WO1997020536A1

WO1997020536A1 - Device for preparing a medicinal solution reconstituted from two components

Info

Publication number: WO1997020536A1
Application number: PCT/CH1996/000429
Authority: WO
Inventors: Gabriel Meyer; Grégoire MEYER
Original assignee: Gabriel Meyer; Meyer Gregoire
Priority date: 1995-12-06
Filing date: 1996-12-04
Publication date: 1997-06-12
Also published as: AU7617296A

Abstract

A device (10) for preparing a liquid medicinal solution reconstituted from two components of which at least one is liquid, both components at first being stored in two respective separate sterilised hermetically sealed containers (15, 16). One of the components is an active substance and the other is the active or neutral diluent liquid component. The device comprises a central portion provided with a cannula (17), two container housings (13, 14) on either side of the central portion, and a channel having a first end opening for communication with the container (16) containing said active substance, and a second end opening for connection to a coupling for transferring said reconstituted liquid medicinal substance. The cannula (17) is arranged to establish communication between the two containers placed head-to-tail in the housings (13, 14), and coaxial with said containers, and comprises a first end projecting into the diluent container (15) substantially in the region of the outlet thereof, and a second end projecting into the active substance container (16) substantially in the central portion thereof. The volume of said container is selected to be more than twice the volume of the reconstituted liquid medicinal substance.

Description

DEVICE FOR THE PREPARATION OF A RECONSTITUTED MEDICINAL SOLUTION FROM TWO COMPONENTS

The present invention relates to a device for the preparation of a liquid medicinal solution reconstituted from two components, at least one of which is in the liquid state, the two components being initially contained respectively in two independent sterilized containers hermetically closed, l at least one of these components being an active substance and the other component being said component in the active liquid state or neutral diluent, this device comprising at least one element carrying a cannula for bringing the two containers into communication when they are arranged head to tail, mounted on this element, and a conduit arranged to open through a first orifice in said container containing said active substance and to lead, through a second orifice, to a transfer nozzle for said reconstituted liquid medicinal substance

It is well known that many medicinal substances intended to be administered by injection or drip are relatively unstable in solution and can only be used in the reconstituted state immediately before their use. These solutions are prepared by a mixture of two basic components which are one an active substance and the other a liquid diluent This diluent can be neutral or, in certain cases, it can also be an active component The active substance can be a liquid or a lyophilisate, a powder, granules or may have any other physical aspect The components are stored in hermetically sealed vials or in glass vials sealed with flame, sterilized and preserved from any contact with another substance or the external environment The most conventional method for preparing the mixture or the solution of the active substance in the diluent, consists in manually proceeding to this effect, one generally uses a syringe using which one punctures the stopper which closes the vial of the diluent and this diluent is taken to introduce it after puncturing the stopper in the bottle of the active substance After shaking this bottle to ensure the homogeneity of the solution, the latter can be withdrawn using the same syringe or another syringe for later use The solution is then either injected directly into the patient, or transferred to an infusion bag or other suitable reservoir

These manipulations are complex and their reliability is completely dependent on the qualification of the nursing staff. The medical risk in the event of handling error is far from being negligible. In addition, the direct withdrawal of the reconstituted solution from the bottle used to carry out the mixture is not without risk, since the perforation of the caps or the breaking of the glass tip of a sealed ampoule generates particles which can, in certain cases, be injected into the patient's body and cause accidents such as embolism for example

Finally, the system being overpressure, the withdrawal of the syringe can cause contaminating projections, unless using a syringe needle of special construction provided with a. vent or a two-way valve with a predetermined opening threshold and, in some cases, a guard or a valve system that opens only when the needle is connected to a vial, to a pocket infusion or similar

The needle of the syringe used to carry out the transfer is a hypodermic needle which will have to be changed between the two operations which consist one of reconstituting the solution and the other has to inject this solution according to the prescriptions defined by the rules of hygiene medical In some cases the diluent may already be contained in a pre-filled syringe which it is sufficient to connect to the bottle of active substance to effect the reconstitution and the transfer of the mixture into the syringe If the whole mixture is not transferred into the syringe, there is an overpressure in the system, overpressure which will cause contaminating projections during the separation of the syringe and the vial

Another way of carrying out the mixing consists in using a device as described by the Luxembourg patent No D 34 322 and commonly called "transfer set", which comprises two parallel conduits held by a central flange perpendicular to the two conduits The first two ends of these conduits are arranged to be introduced into a first vial containing for example an active substance, and the other two ends of this conduit are arranged to be introduced into a second vial containing the diluent The vials are pushed upside down one in the direction of the other until their respective necks are in abutment against the two faces of the central flange The diluent flows by gravity from the bottle which initially contains it into the one which contains the active substance through one of the two parallel conduits, the gas from the bottle containing the active substance being evacuated through the second conduit towards the e bottle of thinner

The parenteral medicinal solution reconstituted from the two basic components is in the bottle which initially contained the active substance, from which it can be withdrawn after removal from the transfer set, using a syringe by aspiration, after puncturing the cap. of the vial using the hypodermic needle of this syringe

These operations are dangerous because of the risk of contamination of the operator by the drug solution. One of the priorities that the pharmaceutical industry has set for itself under pressure from the medical profession and the regulatory authorities, is the development of a system allowing extemporaneous preparation without overpressure of parenteral and sterile medicinal solutions without recourse to or several syringes for passing a liquid component there before reconstitution, involving one or more hypodermic needles The conditions imposed by these bodies tend to prohibit risky handling for nursing staff, given that the reconstituted solution contains products with high activity pharmacological, including anti-cancer products, antibiotics, vaccines, hormones, which may, if necessary, contaminate doctors or nurses

Several two-chamber systems exist commercially which contain an active substance and a solvent respectively, the two components being able to be mixed as a result of the opening of a closure plug which initially separates the two chambers

Patent application PCT / CH93 / 00282 describes a two-chamber system which consists of two separate containers, one of which contains the active substance and the other of the diluent. In this embodiment, the diluent can be sterilized by heat and then aseptically combined. and tightly sealed to the container containing the active substance. Such a device, if it is attractive to the end user, has the disadvantage of being costly for the manufacturer and represents a heavy investment for the pharmaceutical industry.

