SK22896A3 - Device for the preparation of a solution, a suspension or an emulsion of medicinal substance - Google Patents

Abstract

The invention relates to a device for the preparation of a medicinal solution from two compounds, one of which is in the form of a powder, a lyophilisate or a liquid and the other one is a diluent or a liquid solvent. These compounds are respectively stored in a distal closed container (11) and a proximal container (13), each having an opening sealed by an obturator-piston-valve, which isaxially movable. The two obturators-pistons-valves (19, 24) are connected by a transfer rod (15) arranged to provide for a rigid, sealed and sterile couplind link between the two obturators-pistons-valves (19, 24) when the device (10) is in a storage position, and to define a liquid-tight and sterile communication channel between the two containers (11, 13) when the device is in a utilisation position. The obturators-pistons-valves (19, 24) have a central area provided with a slot (31, 33) which is highly compressed and sealingly closed when the device is in a storage position, and opened when an extremity of the transfer rod (15) is inserted therein, the device being then in the utilisation position.

Description

Apparatus for preparing a drug substance solution, suspension or emulsion

Technical field

The invention relates to a device for preparing a solution, suspension or emulsion of an active therapeutic substance, from two components, from at least two components, of which at least one is in the liquid state.

BACKGROUND OF THE INVENTION

Reconstitution of a drug prior to use from one or more components stored in the same assembly hermetically sealed and intended to be mixed in the assembly without introducing external elements presents a number of problems. A large number of two-component vials have been developed for this purpose. These vials generally comprise a single reservoir divided into two compartments by a movable closure device. Both compartments are hermetically sealed during storage. Before using the reconstituted drug, the system activation phase allows the mixing of both substances, at least one of which is in the liquid state. For this purpose, the movable closing device separating the two compartments is pushed so as to penetrate into an area which is expanded or is provided with a bypass allowing the liquid or solvent to flow to the second component, which may be liquid, solid, viscous, pasty, etc. .

The production of these double reservoirs is not always easy and does not always meet the needs of the pharmaceutical industry for particular applications. A syringe with two compartments of the above type is the subject of U.S. Pat. No. 4,014,330, which discloses a syringe with two components, each contained in one compartment, which are closed by corresponding two closures, also having the function of a piston. This device is constructed from two elements that must necessarily be assembled before use. Fitting the vial, which defines distal separation, necessarily corresponds to system activation. Reconstitution and redundancy (transfer) cannot be carried out in a confined environment, which entails significant risks of contamination of the staff performing the therapeutic action with the substance and loss of sterility of the mixture. In addition, the active ingredient is mounted in a proximal reservoir which is open at both ends and is equipped with flanges. This poses particularly problems of manufacture when working with a lyophilisate, powder or liquid.

Indeed, it is a primary requirement that these active substances be stored in a flat-bottomed cylindrical vial closed under flame in order to respect the particular requirements for handling these substances using known equipment, under vacuum preparation (washing, silicone, silicone film fastening, depyrogenation and sterilization) vials), filling (liquid, powder, lyophilisate), closing (stoppering) and moving it towards the assembly unit with the component containing the diluent compartment.

The system described in U.S. Pat. No. 4,014,330 cannot satisfy these requirements because the active substance would have to be stored in a distal reservoir and under these conditions reconstitution would not be possible for design reasons.

One of the problems that can be solved with difficulty when using systems where the components are contained in a single reservoir with two compartments is the individual storage of both components. In other words, the conditions for the preparation and sterilization of one of the components are not necessarily those which are suitable for the preparation of the other component. The solvent cannot be treated in the same way as the lyophilisate or some powders. The lyophilisate does not withstand the heat required to sterilize the solvent by autoclaving.

In a single reservoir, the lyophilisate is separated from the solvent by a movable elastomeric closure. The solvent is in continuous contact with this movable closure and the partial vapor pressure is still at its maximum. The risk of vapor penetration through this movable seal is great and the retention time of the lyophilisate may be adversely affected or limited in time.

As a result, the choice of elastomers is limited to those whose ability to form a tight barrier is as high as possible. This limitation puts real-time demands on stability and compatibility tests, which is very costly and long and burdensome on pharmaceutical companies when they have to make decisions regarding the storage of their substances in bicameral systems.

These drawbacks are accompanied by an increased risk of losing the sterility of the reservoir due to the humid environment. Under monocompact storage conditions, a dry product, which in addition is not capable of autoclaving, has less prospects to allow germ growth when in a dry environment. This risk freeness is lost when liquid is stored in the same reservoir. The addition of preservatives is undesirable and even prohibited in some cases, especially for disposable products.

