operate with diluent <NUM> being injected from repeater pump <NUM> directly into port <NUM> in manifold <NUM>. The operation of liquid transfer system <NUM> with a repeater pump <NUM> may be substantially similar to that described for <FIG> with the exception that diluent container <NUM>, liquid supply tube <NUM>, and dual check valve <NUM> are not required.

Reference is now made to <FIG> which is a flow chart of an exemplary method of using closed system liquid transfer system for drug reconstitution or drug dilution in a plurality of drug containers, according to an embodiment of the present invention. The method may include a first stage which includes setting up the liquid transfer system, and a second stage which includes liquid transfer to the plurality of drug containers following system setup. In describing the method, for clarity purposes, reference is made to liquid transfer system <NUM> described in <FIG> and <FIG>, although reference may also be made to the embodiments of <FIG> and <FIG>.

It may be apparent to the ordinary person skilled in the art that the method may be practiced with more or less steps, or with a different sequence of steps, and which may include adding and/or deleting steps, skipping steps, and rearranging the order of the steps.

At <NUM>, liquid supply tube <NUM> may be connected to diluent container <NUM>. Diluent container <NUM> may be a diluent bag or other suitable container for holding diluent <NUM>. Diluent container <NUM> may be prefitted with an adapter connectable to liquid supply tube 102or alternatively, the adapter may be connected to the container during this step.

At <NUM>, syringe <NUM> is connected to second port <NUM> of double check valve <NUM>. Syringe <NUM> may be a manually operated syringe or may be mounted on an automatic syringe device <NUM>. Alternatively, instead of the syringe (manual or automatic), a repeater pump <NUM> or other suitable injection means may be connected to port <NUM> (or alternatively directly to liquid transport tube <NUM>).

At <NUM>, diluent <NUM> is drawn into syringe <NUM> by pulling the plunger. An amount of diluent shall be sufficient for flushing out and priming the system in order to push the air out and replace it with liquid and also to wash out possible drug residue on any of the system components. Alternatively, if repeater pump is used <NUM>, then there is no need to draw the diluent from the diluent container <NUM> which may not be required at all, rather the repeater pump may pump from optional pump container <NUM> or from external diluent container <NUM> a required amount for flushing and priming (see <NUM>).

At <NUM>, diluent <NUM> is injected into liquid transport tube <NUM> to flush out the system. As part of the flushing process, diluent <NUM> may flow through multi-port manifold <NUM> to CSTD connector <NUM> and into diluent conduit <NUM>. CSTD connector <NUM> is not connected in this step to the vial adaptor so diluent <NUM> may flow from diluent conduit <NUM> through a chamber in the CSTD connector into gas conduit <NUM> (i.e. the CSTD connector may be functionally similar to connector section <NUM> in <CIT>). Diluent <NUM> flowing into gas conduit <NUM> may flow out into gas transport <NUM> and into the gas container <NUM> where it is collected and contained.

At <NUM>, drug container <NUM> with an attached adapter (e.g. vial <NUM> with an attached vial adapter or bag <NUM> with an attached spike adapter) is connected to CSTD connector <NUM>. The following <NUM> may be interchangeable with this <NUM>.

At <NUM>, a required amount of diluent <NUM> to be used for reconstitution or dilution is drawn into syringe <NUM> from diluent container <NUM>. The amount may be measured by a user on the syringe scale while pulling the plunger (to draw the diluent into the syringe) or may be based on other parameters (for example, plunger pulling length) for automatic syringed device <NUM>. Alternatively, instead of the syringe (manual or automatic), repeater pump <NUM> may be used and drawing of diluent <NUM> is not required. Repeater pump <NUM> may inject (see <NUM>) a preprogrammed, required amount.

At <NUM>, diluent <NUM> is injected into liquid transport tube <NUM> by pushing on the plunger or injected by the pump. The diluent may flow through liquid transport tube <NUM> into multi-port manifold <NUM> and through diluent conduit <NUM> in the manifold and CSTD connector <NUM> through the adapter into drug container <NUM>. Gas <NUM> in drug container <NUM> may flow out through gas conduit <NUM> into the gas transport tube <NUM> and thereto into gas container <NUM>. Seal <NUM> in multi-port manifold <NUM> may prevent the injected diluent from flowing out the multi-port manifold into gas transport tube <NUM>.

At <NUM>, following diluent <NUM> having been injected into drug container <NUM>, the adapter (with the drug container attached) may be disconnected from CSTD connector <NUM>.

At <NUM>, if a same drug <NUM> in another ("new") drug container <NUM> is to be reconstituted or diluted, the fifth through eighth steps may be repeated. Similarly if the diluent container <NUM> is replaced by a diluent container with the same diluent. If a different drug is to be reconstituted or diluted, or a new type of diluent is to be used, the first to eighth steps may be repeated.

At <NUM>, once all drug containers <NUM> have been filled, the process ends.

The foregoing description and illustrations of the embodiments of the invention has been presented for the purposes of illustration. It is not intended to be exhaustive or to limit the invention to the above description in any form.

Any term that has been defined above and used in the claims, should to be interpreted according to this definition.

Claim 1:
A system (<NUM>) for reconstituting drugs in a plurality of drug containers, each drug container (<NUM>, <NUM>) of the plurality of drug containers including an adapter, the system comprising:
a transfer device (<NUM>) comprising a multi-port manifold (<NUM>) and a connector (<NUM>) suitable to be removably attached to the adapter of each drug container of the plurality of drug containers, said transfer device further comprising:
a first conduit (<NUM>) to transfer a liquid from an inlet port (<NUM>) of said manifold through said connector and into each drug container, and
a second conduit (<NUM>) to transfer a gaseous fluid (<NUM>) from inside each drug container through said connector and said manifold to an outlet port (<NUM>) of said manifold;
a liquid transporting tube (<NUM>) connected to said inlet port for transporting a liquid to the transfer device; characterised in that the system further comprises,
a gas transporting tube (<NUM>) connected to said outlet port for transporting said gaseous fluid from each drug container away from said transfer device;
a gas collection container (<NUM>) to collect said gaseous fluid from each drug container; and
a dual check valve (<NUM>) with three ports operable to allow unidirectional liquid flow from a first port (<NUM>) to a second port (<NUM>), and from said second port to a third port (<NUM>), wherein the third port is connected to the liquid transporting tube.