EA047655B1 - COMPONENTS OF OPEN LIQUID DRUG TRANSFER SYSTEMS AND A ROBOTIC SYSTEM USING THEM - Google Patents

Description

Field of technology

The present invention relates to the field of devices for transferring liquids. In particular, the present invention relates to components of open systems for transferring liquid medicinal products and their use in automated robotic systems for preparing medicinal products and medicinal products for administration to patients.

State of the art

In U.S. Patent 8,196,614, owned by the applicant of the present invention, devices for transferring liquid with a closed system intended to ensure the transfer of hazardous drugs without contamination are described. Figs. 1a and 1b are schematic cross-sectional views of a device 10 for transferring hazardous drugs without contamination of the environment according to one embodiment of the invention described in U.S. Patent 8,196,614. The main features of this device, which are important for the present invention, will be described herein. Further details can be found in the previously mentioned patent.

The proximal portion of the device 10 is a syringe 12, which is designed to extract the required volume of a dangerous drug from a component for transporting liquid, for example, a vial 16 or a bag for intravenous (IV) infusion, in which it is contained, and then transfer the said drug to another component for transporting liquid. At the distal end of the syringe 12, a connecting section 14 is attached, which in turn is connected to the vial 16 using an adapter 15 for the vial.

The syringe 12 of the device 10 consists of a cylindrical body containing a tubular neck that has a significantly smaller diameter compared to the body, an annular rubber gasket or stopper secured to the proximal end of the cylindrical body, a hollow piston rod that hermetically passes through the stopper, and a proximal tip of the piston rod, by which the user can push and pull the piston rod up and down through the stopper. The piston 28, made of an elastomer material, is securely secured to the distal end of the piston rod.

The piston, which is hermetically engaged with the inner wall of the cylindrical body and can move relative to it, forms two chambers of variable volume: a distal liquid chamber 30 between the distal surface of the piston and the connecting section 14 and a proximal air chamber 32 between the proximal surface of the piston and the plug.

The connecting section 14 comprises a cylindrical hollow outer housing; a distal flange part which projects radially from the housing and ends at the distal end with an opening through which the proximal end of the component for transporting liquid is inserted for connection; an actuator 34 of a double membrane shutter which can perform reciprocating movements within the internal space of the housing; and one or more elastic brackets 35 serving as connecting elements which are connected at their proximal ends to an intermediate part of the cylindrical housing of the actuator which contains the actuator 34 of a double membrane shutter. Two hollow needles which perform the functions of a tube 38 for air and a tube 40 for liquid are fixedly held in a needle holder which projects into the internal space of the connecting section 14 from the central part of the top of the connecting section 14.

Tubes 38 and 40 extend distally from the needle holder, piercing the upper membrane of the actuator 34. The distal ends of tubes 38 and 40 contain pointed ends and openings through which air and liquid can pass into and out of the interior of the tubes, respectively, as needed during the fluid transfer operation. The proximal end of the air tube 38 extends within the interior of the proximal air chamber 32 in the syringe 12. In the illustrated embodiment of the invention, the air tube 38 passes through the piston 28 and continues inside the hollow piston rod. Air flowing through the tube 38 enters the interior of the piston rod / leaves it and leaves the air chamber 32 / enters it through the piston rod directly above the piston. The proximal end of the fluid tube 40 terminates at or slightly closer to the top of the needle holder such that the fluid tube is in fluid communication with the distal fluid chamber 30 through the interior of the syringe neck 12.

The actuator 34 of the double membrane seal comprises a housing that holds a proximal disc-shaped membrane 34a having a rectangular cross-section and a two-level distal membrane 34b. The distal portion of the distal membrane 34b projects in the distal direction from the actuator 34. Two or more elastic elongated brackets 35 of equal length are fixed to the distal end of the housing of the actuator 34. The brackets end in distal enlarged elements. When the actuator 34 is in the first position, the pointed ends of the tubes 38 and 40 are held between the proximal and distal membranes, preventing the pointed ends from being exposed to the user and from being injured by them, and also isolating the ends of the tubes 30 and 40 from the environment, thereby preventing contamination of the internal space of the syringe 12 and leakage of a harmful drug,

- 1 047655 contained in its internal space, into the environment.

The connecting section 14 is configured to be releasably connected to another fluid transport component, which may be any fluid container with a standard connector, such as a medicine bottle, an intravenous infusion bag, or a dropper, to form a fluid transfer unit through which fluid is transferred from one fluid transport component to another.

Pharmaceutical companies typically supply drugs in drug vials in powder or liquid form. These drug vials contain an elastomeric membrane at the top of the vial that can be pierced with a syringe needle to dilute (reconstitute) the powder with a suitable solvent and withdraw the required dose of liquid drug from the vial for administration to the patient. When liquid is pumped into or withdrawn from a drug vial by piercing the membrane with a syringe, excess pressure or vacuum is created in the vial that can interfere with the transfer process. To ensure equalization of pressure within the vial as liquid is pumped into or withdrawn from it, an intermediate connection known as a vial adapter is used.

Fig. 2 and 3 show, respectively, a perspective view and a sectional view of an adapter 15 for a vial of the prior art, which is formed as part of the device 10 for transferring liquid. The adapter 15 for a vial is an intermediate connection, which is used to connect the connecting section 14 to a vial 16 for medicines or any other component having an opening of a suitable shape and size.

The adapter 15 for the vial comprises a collar portion 42 provided with an annular proximal cap 44, and an upwardly projecting structure 46 projecting in the proximal direction from the cap 44. The upwardly projecting structure 46 is the second reason for using the adapter for the vial. It is much longer than the neck of a traditional medicine bottle, and therefore fits into an opening at the distal end of the connecting section 14, allowing the transfer of the medicine, as will be described later in this document. The cuff portion 42 consists of a set of peripheral segments 48 formed by a convex edge 50 on its inner surface to ensure fastening to the head portion of the bottle 14. The structure 46 protruding upward ends in the proximal direction with a membrane shell 52 having a diameter larger than that of the extension 42. The membrane shell 52 contains a proximal central opening 54 which provides access to the membrane 15a fixed therein.

Two longitudinal channels 56 and 58, which are formed inside the upwardly projecting structure and which extend in the distal direction from the membrane in the membrane shell, are designed to receive tubes 38 and 40, respectively. A mechanical guiding mechanism is provided, which ensures that the tubes 38 and 40 will always enter the channel intended for them inside the upwardly projecting structure, when the connecting section 14 is combined with the adapter 15 for the vial. The upwardly projecting structure 46 ends in the distal direction with a tenon element 15b, which projects in the distal direction from the cover 44. The tenon element 15b is formed with openings 60 and 62, connected to the channels 56 and 58, respectively.

The bottle 16 comprises an enlarged round head portion 64, fixed to the main body of the bottle by a narrowed portion. In the center of the head portion 64 there is a proximal membrane 16a, which is designed to prevent leakage of the medicinal product contained therein. When the head portion of the bottle 16 is inserted into the cuff portion of the adapter 15 for the bottle and a force is applied to the adapter 15 for the bottle in the distal direction, the spike element 15b of the adapter 15 for the bottle pierces the membrane 16a of the bottle 16, ensuring communication of the internal channels in the adapter 15 for the bottle with the internal space of the bottle 16 for medicinal products. When this occurs, the peripheral segments 48 at the distal end of the cuff portion 42 of the connecting section are securely engaged with the head portion of the vial 16. After the membrane 16a of the vial 16 is punctured, it is sealed around the pin, preventing the medicinal product from leaking out of the vial. At the same time, the upper parts of the internal channels in the adapter 15 for the vial are sealed by the membrane 15a in the upper part of the adapter 15 for the vial, preventing air from entering the internal space of the vial 16 or the medicinal product from leaking out of it.

The assembly procedure of the device 10 for transferring medicinal products is performed as follows.

Step 1 - after connecting together the vial 16 and the vial adapter 15, with the spike element 15b penetrating through the proximal membrane 16a of the vial, the head part of the vial adapter 15 is placed close to the distal opening of the connecting section 14.

Step 2 - Initialize the double membrane engagement procedure by displacing the body of the connecting section 14 in an axial direction until the membrane shell and the upwardly protruding structure of the adapter 15 for the vial enter the opening on the distal

- 2 047655 end of connecting section 14.

Step 3 - the distal membrane 34b of the actuator 34 is caused to come into contact with the fixed membrane 15a of the adapter 15 for the vial and to be pressed against it by means of an additional displacement in the distal direction of the housing of the connecting section 14. After the membranes are tightly pressed against each other, the enlarged elements at the ends of the brackets of the connecting section 14 are pressed into the narrower proximal section of the connecting section 14, thereby holding the membranes pressed against each other and engaged around the upwardly projecting structure and under the membrane shell of the adapter 15 for the vial, thereby preventing the disconnection of the actuator 34 of the double membrane seal and the adapter 15 for the vial.

Step 4 - additional displacement in the distal direction of the housing of the connecting section 14 causes the actuator 34 to move in the proximal direction relative to the housing of the connecting section 15 until the tips of the tubes 38 and 40 pierce the distal membrane of the actuator 34 and the membrane in the upper part of the adapter 15 for the vial and receive hydraulic communication with the internal space of the vial 16.