Most other two-chamber systems have the disadvantage of not allowing thermal sterilization of the diluent since it is in the same device as the active substance. Therefore, the unsterilized diluent must be sterile filtered and produced aseptically. The risk of contamination of the sterile filtered diluent is one per thousand while that of the thermally sterilized diluent is one per million

Another way of transferring a solution between two bottles consists in using a double-pointed needle, whether or not equipped with a filter, the bottle having to receive the solution to be transferred being already under vacuum. The system has the following drawbacks. the mixing bottle must be packaged and sealed under vacuum, the vacuum must be maintained over time, which is difficult to guarantee, - the user must first couple the bottle containing the solution to be transferred and then couple the bottle under vacuum, if the user does not respect these sequences, he runs the risk of losing the vacuum and being unable to carry out his mixing; - such a system replaces the transfer set using gravity; when mixing is done, disconnect the double needle and puncture the mixture with a syringe and needle in the conventional way.

This product is marketed under the name "Transfer Devices via Direct Vacuum" by the company Braun Médical Inc. Another article of this company allows to transfer the contents of an ampoule in a vacuum bottle by means of a flexible tube connected to the ampoule, ending with a needle with filter to perforate the stopper of the vacuum flask The disadvantages are the same as above.

The device illustrating the closest prior art is described in patent US-2,584,397. It includes a rotating mixer support designed to allow the respective contents of two bottles mounted on this support to be mixed. Transfers from one of the components of its vial to the vial containing the other component and from the mixture to a syringe, are carried out through a sealed circuit The device allows in particular the extemporaneous reconstitution of a medicinal solution and its transfer in a syringe

The transfer of the reconstituted solution into the syringe cannot however be carried out in complete safety. Indeed, given the configuration of the needle inside the vial which contains the reconstituted solution, the solution can return to this vial, then that it is in the transfer chamber which communicates with the syringe

When the user pulls the plunger of the syringe, it generates a vacuum in the two vials due to the flow of the solution to the syringe. If the user releases the traction on the piston, the vacuum creates a liquid booster towards the two bottles, which has the effect of interrupting and compromising the transfer operation II resulting in a risk of malfunction which makes this system unacceptable in practice.

Currently the pharmaceutical industry continues to use standard containers to package both active substances and diluents. The only possible way to solve the transfer safety problem is to associate with the bottles a transfer set which allows to tightly connect the vial containing the active substance, the vial containing the diluent and a syringe for withdrawing the reconstituted solution, the assembly forming a sealed circuit and being designed to ensure the extemporaneous reconstitution of the solution and its transfer into a syringe without the use of a hypodermic needle and without generating an overpressure capable of destroying the molecule and / or of causing contamination by projections, nebulizations or sprays.

This object is achieved by the device according to the invention characterized in that said cannula is arranged coaxially with respect to the two containers mounted head to tail and has a first end which opens out at the interior of said container containing said diluent substantially near its mouth and a second end which opens into said container containing the active substance at a substantially central point, and in that the interior volume of this container is determined so that it is greater than twice the volume of the reconstituted liquid drug substance Said second end of said cannula is located in a central zone, defined as being the central space of said container containing the active substance, which is never crossed by the surface defining the upper level of the drug substance reconstituted in this container, regardless of the position of the latter

According to a first advantageous embodiment, at least said second end of the cannula has a beveled opening extending over a determined height, and this height is less than the smallest dimension of the smallest section of said central space

According to a variant deriving from the first embodiment, at least one of said first and second ends of the cannula comprises a harpoon-shaped retaining member, arranged to lock against the inner face of a cap of a container , after the introduction of the latter in head-to-tail position on the device, this container at least being constituted by a bottle closed by a stopper which can be pierced by said second end of the cannula

According to a second advantageous embodiment, the device comprises at least one support element defining a retaining and guide housing for at least said container containing the active substance and receiving said second end of the cannula

According to a preferred embodiment, the device comprises a first support element defining a first retaining and guide housing arranged to receive a first container containing said component in the liquid state, and a second support element defining a second retaining and guide housing arranged to receive a second container containing said active substance

In the context of this preferred embodiment, said first and second containers are bottles having a narrowed neck closed by a stopper made of an elastomeric material, and said first and second housings respectively comprise a zone of narrowed section defining shoulders, this zone of narrowed section being designed to receive the narrowed neck of the vials at the time of activation of the system composed of the device and of the vials placed in the respective housings, and the shoulders being arranged to serve as support for the bodies of these vials

To allow the pre-assembly of the bottles, said housings are provided with at least one seal forming a tight and antibacterial barrier between the outer walls of the containers and the inner walls of the housings

In the case where the bottles are pre-assembled, the device comprises a second end-piece arranged in the axis of the transfer end-piece, in a central element of the body of this device, this second end-piece being connected by respective conduits to said cross-section areas narrowed of said dwellings

Advantageously, the second nozzle has a filter forming an antibacterial vent

Preferably, at least one of said housings comprises means for allowing a pre-assembly of one of said containers, these means comprising a stop element preventing accidental activation of the system, an antibacterial bead, an anti- return and a blocking element preventing removal of the container after activation According to another embodiment of the device, when the container containing the liquid component is a glass ampoule sealed with flame, the narrowed section area of the housing intended to receive this container comprises a stop with a ramp intended to break a neck of this bulb to release the liquid it contains

According to an advantageous construction method, the transfer tip can be terminated by a female Luer cone and arranged to allow the connection of a syringe having a male Luer tip.