Multiple-use products, in successive doses, are stored with preservatives, not to limit the growth of germs during storage, but to maintain a sterile state after reconstitution for the entire period of use, which may last for several days.

Another problem that is difficult to solve with current systems is to manage the flow when reconstituting the mixture without external intervention by a screwing procedure, as described in European patent specification no. 0 298 067 BI.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome these disadvantages and to provide a simple and efficient device in which the risks of contamination of one component with the other component are eliminated, in which the essential components required for the preparation of the medicament can be subjected to different operations. and where the flow for reconstitution would be handled in a tight and sterile environment without external interference.

SUMMARY OF THE INVENTION

The object is achieved according to the invention by a device for preparing a solution, suspension or emulsion of the active therapeutic substance, of two components, one of which is in the powder, lyophilizate, liquid or paste state and the other is a liquid diluent or solvent, and stored in two corresponding elongated receptacles, namely a distal closed-bottom reservoir and a proximal reservoir, each having at one of their ends an opening closed by a piston and valve cap movable axially in the corresponding reservoir, the two piston and valve caps being connected by an operating rod member adapted for providing a rigid, tight and sterile connection between the two piston and valve shutters when the device is in the first position, the storage position, and for defining a tight and sterile connection channel between the two receptacles when the device is in the second position, the position of use, wherein the distal reservoir comprises said component in a powder, lyophilisate, liquid or paste state, and the proximal reservoir comprises said liquid diluent or solvent, wherein the distal reservoir has a cross-section greater than that of the proximal reservoir, a cross-section greater than the cross-section of the piston and valve plugs of the proximal reservoir, the ends of the transfer rod member being trimmed in a plane substantially perpendicular to its longitudinal axis, and wherein the piston and valve plugs have a central region provided with a slot, strongly compressed and tightly closed; when the device is in the storage position, and open when the end of the transfer bar member is inserted therein, and the device is in said second position.

According to a preferred embodiment, the device comprises a housing in which the proximal reservoir and at least partially the distal reservoir are accommodated.

Said housing may be associated with a push cap and a multiple dose dispensing mechanism. In another embodiment, said housing may be formed in one piece by molding, such as by pressing, with a proximal reservoir.

According to the intended use of the device, said housing is provided with an extension projection forming an eye drop applicator or nasal spray disposed in the proximal reservoir.

In a preferred embodiment, said housing comprises a first tubular element and a second tubular element retractable, wherein said first tubular element houses a proximal reservoir and the second secondary tubular element accommodates said distal reservoir. Preferably, said first tubular element comprises teeth and the second tubular element comprises at least two tongues adapted to interact with said teeth.

Said piston and valve caps preferably comprise each corresponding central recess, said transfer rod member comprising tight and sterile connection means for engaging said piston and valve caps.

According to a further feature of the invention, said transfer rod member comprises stopping stops adapted to abut on opposite faces of a corresponding piston and valve closure when the device is in the position of use.

When the device is in the storage position, said piston and valve shutters are adapted to ensure the tight and sterile closure of the corresponding receptacles by leaning against the inner walls of the receptacles so that said receptacles can be stored and processed independently.

In all embodiments, said transfer rod member is adapted to provide a rigid, tight and sterile connection of said piston and valve caps firmly connected to said distal reservoir and proximal reservoir.

In the device according to the invention, preferably said proximal reservoir is adapted to receive various attachments and applicators depending on the intended therapeutic uses.

BRIEF DESCRIPTION OF THE DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS The invention will be explained in more detail below with reference to the accompanying drawings, in which: FIG. 1 to 4 a preferred embodiment of the device according to the invention progressively in the phases of storage, activation and use; 5 shows a particular embodiment of a device intended for use as an eye drop distributor, FIG. 6 to 9 show other embodiments of the device according to the invention sequentially in the storage, activation, start-up and end-use phases; 10 to 13 show an improvement of the device of FIG. 1 to 4, FIG. 14 to 18 show another variant of the device used as a syringe associated with a multiple dose dispensing mechanism; Figures 19 to 22 of the device according to the invention adapted for ophthalmic use; 23 and 24 are enlarged details of the piston and valve shutters in their rest position; FIG. 25 and 26 are enlarged details of the piston and valve shutters in their actuation and use position; FIG. 27 to 30 show enlarged details of a device adaptable to the device depending on the intended applications; and FIGS. Figures 31 to 61 show the different stages of preparation and assembly of components forming a device according to the invention in different uses of the device and with different basic components and components corresponding to these uses.