After the assembly of the drug transfer unit 10 shown in Fig. 1 as described herein above, the plunger rod can be moved to withdraw liquid from the vial 16 or to pump liquid from the syringe into the vial. The transfer of liquid between the distal liquid chamber 30 in the syringe 12 and the liquid in the vial 16 and the transfer of air between the proximal air chamber 32 in the syringe 12 and the air in the vial 16 occurs due to the process of equalizing the internal pressure in which equal volumes of air and liquid are exchanged by moving through separate channels. This is a closed system that eliminates the possibility of exchanging air, liquid droplets or vapors between the interior of the unit 10 and the environment.

Despite the care that has been taken to separate the air path through the air passage 56 and the air tube 38 from the liquid path through the liquid passage 58 and the liquid tube 40, in the prior art assembly described in U.S. Patent 8,196,614 there are locations where these paths intersect under certain conditions, allowing liquid to migrate through the air tube from the distal liquid chamber 30 or vial 16 to the proximal air chamber.

Solutions to this problem are described in U.S. Patent 9,510,997, owned by the applicant of the present invention. One of these solutions is to introduce a hydrophobic filter membrane 66 at some point in the air passage 38, 58 between the bottle 16 and the proximal air chamber 32. Such a filter, for example a 0.22 μm filter, will not only prevent liquid from entering the proximal air chamber, but will also improve protection against microbial contamination due to additional air filtration.

The location that was identified as the most effective and technically simple to manufacture for inserting the filter into the air duct is in the adapter 15 for the bottle.

Fig. 4 is a sectional view of a modified adapter 15 for a bottle containing a filter membrane 66. The filter is made of a very thin piece of material in a disc shape. An opening is cut in it to allow liquid to pass freely through a liquid passage 58 from the membrane 15a to an opening 62 in the tip of the spike element without passing through the filter 66. The filter 66 is welded or glued or mechanically pressed into the adapter for the bottle at its outer perimeter 67 and inner perimeter 67a. Air moves from the opening 60 in the tip of the spike element 15 through the air passage 56 into the open space formed by the ribs 56 below the filter 66, passes through the filter 66 into the open space above the filter and into the continuation of the air passage 56, passing through the upwardly protruding structure 46 to the membrane 15a.

The pressure exerted on the filter 66 by air or liquid flowing through the air passage 56 may be great enough to tear the filter or cause it to collapse or clog the filter 66 with liquid - even to such an extent as to block the air passage 56. Therefore, in order to provide mechanical support to withstand the pressure, prevent tearing and keep the filter straight and flat, the filter 66 is placed between a plurality of closely spaced support ribs 68 at the top and bottom.

A problem that often occurs with prior art vial adapters is that due to improper fixing of the vial adapter to the vial, they are susceptible to leakage of liquid and vapors into the environment, and vice versa, the drug in the vial is susceptible to microbial contamination when air from the environment enters the vial. The reason for this problem is that when fixing the vial adapters manually, the spike is often not properly centered and/or is usually inserted into the vial stopper at an angle. Such inaccuracy will result in rupture of the rubber stopper of the vial when the vial adapter is fully installed on the vial and the locking wings force the spike and adapter to be centered.

US Patent 9,510,997 describes a vial adapter designed to overcome the problem

- 3 047655 problems of rubber stopper rupture due to imprecise insertion of the vial adapter pin. The vial adapter in this application consists of two parts - a lower part adapted to be secured to the head of a standard drug vial, and an upper part which is adapted to be connected to the lower part as well as to another component of the medical transfer system, such as a connecting section of the drug transfer device described herein above, or a syringe.

The method of operation of this vial adapter consists of holding the spike closed and away from the rubber stopper of the vial until the vial adapter is properly positioned and locked onto the head of the vial. At this stage of fixation, the spike does not yet contact the stopper. Proper positioning and locking achieved in this way ensures that the spike is fixed in a centered and perpendicular position relative to the rubber stopper. Only then is the vial adapter ready for further advancement in the axial direction guiding the spike to accurately pierce the stopper until the vial adapter in its final position is permanently fixed onto the vial.

It is important to emphasize that the procedure is described in this document as consisting of several stages; however, this is done only for the convenience of describing the procedure. It should be understood that in practice, the procedure for reliable engagement using this invention is carried out by one smooth movement in the axial direction.

Fig. 5a and 5b are perspective views showing different views of the lower portion 202 of the bottle adapter of U.S. Patent 9,510,997. The lower portion 202 is a generally cylindrical structure with a hollow interior. The lower portion of the structure has an interior diameter slightly larger than the closure of the bottle to which it will be connected. On the inside of the lower portion 202 is a plurality of inwardly facing teeth 206. The teeth 206 are at the end of flexible arms that allow the teeth 206 to be pushed radially outward and then snap back into their original position when the outward force acting on them is removed. On the inside of the lower part 202, a set of inwardly facing teeth 208 are also visible, connected to the teeth 206. On the outside of the brackets to which the teeth 206 are attached, there are projections 210 for fastening the two parts of the adapter for the bottle to each other.

Fig. 6 shows the upper part 204 of the adapter 200 for the vial. The upper part 204 is a generally cylindrical structure. In the center of said structure there is a downwardly projecting pin 218, which is in fluid communication with an upwardly projecting structure 220, which is designed to be connected in a standard way to another component of the system for carrying drugs. At least two wings 216 project downwardly, some of which contain windows 214, which play a certain role in connecting the upper part 204 to the lower part, as will be explained later in this document.

Not shown in the figures are the air and liquid channels that pass through the interior of the bottle adapter 200 from the membrane at the upper end of the structure 220 to the tip of the spike 218. The membrane and channels indicated are similar to the membrane 15a and channels 56 and 58 shown in Fig. 4.

Fig. 7a and 7b are perspective views showing different views of the adapter 200 for the bottle. The upper part 204 is placed and fixed on the lower part 202 in a first fixed configuration. In Fig. 7a, it can be seen how the projections 210 on the lower part 202 enter the windows 214 on the wings 216 of the upper part 204, fixing the two parts of the adapter 200 for the bottle to each other in such a way that they cannot move relative to each other even when pressed. In Fig. 7a also shows latches 212 with inwardly facing teeth on the lower edge of the lower portion 202 and an outwardly facing projection 222 around the perimeter of the upper portion 204. The latches 212 and the projection 222 cooperate to secure the upper portion 204 to the lower portion 202 in a second fixed configuration described herein below.

Fig. 8-11 show various stages of telescopic attachment of the bottle adapter 200 to the bottle.

In the first stage, shown in Fig. 8, the bottle cap has not yet entered the interior of the lower part of the bottle adapter 200. In the enlarged detail A, it can be seen how the projections 210 of the lower part 202 enter the windows 214 on the wings 216 of the upper part 204, fixing the two parts to each other.

In the second stage, shown in Fig. 9, the bottle cap begins to enter the interior of the lower part of the bottle adapter 200. In the enlarged detail A, it can be seen how the teeth 206 and the teeth 208 are pushed radially outward by the bottle cap, while the wings 216 are pushed radially by the back of the teeth 208. The projections 210 of the lower part 202 are inserted into the windows 214 on the wings 216 of the upper part 204, holding the two parts fixed together and not yet allowing the parts 104 and 202 to enter each other.

In the third stage, shown in Fig. 10, the bottle cap has entered the interior of the lower part of the bottle adapter 200 to the end. In the enlarged detail A, it can be seen how the teeth 208

- 4 047655 continue to push the wing 216 in a radial direction outward. At the same time, the bottle cap no longer pushes the teeth 206 in an outward direction, allowing the bracket to which the teeth 206 and the projections 210 are attached to spring in a radial direction inward. As a result, the teeth 206 move under the edge of the cap, firmly fixing the bottle in the adapter 200 for the bottle, and the projections 210 of the lower part 202 exit the windows 214 on the wings 216 of the upper part 204, thereby stopping the fixation between the two parts.

It should be noted that at this stage the pin has not yet come into contact with the stopper at the top of the bottle; for this all the locks must open, which indicates that the adapter is completely secured and that the pin is in a centered and perpendicular position with respect to the rubber stopper of the bottle and is ready for precise piercing. If at least one of the locks is not opened, the parts 202 and 204 will not move until all are in place and unlocked. As a result, when in the fourth stage shown in Fig. 11 the upper part 204 of the bottle adapter is pushed downwards towards the bottle, the pin is pushed through the stopper of the bottle exactly in the center and perpendicular to the stopper of the bottle. When the upper part 204 slides over the lower part 202, the wings 216 slide over the sides of the bottle and grip them, giving greater reliability to the connection. Eventually, the teeth on the top of the latches 212 slide over the top of the projection 222, locking both parts of the adapter 200 for the bottle together, thereby preventing a reverse movement that could pull the spike out of the bottle. In embodiments of the adapter for the bottle, the latches 212 are designed in such a way that both an audible sound and a visual observation will confirm to the user that the fastening process is complete.

Fig. 12 shows the vial adapter 200 permanently secured in its final position on the medical vial.

An embodiment of the vial adapter 200, intended for connection to transfer devices such as those described herein above, may be equipped with a filter located, for example, in the upper portion 204 above the spike, as described herein above for the vial adapter 15 (see Fig. 4).

Fig. 13 is a sectional view showing a spike connector 160 used in combination with a fluid transfer device 10 for transferring a drug into and out of an intravenous (IV) infusion bag. The spike connector 160 comprises a body 162 ending with a spike element 164 at the proximal end and a standard unscrewing end 166 of the spike channel for connecting to an infusion system at the distal end. A longitudinal extension 168 is located substantially at a right angle to the housing 162. At the end of the longitudinal extension 168 are a membrane shell 170 and a membrane 172. The interior of the spike connector 160 contains two separate channels 174 and 176 for liquid and air from the tip of the spike element 164 to the membrane 172. The connecting section 14 with an attached syringe can be connected to the longitudinal extension 168 exactly as described in this document above with respect to the adapter 15 for the vial of Fig. 3, thereby allowing the introduction of a drug from the syringe into the IV bag or the withdrawal of liquid from the IV bag into the syringe for use in reconstituting the drug.