In a particular embodiment the transfer nozzle can be equipped with a needle arranged to allow connection with an infusion bag

According to another advantageous construction, the transfer tip can contain a syringe needle arranged to be connected to a syringe for activation of the system and transfer of the reconstituted solution

When the container is a glass ampoule, the housing includes an antibacterial filter arranged to filter the liquid component before its transfer through the cannula into the bottle containing the active substance

According to an advantageous embodiment, said transfer nozzle is designed to contain a receptacle constituted by a syringe, an empty cartridge or the like. In this case, the nozzle is preferably removable for use in combination with said empty cartridge.

According to another embodiment, at least one of said housings is arranged to receive a flame-sealed bulb

The invention will be better understood with reference to the description of several embodiments of the device according to the invention and to the accompanying drawing in which FIGS. 1A to 1 H represent a first embodiment of the device according to the invention and the different phases of its use, this embodiment lending itself to the pre-assembly of the bottles, - FIGS. 2A to 21 represent an alternative embodiment of the device of the invention and phases of use of this construction, this embodiment lending itself to the pre-assembly of the bottles,

FIG. 3 represents an embodiment in which the bottles are not pre-assembled,

FIGS. 4A to 4J represent another embodiment comprising a tip with a pre-assembled needle,

FIGS. 5A to 5H represent a variant according to which one of the bottles is replaced by a glass bulb sealed with flame,

FIGS. 6A to 6C represent a simplified embodiment in which the means for guiding and retaining the bottles are eliminated,

FIGS. 7A to 7C represent a variant of the embodiment according to FIGS. 6A to 6C,

FIGS. 8A to 8C show a variant in which a holding and guiding housing is provided for the bottle containing the active substance,

FIGS. 9A to 9C represent the relative position of the bottle and of the end of the cannula when the bottle is oriented in various positions, FIGS. 10A and 10B represent a variant intended for the pre-assembly of the bottles, the sealing being ensured by an O-ring

FIG. 11 shows a variant of the device in which the housings are designed to receive flame-sealed ampoules, FIG. 12 shows another variant of the device intended to receive an ampoule and a bottle,

FIGS. 13, 14 and 15 represent the phases of use of the device of FIG. 12,

FIGS. 16A, 16B, 16C, 16D and 16E show a variant of the device according to the invention, in a particular use, and

- Figures 17A, 17B and 17C show a use of a bottle initially prepared by the device according to Figures 16

With reference to FIGS. 1A to 1 H, the device 10 for the preparation of a medicinal solution reconstituted from two components mainly consists of a body 11, preferably produced by molding in thermoplastic material comprising a central element 12 and two support elements defining two retaining and guide housings 13 and 14 arranged on either side of said central element, and intended to receive respectively two containers, for example two sterilized bottles 15 and 16 (see FIG. 1 B) independent of these two vials 15 and 16 are hermetically sealed and contain one (15) a liquid substance, for example a diluent, and the other (16) an active substance, for example a lyophilisate capable of being dissolved by the diluent II is note that one of the bottles (for example 15) always contains a liquid substance, but that this substance can be an active component, or a neutral solvent The substance says e active contained for example in the bottle 16 can be liquid, pasty or any other suitable consistency as long as it can dissolve in the liquid in the other bottle

The central element 12 carries a cannula 17 which extends on both sides in the housings 13 and 14 and a conduit 18 which opens into the housing 14 through one of its orifices and into a transfer nozzle 19 through a second orifice L ' transfer tip is for example equipped with a Luer cap 19a The two housings 13 and 14 each have a narrowed section zone 13a, 14a which respectively define with the rest of the walls of these housings a shoulder 13b, 14b, whose role will be described below The central element 12 also comprises, in this embodiment a second endpiece 9, disposed substantially in the extension of the transfer endpiece 19, along the same axis, this endpiece having an antibacterial vent function and being equipped at its end of a suitable filter 8 This vent communicates by two conduits 9a and 9b respectively with the retaining and guide housings 13 and 14 Therefore, the air contained in these housings and which is trapped sounded in the housings, more precisely in the heads of these housings, when the bottles 15 and 16 are pre-assembled, can escape Indeed, in the case of pre-assembled bottles, in particular, the two housings 13 and 14 are equipped with an inner belt or beads 7 which seal and form an antibacterial barrier to prevent the passage of bacteria towards the active elements of the device and towards the heads of the bottles. This same objective also justifies the presence of the filter 8 on the second end piece 9

The device of the invention, represented in a preferred embodiment, is illustrated by FIG. 1C in its first phase of use or its storage phase II is intended to be used with two bottles such as those represented in the figure 1 B These bottles 15, 16 are closed by plugs 20, 21 made of elastomer crimped by aluminum capsules 22, 23 which together constitute a hermetic and aseptic barrier. The two bottles are sterilized, the bottle 16 for example during the process of freeze-drying of the active substance it contains, and the bottle 15 by a very common thermal process The use of this three-element system begins with a phase of assembly of the two bottles 15 16 and of the device 10, which consists to put in place the vial 15 of the solvent in the housing 13 of the device and the vial 16 of the active substance in the housing 14 It is noted that the vials are introduced into the housings only up to the tips of the cannula 17, without the plugs 20 and 21 are perforated In the example shown, the bottles are pre-assembled and FIG. 1C represents a storage position for a pre-assembled system comprising the device 10 and the two containers 15 and 16