DETAILED DESCRIPTION OF THE INVENTION

Fig. 1 to 4 show a preferred embodiment of the device 10 allowing the preparation of a therapeutic solution, for example an injectable solution, from two basic components. Specifically, FIG. 1 equipment in storage phase. It comprises a first reservoir 11 storing the lyophilisate 12, a second reservoir 13 containing in this case solvent 14, and a transfer bar member 15 provided with a hollow channel 16. The reservoir 11, hereinafter called distal reservoir (further away from the application site), has a closed bottom 17 and an open end 18 to receive the piston and valve closure 19 defining a chamber 20 containing the lyophilisate 12 within the distal reservoir. It will be appreciated that the lyophilisate 12 may be replaced by another active substance, such as a liquid, powder, or paste substance with greater or lesser viscosity.

The reservoir 13, hereinafter called the proximal reservoir (closer to the site of application), is open at both ends. In the example shown, the open end 21 is closed by a cap 22 secured by peripheral mechanical engagement. This cap, known per se, is used for a variety of vials containing therapeutic agents and can be formed in a composite form of tightness-tight plastic and of aluminum to provide resistance and create an antiseptic hindrance. The open second end 23 of the reservoir 13 is closed by a piston and valve closure 24.

The two piston and valve shutters 19 and 24 are each provided with a corresponding central recess 25, 26 into which the corresponding protrusions 27, 28 are integral with the operating rod member 15. The piston and valve shutter 24 define a chamber with the walls of the reservoir 13 and the cap 22 29 containing solvent 14; Depending on the nature of the drug substance contained in the chamber 20 of the distal reservoir 11, the solvent may be replaced by a diluent. Regardless of the nature of the active substance in the distal reservoir, the substance is always stored in the proximal reservoir in a liquid state and serves to form with the therapeutic substance a solution, suspension or emulsion based on two basic components intended for subsequent use in therapeutic injection applications. or in a sprayable form, administrable externally or internally by any applicator, in particular a needle, a trooper, a drop dispenser, a nebulizer, etc. '.

The piston and valve closure 24 includes a small recess 30 in the extension of the central recess 26 into which the front end of the transfer bar member 15 is inserted. In the extension of this small recess 30, the piston and valve closure comprises a pre-cut slot (slitting) 31. play the role of a valve closure, closed during storage and opened during other phases, i.e. during activation and use. The walls of the elastomeric piston and valve closure 24 that surround the closure portions of the slot 31 are thick, and the slot is formed in an area providing increased compression of said closure portions of the slot when the plunger and valve closure is compressed within the proximal reservoir so when stored, it is perfectly effective to ensure both the tightness and sterility of the chamber and the contents of the proximal reservoir.

Similarly, the piston and valve closure 19 includes a central recess 32 into which the other end of the transfer bar member 15 is inserted. In the extension of this recess, the piston and valve closure is provided with a slit (cut) to provide valve operation during storage and open during further use phases. system, ie activation and use. Here again, the thickness of the material that surrounds the closure portions of the pre-slit slot 33 is sufficient to ensure that the closure portions are relatively squeezed to ensure the tightness and sterility of the chamber 20 of the distal reservoir 11 when the piston and valve caps are fitted within the distal reservoir.

In the embodiment shown, the inner diameter of the distal reservoir is substantially the same as the outer diameter of the proximal reservoir so that they can be at least partially inserted into each other at the time of use. For obvious reasons of simplicity and cost of production, both tanks have a substantially elongated cylindrical shape with a circular cross-section. With respect to the diameter difference of the two reservoirs, the piston and valve closure 19 has a diameter larger than that of the piston and valve closure 24. At the moment of actuation, the first phase of which is shown in FIG. 2 initiated by exerting axial pressure, preferably the bottom 17 of the distal reservoir ^»fe proximal reservoir is maintained in a position in which the ends of said transfer rail member 15 inserted into the respective slots 31 and 33 by a stopper 21, and 29, which results that the chambers 20 and 29 are joined and the solvent 14 is passed through the channel 16 into the chamber 20 containing the lyophilisate.

The diameter and length of the channel 16 are sized so as to obtain a controlled flow at the outlet of solvent 14 through the channel 16. Obviously, the ends of the transfer bar member are not beveled, since their function does not consist in perforating the membrane, but has a planar cross-section arranged in planes perpendicular to the axis of the transfer bar member, possibly extended by a slightly conical truncated cone section. This geometry allows for easy insertion into the slots in a tight and sterile manner, the end of which is intended to expand the closure portions of the slots for opening the valve of the piston and valve closure, contrary to a number of known systems. perforating membrane.