The vial adapters and other components described herein above are presented to demonstrate the operating principles of the Equashield® closed drug delivery systems. Over the years, many improvements have been developed and manufactured to these components. For example, many of these improvements have been made to the connecting section 14, in particular to the actuator that holds the membrane that seals the connecting section to the vial adapter. The actuator 34 of the double membrane seal shown in Fig. 1a has now been replaced by a single membrane septum holder. The latter embodiment is described in co-pending Israeli Patent Application No. 261,024, owned by the applicant of this application. An exploded view of this septum holder, which contains a movable septum, is shown in Fig. 14.

The partition holder 500 consists of a housing part 560 and a support 561 for the partition. The housing part 560 has an upper surface of a disc-shaped form and side elements 592 that project downwards from the upper surface. The elements 592 can have other shapes and sizes than those shown in the figures. Two elastic elongated brackets 562 of equal length, which end in distal enlarged elements 563, are fixed on its side sides, projecting vertically downwards parallel to each other, as shown in Fig. 14. Two pairs of projecting elements 577 project vertically downwards from the lower surface of the housing part 560. Each pair of projecting elements 577 forms a gap 578 between the elements of the pair. The gaps 578 extend vertically upwards through the upper surface of the disc-shaped form of the housing part 560. In Fig. 14 also visible are one of the two windows 580 and one of the two slots 589 in the elements 592 of the housing part 560 and the openings 579 that pass through the upper surface of the housing part 560.

In the embodiment of the invention shown in the figure, the support 561 for the partition consists of

- 5 047655 seats 582 of a partition of a disc-shaped form, from which two elastic elongated brackets 586 project upwardly parallel to the brackets 562. At the lower end of each bracket 586 there is a stop 590 projecting outwardly, and at the upper end of each bracket 586 there is an element 588 of a tooth-shaped form projecting outwardly, comprising a lower horizontal surface and an upper inclined surface. Insert 568, which in this embodiment of the invention comprises two channels 570 (in an embodiment of the invention that is not shown, it comprises only one channel), forms seats of two needle valves. One or two holes 579 (depending on the embodiment of the invention) made in the housing part 560 allow the needles to pass through the holder 500 of the partition. The insert 568 passes through the opening 584 in the seat 582 of the partition and is held in place by small pins 581 and 583. The lower rim of the partition 572 is formed in the form of an inwardly projecting edge, which, when pushed along the seat 582 of the partition, holds the partition 572 on the seat 582 of the partition.

Due to the length of the brackets 586 of the support 561 of the partition and other features of the holder 500 of the partition, the seat 582 of the partition, the fixed insert 568 and the partition 572 can be held releasably in the unlocked configuration and moved relative to the body part 560 to be fixed in the locked configuration.

In co-pending Israeli Patent Application No. 257,778, the applicant for this invention describes a new device for securing a plug-and-socket connection. The device comprises: a socket connector comprising a locking actuator section; a plug connector, one or more anchor projections; and at least one rotating gear. The device is shown for use in connecting components of a system for transferring liquids between two containers, such as from a medicine vial to a syringe or vice versa.

Fig. 23 is a perspective view of the housing of an embodiment of a socket connector 1201, in which the interior of the receiving section 1202 is visible through an opening 1203 on the proximal side of the connector 1201. A ladder 1204, containing a plurality of steps (for example, 1205), is formed on the front or back side of each of the left and right sides of the interior of the receiving section 1202. A guide bar 1206 is formed on the opposite (i.e., back or front) side of each of the left and right sides of the interior of the receiving section 1202. A track, generally indicated by the numeral 1207, is formed between the guide bar 1206 and the ladder 1204, along which a gear can move in the longitudinal direction, provided that the gear has teeth, the size of which corresponds to the gaps between the steps 1205.

Fig. 24 is a perspective view of a locking actuator 1401, respectively comprising rotating gears 1402, rotatably connected to a guide 1403 on each side of a base 1407. Each gear 1402 comprises a plurality of teeth (e.g. 1404), arranged along the perimeter around a hollow portion 1405, in which a gap 1406 is formed by removing a part of the periphery, thereby providing access from outside the periphery of the gears into the hollow portion. Not shown in Fig. 24 is a membrane (see Fig. 28 - reference number 1706), which is fixed to the lower part of the base 1407.

Fig. 25 is a perspective view with a partial section of the socket connector 1201 with the locking actuator 1401 present therein. The guides 1403 are arranged on the tracks 1207 in such a way that the teeth of each gear 1402 are inserted between the steps 1205 of the ladder 1204. The longitudinal movement of the actuator 1401 along the tracks 1207 causes the gears 1402 to rotate due to the teeth being forced to rotate about their axis of rotation. Accordingly, the orientation of the gap 1406 relative to the opening 1203 changes with the longitudinal movement of the actuator 1401.

Fig. 26 is a sectional view of the projecting portion 1222 of the plug connector 1221. The projecting portion 1222 may be, for example, the upwardly projecting structures of the bottle adapters shown in Fig. 5a-12, or the tenon connecting element shown in Fig. 13. On opposite sides of the recess surrounding the membrane 1224, in the upper part of the projecting portion 1222, there are two anchor projections 1223.

Fig. 27a-27c show a perspective view of the projecting portion 1222 of the plug connector inserted into the receiving section 1202 of the socket connector 1201 (shown in a partially cut-away view). The width of the anchor projections 1223 corresponds to the size of the gaps 1406 such that the projections 1223 can pass through the gaps 1406 and fit into the hollow portions 1405. The height and depth of the anchor projections 1223 correspond to the diameter and depth of the hollow portions 1405, respectively, such that the gear 1402 can rotate freely while the projection 1223 is present inside the hollow portion 1405. Fig. 27a shows the anchor projection 1223 inserted through the gap 1406 into the hollow portion 1405. In this position, rotation of the gears 1402 is impossible, since the gaps 1406 of the gears engage the anchor projections 1223 from the side, and therefore any movement of the actuator 1401 as a whole is impossible. Upon further insertion of the protruding portion

- 6 047655 ka 1222 into the receiving section 1202, the anchor projection 1223 passes completely through the gap 1406 and is located inside the hollow part 1405, as shown in Fig. 27b. When the protruding portion 1222 continues to be inserted into the receiving section 1202, the gear 1402 rotates in accordance with the direction set by the ladder 1204 (that is, clockwise in the embodiment of the invention shown in Fig. 27c, as indicated by the round arrow A). With the initial rotation of the gear 1402, the anchor projections 1223 are captured and locked inside the hollow part 1405 and remain locked throughout the entire process of connection and disconnection. For the above-mentioned process of compression of two elastic membranes, the moment of initial rotation of gears 1402 means the exact position of blocking of membranes in a certain inseparable compression. Further introduction of projecting section 1222 into receiving section 1202 leads to piercing of blocked membranes above fixed needles of socket connector.

In the position of the actuator 1401 shown in Fig. 27c, the anchor projections 1223 cannot emerge from the hollow portions 1405, and therefore the proximal displacement of the projecting portion 1222 of the plug connector 1221 is prevented, unless the gear 1402 rotates and the anchor projections 1223 are released from the gears. Of course, as will be obvious to one skilled in the art, in any position of the gear 1402 along the ladder 204, in which the gap 1406 is not opposite the opening 1203, the anchor projections 1223 are retained within the hollow portion 1405.

When disconnecting the socket connector 1201 and the plug connector 1221, the process is reversed, the extraction of the projecting portion 1222 from the receiving section 1202 causes the gear 1402 to rotate counterclockwise along the ladder 1204 until the anchor projections 1223 are opposite the gap 1406 and are able to exit the hollow part 1405. During the disconnection in the above-mentioned parallel extraction process, the needles first exit the membranes, and at the moment when the anchor projections 1223 are opposite the gap 1406 and exit the hollow part 1405, the membranes are safely separated, leaving their surfaces clean of any liquid residues.

Fig. 28 schematically illustrates the socket connector 1201 and the connected syringe 1704 of the drug delivery system in a sectional view. When the actuator 1401 is in its lower position in the socket connector 1201, the needles 1703 and 1705 are located in the space above the membrane 1706, and their tips are isolated from the surrounding space. When the actuator 1401 is pushed in an upward direction (in Fig. 28 artificially without inserting the plug connector), the needles 1703 and 1705, which in this particular embodiment of the invention are part of the connector 1201, pierce the membrane 1706.

Fig. 29 shows a side view in section of the plug 1221 and socket 1201 connectors in a position in which the actuator 1401 with the plug connector 1221 secured by means of projections 1223 locked inside the gears 1402 is pushed upwards as far as possible inside the receiving section 1202 of the socket connector 1201, until their relative membranes 1224 and 1706 are pressed against each other, and the needles have pierced both membranes and are inside the vial.

All of the advanced components described in this document above contain separate internal passages for air and liquid to provide pressure equalization when liquid is transferred from one container to another without venting or introducing air to the atmosphere.