The next step represented by FIG. 1 D consists in exerting a push respectively P1 and P2 on the bottoms of the bottles 15 and 16 so that the tips of the cannula 17 perforate the plugs 20 and 21 and that the ends of the cannula penetrate respectively inside the bottles 15 and 16 The air contained in the housings 13 and 14 escapes through the conduits 9a and 9b and through the vent filter 8, under the pressure of the bottles which remain sealed thanks to the belts 7 of the housings 13 and 14 during the entire activation phase In this phase, the system is activated. It will be noted that this activation is carried out when the necks of the bottles are engaged in the zones of narrowed section 13a and 14a of the housings and the walls of the bodies of the bottles. are in abutment against the shoulders 13b and 14b defined above

During the next step represented by FIG. 1E, a suction syringe 24 comprising a body 25, a plunger 26, a plunger rod 27 coupled to the plunger 26 and a needle holder tip 28 arranged to be adapted to the transfer nozzle 19, is coupled to the device 10 A traction exerted on the piston rod 27 causes a suction which results in a vacuum inside the bottle 16, the suction of the air or gas contained in the bottle 16 is carried out through the conduit 18 Thanks to this depression, the diluent contained in the bottle 15 flows into the bottle 16 through the cannula 17 The solution resulting from the mixture of the two components found in the bottle 16 As soon as all of the diluent has flowed into the bottle 16, the vacuum in the system is balanced through the cannula 17 and the conduit 18

The tip of the cannula 17 which is inside the bottle 16 is located above the surface of the solution contained in this bottle after the operation consisting in dissolving the lyophilisate in the diluent, this operation being called phase of reconstitution In addition, this tip occupies a position such that, whatever the position of the bottle, the substantially flat surface which defines the level of the solution always remains below this tip so that the solution can never flow through cannula 17

The next step, represented by FIG. 1 F, consists in refilling the bottles 15 and 16 which were under vacuum under the action of the vacuum created by the pulling of the piston rod 27 of the syringe 24, by restoring atmospheric pressure in these vials and removing the partial vacuum in the syringe 24 so that it is capable of receiving the reconstituted solution This recovery of atmospheric pressure in the system is done using the syringe 24 which is released ia traction on the piston rod 27 which is sucked up by the vacuum prevailing in the bottles 15 and 16 We can also help this piston return to compensate for the friction forces by mechanically pushing on the piston rod 27 As soon as this piston rod has reached its starting point before suction, atmospheric pressure is restored in the vials 15 and 16, in the cannula 17 and in the conduit 18

To withdraw the solution, as shown in FIG. 1G, or a certain quantity of solution by means of the syringe 24, the device is turned over, so that the bottle 16 is located above the bottle 15 The endpiece carries needle 28, and consequently the syringe, is thus in communication with the interior of the bottle 16 via the conduit 18. The solution can be drawn up by syringe 24 which can draw up to the last drop of liquid since the conduit 18 opens into the interior of the vial 15 flush with the stopper 21 A slight depression occurs in the two vials which remain in communication As a result, when the syringe is detached from the transfer nozzle 19, no liquid is likely to escape and contaminate the nursing staff, since the liquid residues are sucked back into the bottles where there is a depression This slight depression exists from the moment when the first drops of solution are drawn into the syringe This depression does not can never be important, because it automatically balances in the two vials through the cannula 17 This allows the user to withdraw only a small part of the reconstituted solution by precisely measuring this quantity using the syringe and detach this syringe from the device at any stage of collection without any risk of contamination

The fact that the two bottles communicate with each other to balance the depression by the cannula 17 is a very important advantage which allows the existence of the depression without it being too great. Indeed, if this communication between the two bottles by the cannula 17 did not exist, the vacuum which would be generated in the only bottle 16 during the sampling operation would be very quickly important and would force the user to maintain a significant traction on the piston rod 27 before separation, which would make the measurement operation very difficult But since the depression is low, it exerts a weak force on the syringe piston, close to the friction force of this piston II is therefore not necessary to exert a traction important for withdrawing and measuring a predetermined quantity of reconstituted solution This traction can even be interrupted at the time of separation, without risk of losing the precision of the d dare measured

Figure 1H shows the system empty after use The Luer cap 19a has been replaced on the transfer nozzle 19 FIGS. 2A to 21 illustrate an alternative embodiment according to which the device 10 is provided with a pre-assembled needle 30 arranged to ensure the transfer of the reconstituted solution into a transfusion bag 31 or the like. In this case, the central element 12 of the device is provided with a relatively long transfer nozzle 19 which consists of a fixed support carrying the needle 30 and a removable tubular part 32 ensuring sealing with the needle 30, initially closed by a Luer cap 33 All the other components of the device 10 and in particular the housings 13 and 14 are, apart from a few details of shape, identical to those described previously Similarly, the bottles 15 and 16 have shapes and functions similar to those described with reference to the figure 1 B, although the plugs 20 and 21 have some constructive differences

The phase of placing the vials or, in certain cases, the storage phase, represented by FIG. 2C, the activation phase of FIG. 2D, the phase of reconstitution of the drug solution from the two components, represented in FIG. 2E, the pressure balancing phase represented by FIG. 2F, the suction phase represented by FIG. 2G and the phase of separation and neutralization of the system as represented by FIG. 2H, are practically identical to the corresponding phases of figures 1 C to 1 H