In order to provide maximum benefits to users of the Equashield® closed drug transfer systems, the applicant has developed a fully automated robotic system that is designed to assist in a hospital pharmacy in the preparation of medicinal products containing hazardous drugs and in the preparation of syringes and IV bags containing the required amount of liquid drug for administration to patients according to their individual prescriptions. The said system is described in detail in U.S. Patent No. 10,181,186. The system comprises a biological safety cabinet and at least two robotic arm assemblies configured to simultaneously move vials and syringes within the safety cabinet. Each of the robotic arm assemblies comprises three mechanical devices configured to independently move either a vial gripper assembly or a syringe gripper assembly and a syringe infusion pump in three dimensions along three mutually perpendicular axes. Inside the cabinet there is a plurality of work stations configured to perform specific tasks associated with the process of preparing prescription drugs. The workstations comprise: at least one reconstitution module configured to accept at least one vial and introduce a predetermined volume of liquid into the vial; at least one vial shaking module configured to accept one or more vials containing reconstituted medicinal products and shake for a predetermined period of time and in a predetermined shaking method; at least one vial inversion module configured to accept at least one vial and invert it.

- 7 047655 vials; at least one base module for IV bags, to which the system operator can attach IV bags; a syringe magazine; a set of cameras, each of which is installed in a specific location in a safety cabinet or on robotic manipulator units, and a processor. Each of the cameras is designed to provide real-time digital images of a stage of the manufacturing process carried out at the location of its location. Special software and algorithms in the system processor allow the robotic manipulator units to automatically perform virtually all stages of the process of manufacturing drugs according to a prescription without the intervention of an operator or observer, and the cameras and image processing algorithms are designed with the ability to ensure control of all stages of the process of manufacturing drugs according to a prescription in real time with feedback.

Fig. 22a is a schematic illustration of a safety cabinet with a portion of the outer walls and inner partitions removed to show the arrangement of the interior space for receiving vials, syringes and IV bags that an operator loads into it. Fig. 22 shows a work surface 816, a vial insertion area 842, two base modules 826(1) and 826(2) for IV bags, two robotic manipulator assemblies 838 for syringe infusion pumps, a syringe magazine 840 and a robotic manipulator assembly 828 for vials.

Fig. 22b schematically shows the robotic manipulator unit 828 for vials. The robotic manipulator unit 828 for vials, under the control of the system software, is configured to pick up vials from the vial insertion zone 842, move them to any location on the working surface 816 behind the internal partition; connect them to the recovery module, shaking and inverting mechanisms and separate them from them; and release them in a new location on the working surface 816 or in a waste container. The degrees of mobility necessary to perform these tasks are provided by a mechanical device, such as an x-axis motor and gearbox 848, which turns a screw, chain, or belt that moves the y-axis motor and gearbox 852 in the x-direction along the x-axis 850. The y-axis motor and gearbox 852 turns a screw that moves the z-axis motor and gearbox 856 in the y-direction along the y-axis 854. The z-axis motor and gearbox 856 moves the vial gripper assembly 860 up and down in the z-direction along the z-axis 858. The motors 848, 852, and 856, as well as all other motors in the system, are reversible electric motors.

Fig. 22c schematically shows the vial gripping unit 860. The main components of the vial gripping unit are a motor 868, a load cell 870 that provides an estimate of the amount of drug in the vial, and a vial gripping mechanism 866 that is configured to connect to an adapter 864 for a vial. In order to pick up a vial, the control system activates the motors 848 and 852 that position the vial gripping mechanism directly above the adapter 864 for a vial that is secured to the vial 862, then it activates the motor 856 that presses the vial gripping mechanism 866 against the adapter 864 for a vial.

Fig. 22d schematically shows a robotic arm assembly 838 for syringe infusion pumps. The robotic arm assembly for syringe infusion pumps, under the control of the system software, is configured to (1) move the syringe infusion pump in order to remove an empty syringe from the syringe magazine; (2) move the syringe to the appropriate location under the work surface 816; (3) connect the syringe to one of the vials (via a vial adapter) in the vial inverting mechanisms; (4) withdraw liquid from the vial; (5) separate the syringe; (6) move the filled syringe and connect it to the IV bag via a pin connector connected thereto; (7) wait for activation of the syringe infusion pump 36 to inject the contents of the syringe into the IV bag; and (8) repeating the process until the appropriate dose has been injected into the IV bag, and finally moving the empty syringe to the waste container and emptying it therein. The robotic arm assembly for syringe infusion pumps performs steps (1) through (8) with the necessary modifications in cases where the prescribed drug is administered to the patient in a cartridge of the infusion pump. In case the drug is administered to the patient by injection from a syringe, the robotic arm assembly for syringe infusion pumps performs steps (1) through (4), and then connects the syringe to the protective plug on the base module 826 for IV bags and leaves it there, i.e., releases its grip. The operator then pulls the safety plug out of its mount with the syringe attached to it through the slot in the working surface 16 and takes the syringe with the attached plug out of the safety cabinet through the open front part of the safety cabinet above the surface 816.

The unit 838 of robotic manipulators for syringe infusion pumps is configured to pick up syringes and move them to different stations under the working surface 816. The degrees of mobility necessary to perform these tasks are provided by the motor and gearbox 124 of the x-axis, which, for example, turns a screw that moves the motor and gearbox 128 of the y-axis in the x-direction along the x-axis 130. The motor and gearbox 128 of the y-axis turns a screw that moves the motor and gearbox 132 of the z-axis in the y-direction along the y-axis 130. The motor and gearbox 132 of the z-axis moves the syringe infusion pump 36 up and down in the z-direction along the z-axis 134.

Fig. 22e schematically shows the syringe infusion pump 836. The syringe 122 is firmly secured

- 8 047655 flax in the housing 136 with the help of the mechanism 144 of gripping the syringe barrel and the mechanism 146 of gripping the lower part of the syringe. The tip of the piston is fixed in the mechanism 140 of gripping the syringe piston. The mechanism 140 of gripping the syringe piston can move up and down along the guide strips 142 of the pump with the help of the lead screw 138, which is rotated by the motor and the gearbox inside the housing 136; thereby drawing liquid into the syringe barrel or throwing it out of it.

In this field of technology, compared to closed transfer systems for hazardous drugs, the use of open transfer systems for safe drugs is much more common. In open systems, pressure equalization during the liquid transfer operation is carried out by releasing air into the environment if there is excess pressure in the system, or by drawing atmospheric air in if the pressure in the system is reduced.

Safety considerations and regulations for handling hazardous drugs require that the Equashield® system has a closed design with special components that allow closed operation, and the components of the Equashield® closed drug transfer systems must be made of relatively expensive and difficult to handle materials with very tight tolerances. Therefore, although the components produced for hazardous drugs can also be used for safe drugs, for use with the latter it would be desirable to provide components for an open transfer system that retain the advantages of a closed drug transfer system, i.e., ease of handling and connection, both manually and by means of a robotic system.

The object of the present invention is to provide components for an open transfer system that provide simple, fast and safe handling and connection.

Another object of the present invention is to provide components for an open transfer system that are capable of being used in a robotic system designed to assist in a hospital pharmacy in the preparation and preparation for administration of medical preparations containing safe drugs.

Additional objects and advantages of the present invention will be presented as the description progresses.

The essence of the invention

The document presents, in a first aspect of the invention, a robotic system for manufacturing and preparing medical preparations containing safe drugs. The system comprises: a cabinet with a laminar air flow; at least one robotic manipulator; and at least one adapter for a drug vial communicating with the atmosphere. The adapter for a drug vial communicating with the atmosphere comprises a hydrophobic ventilation filter. The adapter for a drug vial and the robotic system are configured to extract liquid from the drug vial and place it in the drug vial.

Embodiments of the robotic system comprise: (i) at least two robotic arm assemblies configured to prepare syringes and intravenous (IV) infusion bags containing a prescribed amount of liquid medication for administration to patients according to their individual prescriptions by moving vials for medications, to which vial adapters communicating with the atmosphere are connected, and syringes within a cabinet with a laminar air flow, (ii) chambers, and (iii) a system processor containing software containing image processing algorithms that are configured to provide feedback control in real time of all stages of the process of manufacturing drugs according to the prescription.

In embodiments of the robotic system, the nodes of the robotic manipulator are designed with the ability to move in three mutually perpendicular directions.

The embodiments of the robotic system comprise at least two robotic manipulator units capable of moving in three mutually perpendicular directions for preparing syringes and IV bags containing the required amount of liquid medicine for administration to patients according to their individual prescriptions by moving vials for medicines, to which adapters for the vial communicating with the atmosphere are connected, and syringes, to which connecting sections are connected, within a cabinet with a laminar air flow, a chamber, and a system processor containing image processing algorithms that are capable of providing feedback control in real time for all stages of the process of manufacturing drugs according to the prescription. These embodiments of the invention are characterized in that:

a) each of the connecting sections contains one of the following elements:

(i) a partition holder comprising two elastic elongated brackets which project vertically downwards parallel to each other, fixed to the side of the housing part, each bracket comprising projections of a special shape on the inner side of the distal ends of the brackets; or

- 9 047655 (ii) a section of a locking actuator comprising at least one step formed on the inner wall of the connecting section and at least one rotating gear comprising teeth arranged along the perimeter around the gear, a hollow portion configured to accommodate an anchor protrusion, and a gap formed in the gear such that the hollow portion has an opening whose orientation changes with rotation of the gear;

b) each of the vented vial adapters comprises one of the following:

(i) an upwardly projecting portion comprising a membrane at a proximal end and sockets on the outer side of the proximal end, wherein said sockets have a shape and dimensions adapted to align with specially shaped projections on the inner side of the brackets of the partition holder; or (ii) an upwardly projecting portion comprising a membrane at a proximal end and anchor projections on the outer side of the proximal end, wherein said anchor projections have a shape and dimensions adapted to pass through a gap and enter a cavity in a gear of a section of the locking actuator of the connector.

As a result of these characteristics, the connecting sections can only be connected to drug vials that are connected to vented vial adapters that contain compatible sockets or anchor projections on the outer surface.

In embodiments of the robotic system, the specially shaped protrusions are located on the outer side, protruding upwardly, of the structure of the adapter for the vial, and the corresponding sockets are located on the inner side of the brackets of the partition holder in the connecting section and the holder, as well as on the distal end of the gripping mechanism assembly.

The embodiments of the robotic system comprise a spike connector element configured to be connected to an intravenous (IV) infusion bag. The spike connector element comprises:

a) a housing terminating in a tenon element at the proximal end of the housing, said tenon element comprising separate channels for liquid and air;

b) a standard port for connection to an infusion system at the distal end of the body, said standard port being in fluid communication with an air channel in the spike; and

c) a longitudinal extension connected substantially at a right angle to the body, wherein the proximal end of said longitudinal extension comprises a membrane and is configured to be connected to the connecting section, and wherein said longitudinal extension comprises a fluid channel having a hydraulic communication with a fluid channel in the spike.

The tenon connecting element is characterized in that the said longitudinal extension comprises one of the following elements: (i) a socket having a shape and dimensions made with the possibility of being combined with projections of a special shape on the brackets of the partition holder; or (ii) anchor projections having a shape and dimensions made with the possibility of passing through a gap and entering a cavity in the gear of the section of the locking actuator of the connecting section; thus, the tenon connecting element has the possibility of connecting only with the connecting section, which contains either a partition holder containing compatible projections, or a section of the locking actuator containing a compatible gap and a hollow part.

In embodiments of the robotic system, the cameras and software are configured to recognize nests, protrusions, gaps, hollow parts and anchor protrusions and to warn the user if the wrong components are introduced into the cabinet; and the robotic manipulator units contain mechanical parts that ensure that only components compatible with the open transfer system are used.

In embodiments of the robotic system, the robotic manipulator units configured to pick up, move and release syringes contain special mechanisms for gripping the connector and syringe in various orientations, and the system requires software configured to work with various syringes and various orientations, identifying them and reading the correct dosage; which allows the system to use conventional syringes from various manufacturers, of various shapes and sizes.

In this document, in a second aspect of the invention, there is provided an open system device for transferring liquid medicinal products, comprising a first embodiment of a first embodiment of a vial adapter communicating with the atmosphere and a connecting section; in which, A) the connecting section comprises:

a) a hollow outer body comprising a proximal end adapted to be connected to a conventional syringe and comprising an opening in its distal end adapted to allow insertion of a proximal end of a vented vial adapter for connection;

b) one hollow needle that functions as a tube for the liquid passing through the connector-

- 10 047655 section; and

c) one of the following elements:

(i) a partition holder comprising two elastic elongated brackets which project vertically downwards parallel to each other, fixed to a side of a housing part, each bracket comprising projections of a special shape on the inner side of the distal ends of the brackets; or (ii) a section of a locking actuator comprising at least one step formed on the inner wall of a connecting section, and at least one rotating gear comprising teeth arranged along the perimeter around the gear, a hollow portion configured to receive an anchor projection, and a gap formed in the gear such that in the hollow portion there is an opening, the orientation of which changes with rotation of the gear; and B) a first embodiment of a vial adapter communicating with the atmosphere comprises:

a) a distal structure designed to allow the vial adapter to be secured to a medicinal vial;

b) a tenon element that projects downwards within the distal structure;

c) an upwardly projecting structure projecting upwardly from the distal structure, wherein the upwardly projecting portion comprises a membrane at its proximal end, wherein the proximal end of said upwardly projecting structure is configured to be connected to a connecting section;

d) a fluid channel formed inside the upwardly projecting structure and the spike element, wherein said fluid channel is configured to provide hydraulic communication through the bottle adapter from the openings in the tip of the spike to the proximally located membrane;

e) a hydrophobic filter located in the distal structure beneath the upwardly projecting structure; and

f) an air passage formed inside the bottle adapter at the proximal side of the hydrophobic filter and the spike element, wherein said air passage is configured to provide fluid communication through the bottle adapter from the openings in the tip of the spike to a ventilation opening located at the proximal side of the hydrophobic filter, providing fluid communication between the air passage and the space outside the bottle adapter; and

g) wherein the structure projecting upward comprises one of the following elements:

(i) sockets on the outer side of the proximal end, wherein said sockets have a shape and dimensions adapted to align with specially shaped projections on the inner side of the brackets of the partition holder; or (ii) an upwardly projecting portion comprising a membrane on the proximal end and anchor projections on the outer side of the proximal end, wherein said anchor projections have a shape and dimensions adapted to pass through the gap and enter a cavity in the gear of the connector locking actuator section.

The features of the projections, sockets, spaces and anchor projections allow the connecting sections to be connected only to vials for medicinal products connected to the first embodiment of the vented adapter for a vial containing compatible sockets or anchor projections.

In embodiments of the device of an open system for transferring liquid medicinal products, comprising a first embodiment of an adapter for a vial communicating with the atmosphere, projections of a special shape are located on the outer side, protruding in an upward direction of the structure of the adapter for a vial, and the corresponding sockets are located on the inner side of the brackets of the partition holder in the connecting section.

The embodiments of the device of an open system for transferring liquid medicinal products, comprising the first embodiment of an adapter for a vial communicating with the atmosphere, additionally comprise a spiked connecting element, designed with the possibility of connection to a bag for intravenous (IV) infusion.

The tenon connecting element contains:

a) a housing terminating in a tenon element at the proximal end of the housing, said tenon element comprising separate channels for liquid and air;

b) a standard port for connection to an infusion system at the distal end of the body, said standard port being in fluid communication with an air channel in the spike; and

c) a longitudinal extension connected substantially at a right angle to the body, wherein the proximal end of said longitudinal extension comprises a membrane and is configured to be connected to the connecting section, and wherein said longitudinal extension comprises a channel

- 11 047655 for liquid, having hydraulic communication with the liquid channel in the spike.

The tenon connecting element is characterized in that the longitudinal extension contains one of the following elements:

(i) a socket having a shape and dimensions adapted to mate with specially shaped projections on the brackets of the partition holder; or (ii) anchor projections having a shape and dimensions adapted to pass through the gap and to enter a cavity in the gear of the section of the locking actuator of the connecting section; thus, the tenon connecting element is capable of connecting only with the connecting section, which includes either a partition holder comprising compatible projections or a section of the locking actuator comprising a compatible gap and a hollow part.

In the embodiments of the device of the open system for transferring liquid medicinal products, the first embodiment of the adapter for the vial communicating with the atmosphere is replaced by a second embodiment of the adapter for the vial communicating with the atmosphere, which contains:

(a) a lower portion adapted to be secured to the head of a medical bottle or vessel or device of any type that contains a head similar to the head of a standard medical bottle;

(b) an upper portion containing:

(i) a central part of a disc-shaped form and a set of wings designed to ensure fixation of the upper part on the lower part, wherein said wings are fixed along the perimeter of said central part of a disc-shaped form and project in the distal direction from it;

(ii) an upwardly projecting structure projecting upwardly from said central disc-shaped part, said upwardly projecting structure being capable of being connected to a connecting section;

(iii) a membrane that seals the proximal end of said upwardly projecting structure;

(iv) a tenon element which projects distally from the center of said central disc-shaped part;

(v) an air passage and a liquid passage, both of which are formed within the bottle adapter on the proximal side of the hydrophobic filter and the spike element, said passages being configured to provide hydraulic communication through the bottle adapter from the membrane that seals the proximal end of the upwardly projecting structure to the openings in the tip of the spike;

(c) a first locking mechanism; and (d) a second locking mechanism;

(e) a flat hydrophobic filter of an annular shape located in the central part of the disc-shaped shape under the upwardly projecting structure, wherein the adapter for the bottle and said filter are designed to allow the passage of liquid flowing in the liquid channel through the adapter for the bottle without passing through the filter, and the filter is located with an intersection of the air channel, which allows air flowing through the air channel to pass through the filter and prevents liquid flowing through the air channel from passing through the filter;

in this case:

(i) the first locking mechanism is configured to lock the upper portion to the lower portion in such a way that the tip of the pin cannot come into contact with the plug in the head portion when the head portion is connected to the lower portion, and to release the upper portion from the lower portion after the lower portion is secured to the head portion;

(ii) the second locking mechanism is designed to ensure, after the lower part is secured to the head part, that the spike penetrates the plug in the head part and that the upper part is permanently fixed to the lower part;

(iii) the air passage above the filter comprises the entire internal volume of the upwardly projecting structure not occupied by the fluid tube and the vent on the side of the upwardly projecting structure that provides fluid communication between the air passage and the space outside the bottle adapter; and (iv) the upwardly projecting structure comprises one of the following:

(a) a socket having a shape and dimensions adapted to mate with specially shaped projections on the brackets of the partition holder; or (b) anchor projections having a shape and dimensions adapted to pass through the gap and enter the cavity in the gear section of the locking actuator of the connecting section; thus, the tenon connecting element is capable of being connected

- 12 047655 only with a connecting section that comprises either a partition holder containing compatible projections or a locking actuator section containing a compatible gap and a hollow portion.