The transfer phase of the entire mixture or of the balance of this mixture remaining after withdrawal of a certain quantity during the aspiration phase represented by FIG. 2G, into a transfusion bag 31 or the like takes place when the needle 30 is exposed after the removal of the removable tubular part 32 The transfer is made by pressurizing the system by applying pressure to the bag which transfers pressurized air into the bottles After releasing this pressure on the pocket, the overpressure prevailing in the system causes the solution to flow into the pocket The reconstitution and the transfer of the solution to the transfusion bag 31 or similar can be done directly by exposing the needle 30 from the start and by connecting this needle to the bag 31 before reconstitution without going through the phases 2E, 2F , 2G and 2H which use an intermediate syringe

The mixing is done by putting the system under pressure by exerting a push on the pocket which transfers air into the bottles, the diluent bottle being directed upwards After this pressure is released on the pocket , a vacuum is created in the reconstitution bottle and the diluent flows through the cannula Transfer is done in the same way as above, but taking care to direct the bottle containing the reconstituted solution upwards Construction of the system represented by FIGS. 2A to 21 has the following advantages - the reconstitution and the transfer can be done by means of a syringe in order to withdraw a small part of the reconstituted solution in the syringe, as represented by FIG. 2H and to inject this small bolus dose to a patient, the rest of the solution can be transferred to an infusion bag, - in case it is not necessary to inject a small bolus dose , the use of the syringe is unnecessary and the entire mixture can be reconstituted using the bag and transferred to this bag in a closed circuit This combination of possibilities would be impossible to achieve if there was a moving part of the tap type between the two vials, which would require the transit of the solvent before reconstitution in a syringe

FIG. 3 represents an alternative embodiment of the device as shown in FIG. 1A As it is intended for use without pre-assembly, the housings 13 and 14 do not have a belt or beads to form a waterproof antibacterial barrier 11 exists between the walls of the housings and those of the bottles sufficient clearance to allow the air to escape when these bottles are put in place. As a result, the nozzle 9 with its vent filter 8 have been eliminated since they are not justified in this case. Furthermore, all the phases of use after the placement of the bottles, are identical to those described with reference to FIGS. 1A to 1 H The same parts have the same references as those of FIG. 1A

The variant embodiment shown in FIGS. 4A to 4J derives from the previous embodiments and the parts identical to components already described have the same reference numbers. With reference to these figures, the device 10 comprises, as before, a body 11 with an element central 12 and two support and guide elements 13 and 14 Given that this device is intended for pre-assembly of the two bottles 15 and 16 illustrated in FIG. 4B, the housings 13 and 14 include beads 7 forming both a gasket and an antibacterial barrier between the interior walls of the housings and the exterior walls of the bottles

In this embodiment, as in that which is shown with reference to FIGS. 2A to 21, the central element 12 of the device is provided with a relatively long transfer nozzle 19, of substantially cylindrical shape, and which ends in a section d end 40, frustoconical arranged to receive a needle-carrying element 41, for example of the Luer cone type, which effectively carries a needle 42 housed in the transfer nozzle 19 The needle-carrying element 41 is closed by a Luer cap 19a identical to those described above. It will be noted that the transfer nozzle 19 has an inner ring 43, preferably made of an elastomeric material, which ensures both centering, holding in position and sealing at the level of this needle, when '' it is housed, as shown precisely in Figure 4A inside the transfer nozzle 19 As mentioned above, when the device is intended for pre-assembly of the bottle, a second nozzle 9 equipped with a vent filter 8 is necessary

FIG. 4C represents the device in an initial position, which is preferably its storage position, in which the bottles of FIG. 4B are pre-assembled in the housings 13 and 14

FIG. 4D represents the activation phase in which the user has exerted respectively a push P1 on the bottle 15 containing the diluent and a push P2 on the bottle 16 containing the active substance so as to put the two bottles in communication through the cannula 17, the tips of which have respectively punctured the plugs 20 and 21 The gas contained in the housings 13, 14 escapes through the conduits 9a and 9b and through the filter 8 under the pressure of the bottles which remain sealed thanks to the belt 7 .

After removal of the Luer cap 19a and connection of a syringe 24, provided with a body 25 with a piston 26 and a piston rod 27, on the needle-holder element at the end of the nozzle transfer 19 (FIG. 4E), the transfer of the solvent contained in the vial 15 into the vial 16 for the purpose of reconstituting the drug solution can be carried out This operation is carried out following the creation of a vacuum at the inside of the bottle 16 due to a suction of the air which it contains through the conduit 18 by means of the syringe 24

FIG. 4F represents the balancing of the pressures in the two bottles which communicate with each other by means of the cannula 17

FIG. 4G represents a phase of sampling part of the reconstituted solution To perform this sampling, part of the mixture is aspirated by means of the syringe, the device having previously been turned over so that the bottle 16 containing the solution reconstructed is found above and that the solution can flow through the conduit 18 It will be noted that the end of the cannula 17 is situated substantially in a central zone of the bottle 16 so that no part of this solution can flow through the cannula 17, whatever the position of the device and the vials

FIG. 4H represents a phase during which the syringe 24 is disconnected from the device 10. It will be noted in particular that during this disconnection the needle remains fixed at the end of the syringe, after having been withdrawn from the tip transfer 19 The device 10 is neutralized after the Luer cap 19a has been fitted at the end of the nozzle 19

FIG. 41 diagrammatically represents the transfer of the reconstituted drug solution withdrawn by means of the syringe 24 into an infusion bag 31

FIG. 4J schematically represents the transfer of the medicinal solution withdrawn by means of the syringe 24 into another container, for example a vial 44