In embodiments of the device of an open system for transferring liquid medicinal products, comprising a second embodiment of an adapter for a vial communicating with the atmosphere, projections of a special shape are located on the outer side, protruding in an upward direction of the structure of the adapter for a vial, and the corresponding sockets are located on the inner side of the brackets of the partition holder in the connecting section.

The embodiments of the device of the open system for transferring liquid medicinal products, comprising the second embodiment of the adapter for the vial communicating with the atmosphere, additionally comprise a spiked connecting element, made with the possibility of connection with a bag for intravenous (IV) infusion. The spiked connecting element comprises:

a) a housing ending in a tenon element at the proximal end of the housing, said tenon element comprising separate channels for liquid and air;

b) a standard port for connection to an infusion system at the distal end of the body, said standard port being in fluid communication with an air channel in the spike; and

c) a longitudinal extension connected substantially at a right angle to the body, wherein the proximal end of said longitudinal extension comprises a membrane and is configured to be connected to the connecting section, and wherein said longitudinal extension comprises a fluid channel having a hydraulic communication with a fluid channel in the spike;

The tenon connecting element is characterized by the fact that the longitudinal extension contains one of the following elements:

(i) a socket having a shape and dimensions adapted to mate with specially shaped projections on the brackets of the partition holder; or (ii) anchor projections having a shape and dimensions adapted to pass through the gap and enter the cavity in the gear of the locking actuator section of the connector;

Thus, the tenon connecting element has the ability to connect only with a connecting section that contains either a partition holder containing compatible projections or a section of the locking actuator containing a compatible gap and a hollow part.

All the above and other characteristics and advantages of the present invention will be more clearly understood thanks to the illustrative and non-limiting description of the embodiments of it with reference to the attached graphic materials.

Brief description of graphic materials

Fig. 1a and 1b are schematic sectional views of a device for transporting hazardous drugs without polluting the environment according to the prior art.

Fig. 2 and 3 show, respectively, a perspective view and a sectional view of an adapter for a prior art vial, which is designed as part of a device for transporting hazardous medicinal products without polluting the environment.

Fig. 4 is a sectional view of a modified adapter for the prior art vial of Figs. 2 and 3 containing a filter membrane.

Fig. 5a-12 are various views showing another embodiment of a prior art vial adapter which is formed as part of a device for transporting hazardous drugs without polluting the environment.

Fig. 13 is a sectional view showing a prior art spike connector used in combination with a fluid transfer device and a connecting section for transferring a drug into and out of an intravenous (IV) infusion bag.

Fig. 14 schematically shows an exploded view of a baffle holder for a single diaphragm valve actuator in a connecting section.

Fig. 15a is a sectional view schematically showing a vial adapter that is configured to be used in an open transfer system.

Fig. 15b schematically shows the bidirectional flow paths of liquid and air through the bottle adapter of Fig. 15a.

Fig. 16a and 16b show alternative locations for the vent hole in the vial adapter of Fig. 15.

Fig. 17 shows another embodiment of a vial adapter designed for use with an open transfer system.

Fig. 18a shows the open transfer system partially assembled for use.

Fig. 18b shows a sectional view of the open transfer system of Fig. 18a in a locked configuration.

- 13 047655

Fig. 18c shows a connecting section in the open transfer system of Fig. 18a.

Fig. 19a shows the open transfer system of Fig. 18a in a fully assembled configuration for transferring liquids.

Fig. 19b is a sectional view of the open transfer system of Fig. 19a.

Fig. 19c is an enlarged view of section A in Fig. 19b, focusing on the vial adapter and connected syringe connector.

Fig. 20a and 20b schematically illustrate elements that allow two components of an open transfer system to be connected to each other and prevent a component of an open transfer system from being connected to a component of a closed transfer system.

Fig. 21a schematically illustrates a tenon connecting element for connection to a high-voltage package.

Fig. 21b is a sectional view of the tenon joint element of Fig. 21a.

Fig. 22a is a schematic representation of the interior space of a safety cabinet of a robotic system for preparing drugs and medical preparations for administration to patients.

Fig. 22b schematically shows the robotic manipulator assembly for vials.

Fig. 22c schematically shows the bottle gripping unit.

Fig. 22d schematically shows a robotic arm assembly for syringe infusion pumps.

Fig. 22e shows schematically a syringe infusion pump.

Fig. 23 schematically illustrates a perspective view of the housing of a socket connector of the prior art.

Fig. 24 is a perspective view of a locking actuator of the prior art;

Fig. 25 is a perspective view with a partial section of the housing of the socket connector of Fig. 23 with the locking actuator of Fig. 24 present therein.

Fig. 26 is a sectional view of the upper portion of a plug connector of the prior art.

Fig. 27a-27c are perspective views with partial section of a plug part of the prior art inserted into the housing of the socket connector of Fig. 23 in several successive positions.

Fig. 28 is a sectional view showing the socket connector of Fig. 23 in which the actuator of Fig. 24 has been artificially moved upward for the purpose of clarity, without inserting the plug connector, thus exposing the needles which have passed through the membrane of the actuator.

Fig. 29 shows a sectional view of the socket and plug connectors of Figs. 26 and 25 in a position in which they are brought into close proximity in such a way that the relative pressure of their membranes against each other prevents leakage of liquid, and the needles have pierced both membranes and are located inside the vial, viewed from the front.

Detailed description of embodiments of the invention

For over ten years, the applicant of this application has been developing, manufacturing and marketing components for closed system liquid transfer devices designed to provide contamination-free transfer of hazardous drugs. These products are used to reconstitute powdered drugs and to transfer hazardous drugs in liquid form between drug vials, syringes and IV bags. Some of the developed products and a robotic system that uses them to automatically prepare prescription drugs are described in the background section of this application. This invention builds on work done to date on closed system components to develop similar components for use in preparing prescription drugs containing safe drugs.

Manufacturers supply medicines in vials as either liquids or powders. If in powder form, it must be reconstituted by adding a measured amount of liquid diluent to the inside of the vial. In either case, preparing a prescription drug involves withdrawing a measured amount of liquid medicine from the vial into a syringe.

Fig. 15a is a sectional view schematically showing an adapter 300 for a vial, which is adapted for use in an open transfer system. The adapter 300 for a vial comprises two parts, an upper part 304 and a lower part 302. The design of these two parts of the adapter 300 for a vial and the telescopic way in which they are secured to each other when connected to a vial for medicines are in most respects similar to the corresponding parts of the adapter 200 for a vial, described herein above with respect to Figs. 5a-12.

Unlike the 200 adapter for a bottle with a closed system, the 300 adapter for a bottle with

- 14 047655 holds only one tube - the liquid tube 308 - which passes through the entire bottle adapter from the bottom of the partition 322, which rests on the seat 310 of the partition and seals the top of the bottle adapter, through the upwardly projecting structure 306 to the tip of the spike 312.

The adapter 300 for the vial contains a hydrophobic filter 316. The said filter is made of a thin piece of hydrophobic material of a disc shape. An opening is cut in it, allowing liquid to pass freely through the tube 308 for liquid. The filter 316 is located between a set of support ribs located at a close distance from each other at the top and bottom, and its outer and inner edges are welded, glued or mechanically pressed into the upper part 304 of the adapter for the vial, as described in this document above with respect to Fig. 4.

The air passage 314 through the spike ends in an open space 324 below the filter 316. The interior of the upwardly projecting structure 306 contains a hollow air chamber 318 surrounding the liquid tube 308. The air chamber 318 is sealed at the top by a partition 322 and sealed at the bottom to prevent liquid from entering by the filter 316. A vent 320 close to the top in the side of the upwardly projecting structure 306 above the filter 316 provides a fluid communication between the interior of the air chamber 318 and the air outside the bottle adapter.

Fig. 15b schematically shows the bidirectional flow paths of liquid and air through the bottle adapter of Fig. 15a.

Fig. 16a and 16b show alternative locations in the adapter 300 for the vent hole 320, which can be located anywhere on the proximal side, that is, above or outside the filter 316. A person skilled in the art can select the location and shape of the vent element in various places and in various ways.

Fig. 17 shows another embodiment of the vial adapter adapted for use with an open transfer system. It is identical to the vial adapter 15 shown in Fig. 4, except that the air passage 56 comprises a vent hole 402 in the side, which provides unimpeded fluid communication between the interior of the air passage 56 and the space outside the vial adapter 400. The vent hole 402 is located above the filter 66. Pressure equalization occurs in the vial adapter 400 exactly as described for the vial adapter 300 described with reference to Figs. 15a and 15b.

Fig. 18a shows an open transfer system partially assembled for use. The system comprises a vial adapter 300 (see Fig. 15a) which is connected to a medicine vial 16 and a conventional syringe 450 which is connected to a connector 452 of the open system.

Fig. 18b shows a sectional view of the open transfer system of Fig. 18a. Fig. 18b shows: a conventional syringe 450, a connector 452 and a vial 16 with a fixed adapter 300 for the vial. Also shown is an upwardly projecting structure 306, a partition 322, a fluid channel 308 and a vent hole 320 of the adapter 300 for the vial.

Fig. 18c shows a connector 452 which is similar to the connector section 14 of the prior art with the following modifications: (a) the actuator 34 of the double membrane seal shown in Fig. 1a is replaced by a septum holder 500 (shown in Fig. 14) containing a septum 572 in its lower part; and (b) there is only one needle 454 acting as a tube for the liquid inside the connector 452. The connector 452 is shown in its locked configuration.