The embodiment according to FIGS. 5A to 5H corresponds substantially to that of FIGS. 1A to 1H in which the bottle 15 containing a liquid substance, in particular a diluent, has been replaced by a glass bulb sealed with flame. Consequently, the device 10 shown by FIG. 5A is substantially identical, at least as regards the functional aspect of the device represented by FIG. 1A However, the housing 13 which is intended to receive a bulb 50 (see FIG. 5B), has a construction adapted to the shape and dimensions of this ampoule As previously, the device 10 is intended to receive containers, in this case the ampoule 50 containing the diluent and the bottle 16 containing an active substance, in the pre-assembled state. housings 13 and 14 include sealing beads 7 and the central element 12 of the device is fitted with the nozzle 9 provided with the vent filter 8 whose functions have been described previously, which communicates only with the housing 14 by the conduit 9b It will be noted that the conduit 9a has been removed and that the end of the cannula 17 is interrupted at the base of the housing 13, and that this base of the housing comprises an antiparticulate filter 6 separating the housing 13 from the cannula 17

FIG. 5C represents the storage phase or the initial phase of use of the device, its containers being pre-assembled

FIG. 5D represents the activation phase due to the exercise of a push P1 on the bulb 50 and a push P2 on the bottle 16 In this regard, it should be noted that to allow the flow of the diluent contained in the bulb 50, the neck of the latter must be broken This break can be carried out before mounting the bulb 50 in its housing 13, or even, the contents of the bulb can be emptied in the housing 13 so that 'it rests on the aπtiparticulate filter 6 The breakage of the bulb is preferably obtained thanks to the existence of a stop 60 disposed inside the housing 13, this stop 60 having a ramp 61 which has the effect of repelling the end of the neck of the bulb, the body of which is held firmly inside the housing 13, causing the hedge to fracture between the neck and the body and thereby the opening of this bulb

The anti-particle filter 6 or sterilizing filtration which equips the bottom of the housing 13 makes it possible to retain the glass particles or to sterile filter the solution of the bulb which flows through this filter through the channel 17 The sterilizing filter becomes an imperative in the case where the solution of the ampoule is poured manually into the housing 13 which forms, in this case, a filtration receptacle

The reconstruction phase represented by FIG. 5E is carried out as previously using a syringe 24 ^• yy

Phase 5F represents the balancing of pressures inside the system. It will be noted that a dead volume of diluent remains trapped inside the neck of the ampoule. It will of course be necessary to take this dead volume into account when dosing. of the quantity of solvent initially contained in the ampoule The transfer phase of the reconstituted drug solution is represented by FIG. 5G It is carried out by aspiration using the syringe 24 It will be noted that the dead volume, initially present in the cervix of the ampoule, drops to the bottom of this ampoule during the inversion of the system and cannot mix with the reconstituted solution

The final phase of neutralization of the system, represented by FIG. 5H, is obtained by replacing the Luer cap 19a on the nozzle 19

In all the embodiments described above, the device is provided with housings 13 and 14 intended to receive the two vials 15 and 16 or the ampoule 50 and the vial 16 These housings have essentially two functions, namely to provide guidance containers during their installation and during activation, and ensuring their maintenance during storage for pre-assembled systems, or during the other phases of use

It turns out that the presence of the housings constitutes a comfort solution, but not an absolute necessity for the device to be operational. Indeed, a device as represented by FIGS. 6A to 6C associated with two bottles 15 and 16 closed by caps 20 and 21 can also achieve the objective set by the present invention

The device 10 represented by FIG. 6A consists of a single element 112 made of synthetic material which carries a cannula 17 and a conduit 18 which opens into a transfer nozzle 19 closed during storage by a Luer cap 19a Two support elements 70 , 71 designed as two transverse discs relative to the axis of the cannula 17, are arranged on either side of the transfer nozzle 19 and serve as support for the two bottles in the phases of use

The use begins with an activation phase, represented by FIG. 6C, which begins with the placing of the bottles 15, 16 of FIG. 6B in a manner centered on the support elements 70, 71 following the piercing of the plugs 20 and 21 by means of the tips of the cannula 17 The other phases of use are similar to those already described

Such a system can have faults if some precautions are not taken at the start and during use It is necessary to center the tips of the cannula well when placing the vials It is also necessary to maintain the vials during use, in particular to avoid accidental withdrawal of the tips of the cannula from the caps

To partially avoid these drawbacks, it is possible to associate with the cannula retaining members preventing withdrawal of the vials, after their installation. Such a device is represented by the assembly of FIGS. 7A to 7C

The device 10 has the same components as that of FIG. 6A, but the two tips of the cannula 17 each comprise a retaining member 80, respectively 81, in the form of a harpoon as shown in FIG. 7A This device is arranged to cooperate with two bottles 15 and 16 (fig 7B), identical to those described above

The activation represented by FIG. 7C takes place as in the embodiment of FIG. 6C The retaining members 80 and 81 in the form of harpoons are locked against the internal faces of the plugs 20 and 21 and thereby prevent withdrawal accidental vials relative to the tips of the cannula 17 In the two constructions according to FIGS. 6 and 7, the device and the cannula are made in one piece from an injected synthetic material.

Another embodiment is shown in FIGS. 8A to 8C. This variant is a mixed solution between the pre-assembled system and the system to be assembled by the end user. In this construction, the device 10 comprises a body 11 with a central element 12 which carries the cannula 17 and a support element forming a housing 14 in which is pre-assembled a bottle 16 containing the active substance. It will be noted that this bottle is closed by the stopper 20 which is covered with a cap 20a made of plastic, for example a material having a certain flexibility and capable of sealing with the internal bead provided for this purpose. One of the tips of the cannula 17 has a harpoon-shaped retaining member 80. The bottle 16 being pre-assembled, a seal and a bacterial barrier must be provided in the housing 14. For this purpose, the housing 14 comprises a stop element 90 in the form of a discontinuous stop, which prevents accidental activation of the system, a bead antibacterial 81 which constitutes said antibacterial barrier, a non-return element 92 in the form of discontinuous tabs which prevents accidental withdrawal of the bottle 16 from the housing 14 and finally a blocking element 93 in the form of discontinuous stop which prevents movement of the bottle 16 relative to the housing, after the placement of this bottle in the activated position (see FIG. 8C)

The other tip of the cannula 17 is, in the storage position of the system represented by FIG. 8A, masked by a cap 94, sealing and forming an antibacterial barrier with the cannula 17, which will have to be removed to allow the placement of the bottle 15.

The phases of use are substantially the same as those already described. This latter variant may be of interest to manufacturers since it is very easy to assemble the transfer device and the bottle containing the active substance and then to carry out the final control and labeling without having to combine bottles from different production lines In particular, the diluent can be autoclave, controlled and labeled according to conventional methods and equipment

In addition, in this embodiment, the guidance of the bottle containing the active substance, for which the tip of the cannula is longest, is ensured, which is particularly advantageous since the end of the cannula must be positioned so central

Various variants can also be imagined. For example, in pre-assembled systems, the seal between the housings and the bottles can also be obtained by an O-ring attached at the neck and the bottle.

As regards the bottle containing the active substance, it is essential that its dimensions are determined in such a way that, whatever its position, the reconstituted solution can never penetrate into the centrally placed cannula

This condition is illustrated by FIGS. 9A, 9B and 9C which show the bottle 16 in three different positions When the bottle is turned in all directions, the surface of the solution always remains tangent to a central space 100 which surrounds the end of the cannula, and which is never crossed by the surface 101 defining the level of the liquid In fact, the internal volume of the bottle 16 is greater than twice the volume of the reconstituted mixture It will further be noted that the conduit 18 is present under the forms an annular passage formed all around the needle 17 which facilitates the flow of the reconstituted solution The variant embodiment according to FIGS. 10A and 10B corresponds to a pre-assembled system comprising the device 10 already described and the housings 13 and 14 intended to receive the bottles 15 and 16 respectively. As these bottles are pre-assembled, it is necessary to provide an antibacterial barrier between the interior walls of the housings and the exterior walls of the bottles This barrier is produced by means of an O-ring 110 which is housed at the base of the neck of the bottles In the storage position shown in FIG. 10A, the O-ring 110 is compressed due to a narrowing of the internal diameter of the housings in a zone 111 delimited by two beads 113 and 114 The sealing and the antibacterial protection are ensured in this zone which is followed by a zone 115 in which the diameter is larger, which allows the air contained inside the accommodation to be evacuated during the activation phase A bo 116 non-return urrelet ensures the bottles are locked in position after system activation

Thanks to these differences in interior diameters of the housings and the presence of the O-ring 110, it is possible to remove the end piece 9 with its vent filter 8, the evacuation of the air being able to be done thanks to play between the walls of the bottles and housings, and the guarantee of watertightness in certain areas

FIG. 11 represents a variant according to which the device 10 is provided with two housings 13 and 14 intended respectively to receive two ampoules 150 and 160 sealed with flame. The ampoule 150 contains a solvent and the ampoule 160 contains a solid substance, for example example a lyophilizer A syringe 170 is already mounted on the device, the transfer nozzle 19 being appropriately designed The insertion of the ampoules is carried out after rupture of their narrowed neck, in a manner known per se It will be noted that the inner duct 171 which replaces the needle 17 of the embodiment according to Figures 1, is not beveled and is made in one piece with the entire device 10 Its manufacture is therefore particularly economical

FIG. 12 illustrates a mixed variant in which the device 10 is provided with housings 13 and 14 designed to receive respectively an ampoule 150 containing the solvent and a vial 16 containing the solid active substance As in the previous embodiment, the syringe 170 is preassembled L needle 17 is double Its points are closed and have radial openings 171 and 172

Figure 13 illustrates the variant of Figure 12 when the bottle 16 and the ampoule 150 are in place in their housings

Figure 14 illustrates the mixing phase of the device as shown in Figures 12 and 13. The reconstituted solution is in the bottle 16, the ampoule 150 being emptied of its content

As shown in FIG. 15, after the device 10 has been turned over, the bottle 16 containing the reconstituted solution is found overturned above the flow conduit which ensures communication with the syringe 170 Traction on the piston rod of this syringe allows to suck the solution

FIGS. 16A, 16B, 16C, 16D and 16E illustrate the phases of use of an alternative embodiment of the device according to the invention The device 10 is designed to receive in its two housings 13, 14 a bulb 150 sealed with a flame and containing the solvent and a bottle 16 containing the solid active substance Furthermore, the device is associated with an empty cartridge 200, which is on hold II is closed at its distal end by a plug 201 set FIG. 16B shows the device 10 when the bottle 16 and the bulb 150 are in place

FIG. 16C shows the device 10 after mixing. A pull represented by the arrow T shows the displacement of the empty bottle 200 which creates the vacuum allowing the solvent to flow into the bottle

After the device 10 has been turned over, illustrated by the arrow R, the expanded gas resulting from the traction T (see FIG. 16C) coming from the empty cartridge 200, from the bottle 16 and from the bulb 150, can flow into the bottle 16 and in the bulb 150 by a thrust or a suction of gas, as illustrated by the arrow T 'The empty cartridge 200 is found in the initial position of FIG. 16B, which has the effect of restoring the balanced atmospheric pressure uniformly in bottle 16 and ampoule 150