Fig. 19a shows the open transfer system of Fig. 18a in a fully assembled configuration after the vial adapter 300 has been connected to the drug vial and the spike 312 has penetrated the membrane at the top of the vial, as described herein above with reference to Figs. 8-11. The vial adapter 300 with the drug vial 16 secured is connected to a conventional syringe 450 via a connector 452.

Fig. 19b is a sectional view of the open transfer system of Fig. 19a.

Fig. 19c is an enlarged view of section A in Fig. 19b, focusing on the vial adapter with the syringe connector connected.

The use of an open transfer system is shown in Fig. 18a-19c, the drug in powder form can be reconstituted by filling a conventional syringe 450 with the required amount of diluent, then the connector 452 for the syringe, which is connected to the syringe, is pushed down along the upwardly projecting structure 306 of the adapter for the vial with an open system (Fig. 18a and 18b) until the connection is established as shown in Fig. 19a-19c, during which the needle 454 of the connector 452 penetrates through both the partition 572 of the adapter holder in the connector 452 and the partition 322 of the adapter for the vial, and enters the tube 308 for liquid in the adapter for the vial.

Once the connection is made, the plunger of the syringe 450 can be pushed down, forcing the liquid diluent to flow through the needle 454 in the connector and the liquid tube 308 in the adapter

- 15 047655 for the vial into the interior of the vial (arrow B). When the liquid enters the vial, the air is displaced and the pressure is equalized by air flowing out of the vial through the air channel 314, through the hydrophobic filter 316 into the air chamber 318 and out of the vial adapter through the vent hole 320 (arrow C).

To extract liquid from a medicine vial, the connected vial and syringe, connected as shown in Fig. 19a-19c, are tilted and turned upside down so that the vial is located above the syringe. After turning, the plunger of the syringe can be pulled in a downward direction, extracting liquid from the interior of the vial through the liquid tube 308. When liquid is extracted from the vial, a partial vacuum is created in the vial, which is balanced by suction, in which air is drawn into the vial from the space outside the vial adapter 300 through the vent hole 320, the air chamber 318, the filter 316 and the air channel 314.

As mentioned above, components of closed systems may be used in the preparation of prescription drugs and filling of prescription drugs from hazardous and non-hazardous medicinal products; however, components of open systems may only be used for non-hazardous medicinal products. In order to prevent interchangeability of components of open and closed systems, the applicant uses different configurations of connecting elements connecting the components of each system.

Fig. 20a and 20b schematically illustrate elements that allow two components of an open transfer system to be connected to each other and prevent a component of an open transfer system from being connected to a component of a closed transfer system. For illustrative purposes, the septum holder 600 of the open system, which is a component of the connecting section, should be connected to the upwardly projecting structure 306 of the adapter for a vial of the open system (see Fig. 15a) and the upwardly projecting structure 220 of the adapter for a vial of the closed system (see Fig. 6).

The partition holder 600 is identical to the partition holder 500 shown in Fig. 14, except for the distal end of the inwardly facing side of the brackets 662, which are connected to the part of the partition holder body. The partition 672 is shown fixed to the partition support. On the outer side of the brackets 662 are distal enlarged elements 668, and on the inner side of the brackets opposite the enlarged elements 668 are projections 602 of a special shape, comprising, for example, as shown, vertical and horizontal bars in the shape of an inverted letter L. As shown in Fig. 20a, the upwardly projecting structure 306 comprises a seat 604 in the shape of an inverted letter L on its side below the partition 622. The seat 604 has a shape and dimensions that correspond to the specially shaped projections 602 on the brackets of the partition holder, which allows the specially shaped projections 602 to enter the seats 604, connecting the partition holder to the adapter for the bottle. On the other hand, the components of a closed system comprise projections and seats that have shapes different from the shapes of the components of an open system, for example, for a closed system, the projection on the brackets can be a vertical bar, and the seat is a vertical groove. In this case, as shown in Fig. 20b, the horizontal bar at the top of the specially shaped projection 602 will prevent the projection 602 from entering the vertical socket 606 on the upwardly projecting structure 220 of the closed system vial adapter, thereby preventing the open system partition holder from being connected to the closed system vial adapter. It should be noted that the described shapes of projections and sockets are intended for illustrative purposes only, and many other special shapes can be used for the same purpose.

Fig. 21a schematically shows a spike connector 700 used in combination with a device 10 for transferring a liquid for transferring a drug into and out of an intravenous (IV) infusion bag. The spike connector 700 comprises a body 762 ending in a spike element 764 at a proximal end and a standard port 766 for connecting to an infusion system at a distal end. A longitudinal extension 768 is located substantially at a right angle to the body 762. At the end of the longitudinal extension 768 are a membrane shell 770 and a membrane 772. On the side of the longitudinal extension 768, under the membrane shell 770, is a socket 604 configured to align with specially shaped protrusions on the brackets of the septum holder in the connector, as shown in Fig. 20a. A connecting section, such as connector 452 (see Fig. 18) with a conventional syringe attached can be connected to the longitudinal extension 768, exactly as described herein above with respect to the connection to the vial adapter 300 in Figs. 19a-19c, thereby allowing the drug to be introduced from the syringe into the IV bag or liquid to be withdrawn from the IV bag into the syringe for use in reconstituting the drug.

Fig. 21b is a sectional view of the tenon connector. In this figure, it can be seen that the interior of the tenon connector 700 contains two separate channels 774 for liquid and 776 for air. In this open system tenon connector, the channel 774 for liquid extends from the tip of the tenon element 764 to the membrane 772 for use

- 16 047655 if fluid needs to be transferred to the IV bag from a syringe or vice versa. Channel 776 extends from the tip of the spike to port 766 for transferring fluid from the IV bag to the patient. In an open system for introducing or withdrawing fluid from a syringe into an IV bag, there is no need for communication with the atmosphere because, unlike a rigid glass vial, the IV bag is flexible, allowing it to expand under pressure or contract when pumped.

The device for fixing the plug-and-socket connection described with respect to Figures 23-29 can be easily modified by making the necessary changes for use with an open drug delivery system. For an open system, the socket connector, for example, the connecting section 452 in Figures 18a-18c, will contain only one needle, and the septum holder 500 can be replaced by ladders, gears and other parts of the socket connector 1201. The vial adapters of Figures 15a and 17 and the tenon connector of Figure 21a can also be modified so that their upwardly projecting structures 306, 46 and 768 will contain smooth sides and two anchor projections 1223 on opposite sides near the top.

Referring to Fig. 27a, it can be seen how the components are configured to prevent the components of the open and closed systems from connecting to each other. For example, for a closed system, the projection 1223 may be wider than the gap 1406 in the gear 1405 of the locking actuator 1401 for the open system, thereby preventing the adapter for the vial of the closed system from connecting to the connector 1201 of the open system. Alternatively, for an open system, the projection 1223 may be wider than the gap 1406 in the gear 1405 of the locking actuator 1401 for the closed system, thereby preventing the adapter for the vial of the open system from connecting to the connector 1201 of the closed system.

The open system components described in this document have been developed for use in a robotic system that can be installed in a hospital pharmacy to assist in the preparation of prescription medications containing safe drugs and the preparation of syringes and IV bags containing the required amounts of liquid drugs for administration to patients according to their individual prescriptions. The robotic system is similar to that described in the prior art for use with hazardous drugs and shown in Fig. 22. According to regulations, the two robotic systems will be stored in separate areas of the pharmacy.

For safe medicinal products, the safety requirements are much less stringent; however, as in the case of the system for dangerous medicinal products, the system comprises at least two robotic manipulator units configured to simultaneously move vials and syringes inside the cabinet. Each of the robotic manipulator units comprises three mechanical devices configured to independently move either a vial gripping unit or a syringe gripping unit and a syringe infusion pump in three dimensions along three mutually perpendicular axes. Inside the cabinet there is a set of workstations configured to perform specific tasks associated with the process of manufacturing prescription drugs. The workstations comprise: at least one reconstitution module, at least one vial shaking module, at least one vial inversion module, at least one base module for IV bags to which the system operator can attach IV bags; a syringe magazine; a set of cameras, each of which is installed in a specific location in the safety cabinet or on the robotic manipulator units, and a processor. Each camera is designed to provide real-time digital images of the stage of the manufacturing process taking place at its location. Special software and algorithms in the system processor allow the robotic manipulator units to automatically perform virtually all stages of the prescription manufacturing process without operator or observer intervention, and the cameras and image processing algorithms are designed to provide real-time feedback control of all stages of the prescription manufacturing process.

One important difference between a robotic system designed for a closed transfer system and one designed for use in an open transfer system is that the closed transfer system relies on the use of Equashield® syringes, which must be manufactured with perfect orientation and alignment with their connectors. This is important because Equashield® syringes will be picked up and placed when the connector extension tabs and the extensions on the syringe barrel are always in the same position relative to each other, and because of this identical orientation, only simple pick-up mechanisms are needed, and the processes of placing and handling the syringes are a simple and quick task. In contrast to the well-aligned Equashield® syringes, the open transfer system uses conventional syringes from different manufacturers, in different shapes and sizes, and the connector tabs on the handles and the extensions on the syringe barrel are rarely in the same position relative to each other.