As shown in FIG. 16E, a pull represented by the arrow T ensures the transfer of the solution in the cartridge 200 This bottle is closed at its distal end by the crimped stopper 201 and at its proximal end by a piston-valve 202 which was initially linked to a transfer rod 203 secured to the device 10

FIGS. 17A, 17B and 17C illustrate the three phases of use of the bottle 200 prepared as described in FIGS. 16, in combination with a metering and mechanical propulsion system 210, for the injection of predetermined doses. It will be noted that in the embodiment according to Figures 16 and 17, the transfer nozzle 19 of the device 10 is removable and arranged to detach and accompany the cartridge 200 for subsequent use

Claims

1 Device for the preparation of a liquid medicinal solution reconstituted from two components, at least one of which is in the liquid state, the two components being initially contained respectively in two independent sterilized containers hermetically closed, at least one of these components being an active substance and the other component being said component in the active liquid or neutral diluent state, this device comprising at least one element (12, 112) carrying a cannula (17) for bringing the two containers into communication when they are arranged head to tail, mounted on this body, and a conduit (18) arranged to open through a first orifice in said container containing said active substance and to lead, through a second orifice, to a transfer nozzle (19 ) of said reconstituted liquid medicinal substance, characterized in that said cannula is arranged coaxially with respect to the two containers mounted head-to-head che and has a first end which opens into the interior of said container containing said diluent substantially near its mouth and a second end which opens into said container containing the active substance at a substantially central point, in that the interior volume of this container is determined so that it is greater than twice the volume of the reconstituted liquid drug substance, and in that said second end of said cannula (17) is located in a central area, defined as the central space (100 ) of said container (16) containing the active substance, which is never crossed by the surface (101) defining the upper level of the drug substance reconstituted in this container, whatever the position of the latter

2 Device according to claim 1, characterized in that at least said second end of the cannula (17) has a beveled opening extending over a determined height, and in that this height is less than the smallest dimension of the smallest section of said central space (100)

3 Device according to claim 1, characterized in that at least one of said first and second ends of the cannula (17) comprises a retaining member (80 and / or 81) in the form of a harpoon, arranged to lock against the inner face of a plug (20 and / or 21) of a container (15 and / or 16), after the positioning of the latter in head-to-tail position on the device (10), this container at least being consisting of a bottle closed by a stopper which can be pierced by said second end of the cannula (17)

4 Device according to claim 1, characterized in that it comprises at least one support element defining a retaining and guide housing (14) for at least said container (16) containing the active substance and receiving said second end of the cannula (17)

5 Device according to claim 4, characterized in that it comprises a first support element defining a first retaining and guide housing (13) arranged to receive a first container (15, 50) containing said component in the liquid state , and a second support element defining a second retaining and guide housing (14) arranged to receive a second container (16) containing said active substance

6 Device according to claim 5, characterized in that said first and second containers are bottles (15, 16) having a narrowed neck closed by respectively by a stopper (20, 21) of an elastomeric material, and in that said first and second housings (13, 14) respectively have a narrowed section area (13a, 14a) defining shoulders (13b, 14b), this narrowed section area being designed to receive the narrowed neck of the bottles (15, 16) at the time of the activation of the system composed of device and bottles placed in the respective housings, and the shoulders being arranged to serve as support for the bodies of these bottles

7 Device according to claim 6, characterized in that said housings (13, 14) are provided with at least one seal (7) forming a tight and antibacterial barrier between the outer walls of the containers (15, 16) and the interior walls of the housings (13,14)

8 Device according to claim 1, characterized in that it comprises a second endpiece (9) disposed in the axis of the transfer endpiece (19), in the central element (12) of the body (11) of this device (10), this second endpiece being connected by respective conduits (9a, 9b) to said zones of narrowed section (13a, 14a) of said housings (13, 14)

9 Device according to claim 8, characterized in that the second nozzle (9) comprises a filter (8) forming an antibacterial vent

10 Device according to claim 6, characterized in that at least one (14) of said housings (13, 14) comprises means for allowing a pre-assembly of one (16) of said containers (15, 16), these means comprising a stop element (90) preventing accidental activation of the system, an antibacterial bead (91), a non-return element (92) and a blocking element (93) preventing the withdrawal of the container after activation

11 Device according to claim 6, characterized in that the container containing the liquid component is a glass ampoule (50) sealed with flame, and in that the narrowed section area (13a) of the housing (13) intended to receive this container comprises a stop (60) with a ramp (61) intended to break a neck of this bulb to release the liquid which it contains 12 Device according to claim 1, characterized in that the transfer nozzle (19) is terminated by a female Luer cone and arranged to allow the connection of a syringe (24) having a male Luer nozzle

13 Device according to claim 1, characterized in that the transfer nozzle (19) is equipped with a needle (30) arranged to allow connection with an infusion bag (31)

14 Device according to claim 1, characterized in that the transfer nozzle (19) contains a syringe needle (42) arranged to be connected to a syringe (24) for activation of the system and transfer of the reconstituted solution

15 Device according to claim 11, characterized in that the housing (13) comprises an antibacterial filter (6) arranged to filter the liquid component before its transfer through the cannula (17) into the bottle containing the active substance

16 Device according to claim 1, characterized in that said transfer nozzle (19) is arranged to contain a receptacle, constituted by a syringe (170), an empty cartridge (200) or the like

17 Device according to claim 16, characterized in that the transfer nozzle (19) is removable for later use with said empty cartridge (200)

18 Device according to claim 6, characterized in that at least one of said housings (13, 14) is arranged to receive a bulb (150, 160) sealed with flame