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Claims (10)

each other, which requires special mechanisms built into the robot to grip the connector and syringe in different orientations. This also requires software that can handle different syringes, different orientations, identify them and read the correct dosage. When using a robotic system, prescriptions to be filled are entered into a system processor, which prompts the user to insert medicine bottles containing the required medications into the cabinet, load syringes of the correct sizes into the syringe magazine, and secure IV bags into IV bag base modules. In order for the robotic arms to be able to grip vials and syringes, the user connects a vial adapter to each vial and a connecting section to each syringe before placing them in the cabinet. Once the medicine vials, syringes and IV bags are placed in the cabinet, all further operations to prepare the prescription drugs and prepare the required doses in syringes or IV bags for administration to patients are carried out automatically by the robotic arms according to the commands of the processor under the observation of cameras. In the open robotic transfer system, the cameras and software are configured to recognize the sockets 604 and the projections 602 on the adapter 220 for the vial and the holder 600 of the partition in Fig. 20a and 20b, the gaps 1406 and the hollow parts 1405 in the locking actuator and the projections 1223 on the plug connector 1221 in Fig. 24 and 26 and to warn the user if the wrong components are placed in the cabinet. In addition, as a safety feature, the robotic manipulator assemblies comprise mechanical elements, such as protruding pins, which must be aligned with corresponding grooves on the components being lifted, ensuring that only components compatible with the open transfer system are used. The components of the open transfer system for use with the robotic system are comprised of two kits - a basic kit containing a vial adapter and a connecting section, and an extended kit which additionally contains a barbed connector for IV bags. These kits will be supplied in several embodiments containing vial adapters suitable for vials of various sizes and connectors for various types of connections, such as Luer locks or bayonet connectors that fit standard syringes without needles. Although embodiments of the present invention have been described by way of illustration, it should be understood that the invention can be embodied with many variations, modifications and adaptations without exceeding the scope of the appended claims. CLAUSE OF THE INVENTION 1. A robotic system for the prescription manufacturing and preparation of medical products containing safe medicinal products, comprising: a laminar air flow cabinet; at least one robotic manipulator; and at least one vented adapter for a medicinal product vial, wherein said at least one vented adapter for a medicinal product vial and said robotic system are configured to ensure the extraction of liquid from a medicinal product vial and its introduction into a medicinal product vial, wherein said at least one vented adapter for a medicinal product vial comprises: fluid tubes passing at least partially through said at least one vented drug vial adapter; an upper portion comprising a hollow air chamber at least partially surrounding the fluid tubes, wherein said upper portion further comprises a vent configured to provide fluid communication between the hollow air chamber and a space outside of at least one vented adapter for the medicine vial; a lower portion connected to the upper portion; and a hydrophobic ventilation filter placed between said upper and lower portions. 2. The robotic system of claim 1, comprising: (i) at least two robotic arm assemblies configured to prepare syringes and intravenous (IV) infusion bags containing a prescribed amount of liquid medication for administration to patients according to their individual prescriptions by moving medication vials, to which vial adapters communicating with the atmosphere are connected, and syringes within a laminar air flow cabinet, (ii) a chamber, and (iii) a system processor comprising software comprising image processing algorithms that are configured to provide real-time feedback control of all steps of the process. - 18 047655 process of manufacturing prescription drugs. 3. A robotic system according to item 2, characterized in that the nodes of the robotic manipulator are designed with the possibility of movement in three mutually perpendicular directions. 4. The robotic system of claim 3, comprising at least two robotic arm assemblies configured to prepare syringes and IV bags containing a required amount of liquid medication for administration to patients according to their individual prescriptions by moving medication vials, to which vial adapters communicating with the atmosphere are connected, and syringes, to which connecting sections are connected, within a laminar air flow cabinet, a chamber, and a system processor comprising image processing algorithms that are configured to provide real-time feedback control of all stages of the prescription drug manufacturing process, characterized in that: a) each of the connecting sections contains one of the following elements: (i) a partition holder comprising two elastic elongated brackets which project vertically downwards parallel to each other, fixed to the side of the housing part, each bracket comprising projections of a shape on the inner side of the distal ends of the brackets complementary to the sockets; or (ii) a section of a locking actuator comprising at least one step formed on the inner wall of the connecting section and at least one rotating gear comprising teeth arranged along the perimeter around the gear, a hollow portion configured to receive an anchor projection, and a gap formed in the gear such that in the hollow portion there is an opening, the orientation of which changes with the rotation of the gear; b) each of the vented vial adapters comprises one of the following: (i) an upwardly projecting portion comprising a membrane at a proximal end and sockets on the outer side of the proximal end, said sockets having a shape and dimensions adapted to align with projections of complementary shape on the inner side of the brackets of the partition holder; or (ii) an upwardly projecting portion comprising a membrane at a proximal end and anchor projections on the outer side of the proximal end, said anchor projections having a shape and dimensions adapted to pass through a gap and enter a cavity in a gear of a section of the locking actuator of the connector; thereby allowing the connecting sections to be connected only to drug vials connected to vented vial adapters containing compatible sockets or anchor projections on the outer surface. 5. The robotic system according to claim 4, characterized in that said projections are located on the outer side, protruding in the upward direction of the structure of the adapter for the vial, and the sockets complementary to the projections are located on the inner side of the brackets of the partition holder in the connecting section and the holder, as well as on the distal end of the gripping mechanism assembly. 6. The robotic system of claim 4, comprising a spike connector adapted to be connected to an intravenous (IV) infusion bag, comprising: a) a housing ending in a tenon element at the proximal end of the housing, said tenon element comprising separate channels for liquid and air; b) a standard port for connection to an infusion system at the distal end of the body, said standard port being in fluid communication with an air channel in the spike; and c) a longitudinal extension connected substantially at a right angle to the body, wherein the proximal end of said longitudinal extension comprises a membrane and is configured to be connected to the connecting section, and wherein said longitudinal extension comprises a fluid channel having a hydraulic communication with a fluid channel in the spike; wherein said tenon connecting element is characterized in that said longitudinal extension comprises one of the following elements: (i) a socket having a shape and dimensions adapted to align with projections of a shape complementary to align with the sockets on the brackets of the partition holder; or (ii) anchor projections having a shape and dimensions adapted to pass through a gap and enter a cavity in a gear section of the locking actuator of the connecting section; thus, the tenon connecting element has the ability to connect only with the connecting section according to claim 4. 7. The robotic system of claim 4, wherein the cameras and software are configured to recognize nests, protrusions, gaps, hollow parts and anchor protrusions and to warn the user if the wrong components are introduced into the cabinet; and the robotic arm assemblies contain mechanical parts that ensure that only components compatible with the open transfer system are used. 8. The robotic system according to item 3, characterized in that the nodes of the robotic manipulator - 19 047655 ra, designed with the ability to pick up, move and release syringes, contain special mechanisms for gripping the connector and syringe in different orientations, and the system requires software designed with the ability to work with different syringes and different orientations, identifying them and reading the correct dosage; which allows the said system to use common syringes from different manufacturers, different shapes and sizes. 9. An open assembly liquid drug transfer system comprising a vented drug vial adapter and a connecting section; wherein: A) the connecting section contains: a) a hollow outer body comprising a proximal end adapted to be connected to a conventional syringe and comprising an opening in its distal end adapted to allow insertion of a proximal end of a vented vial adapter for connection; b) one hollow needle acting as a tube for the fluid passing through the connecting section; and c) one of the following elements: (i) a partition holder comprising two elastic elongated brackets which project vertically downwards parallel to each other, fixed to the side of the housing part, each bracket comprising projections of a special shape on the inner side of the distal ends of the brackets; or (ii) a section of a locking actuator comprising at least one step formed on the inner wall of the connecting section, and at least one rotating gear comprising teeth arranged along the perimeter around the gear, a hollow portion configured to receive an anchor projection, and a gap formed in the gear such that in the hollow portion there is an opening, the orientation of which changes with the rotation of the gear; and B) the first embodiment of the vented adapter for the vial comprises: a) a distal structure designed to allow the vial adapter to be secured to a medicinal vial; b) a tenon element that projects downwards within the distal structure; c) an upwardly projecting structure projecting upwardly from the distal structure, wherein the upwardly projecting portion comprises a membrane at its proximal end, wherein the proximal end of said upwardly projecting structure is configured to be connected to a connecting section; d) a fluid channel formed inside the upwardly projecting structure and the spike element, wherein said fluid channel is configured to provide hydraulic communication through the bottle adapter from the openings in the tip of the spike to the proximally located membrane; e) a hydrophobic filter located in the distal structure beneath the upwardly projecting structure; and f) an air passage formed inside the bottle adapter at the proximal side of the hydrophobic filter and the spike element, wherein said air passage is configured to provide fluid communication through the bottle adapter from the openings in the tip of the spike to a ventilation opening located at the proximal side of the hydrophobic filter, providing fluid communication between the air passage and the space outside the bottle adapter; and g) wherein the structure projecting upward comprises one of the following elements: (i) sockets on the outer side of the proximal end, wherein said sockets have a shape and dimensions adapted to align with specially shaped projections on the inner side of the brackets of the partition holder; or (ii) an upwardly projecting portion comprising a membrane on the proximal end and anchor projections on the outer side of the proximal end, wherein said anchor projections have a shape and dimensions adapted to pass through the gap and enter a cavity in the gear of the locking actuator section of the connector; thereby allowing the connecting sections to be connected only to drug vials connected to vented vial adapters containing compatible sockets or anchor projections on the outer surface. 10. An open system for transferring liquid medicinal products according to claim 9, characterized in that the projections of a shape complementary to the sockets are located on the outer side, protruding upwards, of the structure of the adapter for the bottle, and the corresponding sockets are located on the inner side. -