Tightness between the membrane and the bevel end can only be ensured if the thickness of the membrane is significantly greater than the length of the bevel, which is incompatible with the compact design and the ease of perforation of the membrane. In addition, it is also evident that the transfer bar member is provided with a first stop 34 and a second stop 35 which, in addition to the storage position, are supported on corresponding plots opposite the piston and valve shutters 24 and 19. These stops serve to define precisely the penetration member into corresponding proximal and distal reservoir chambers.

When the user further leans against the bottom 17, all the solvent contained in the proximal reservoir 13 flows into the chamber 20, coming into contact with the lyophilisate 12 to form a solution 12 + 14, which constitutes the reconstituted therapeutic agent. Combining the pressures and surface differences between the two piston and valve caps, the piston and valve caps 24 reach the front end of the proximal reservoir 13 and the piston and valve caps 19 are positioned such that degassing can be ensured when the vial is equipped with a corresponding extension depending on the intended use of the treatment solution.

If this solution is for injection, the needle will be the extension. For example, if the solution is to be dispensed into a transfusion bag, the attachment will be a trocar. If the solution is intended for other use, the extension is selected accordingly. Regardless of the nature of the attachment, the solution is transported via the channel 16. For this purpose, the user can use it! The plunger and valve closure 19 is gradually inserted into the interior of the distal reservoir 11 until it touches the bottom 17. In order to prevent reuse of the device, when used as a syringe, the means for connecting the projections 27 and 28 of the transfer bar member 15 to the corresponding piston and valve shutters 19 and 24 are sufficiently weak to separate when in use! he tried to pull the proximal reservoir out of the distal reservoir, so that any suction of liquid inside the device becomes impossible.

Fig. 5 illustrates a device according to the invention adapted for use in ophthalmic treatment operations. In this case, the distal reservoir 11 and the proximal reservoir 13 are pre-inserted into each other. The distal reservoir 11, which contains the lyophilizate 12, is completely empty, with the piston and valve closure 19 slid into the interior of the reservoir against the substance it contains. The advantage of this arrangement is that it makes it possible to completely eliminate any discharge or removal of bubbles and to prevent oxidation of the mixture upon reconstitution, i.e. when the device is activated.

The proximal reservoir 13, which, as noted, is open at both ends thereof and is closed at one end by a plunger and valve cap 24 and at the other end by a plug 50. A cap 51 is fitted over this plug 50 and a cap 51 is fitted between the cap and plug. an inserted filter 52 as well as a silver plate having an oligodynamic function. The silver plate may be replaced by another material, such as silver oxide or a compound containing substances having similar properties. The entire assembly is closed by a protective cap 53. The end of the cap 51 is provided with a protrusion 54 with a spiral cannula 55. In this case, the transfer bar member 15 is preferably a rigid one-piece synthetic material. Obviously, the plug 50 has a geometry that is substantially identical to the geometry of the piston and valve closure 24, and that it works on the same principles, at least as far as its central opening, making it a valve formed by a pre-cut slot intended for this. to be opened in the use phase of the device by the end of the transfer bar member.

Also, in this embodiment, the cap 51 has a sufficiently long skirt section to cover a portion of the distal canister near its open end. It will also be appreciated that the distal reservoir 11 is also housed within the lid, namely the lid 56 of synthetic material to provide protection. For other applications, the cap 56 may be omitted and the distal reservoir may be directly inserted around its open upper portion within the skirt portion of the cap 51.

Fig. Figures 7 to 9 show another embodiment of a device for use as a syringe for injecting a reconstituted therapeutic agent. Fig. 6 shows the state of storage, FIG. 7 shows the activation state and FIG. 8 and 9 use within a mechanical multi-dose system. As mentioned above, the device 10 comprises a distal reservoir 11 containing, for example, a lyophilisate 12, and a proximal reservoir 13, containing, for example, a solvent 14, as well as a transfer bar member 15, intended to provide a connection between the two reservoirs through a tubular channel 16.

The distal reservoir 11 has a closed bottom 17 and is provided with an opening 18 at the end opposite to the bottom 17. It is closed by a piston and valve closure 19 defining a chamber 20 containing a lyophilisate 12. The proximal reservoir 13 has an upper opening 21 closed by a circumferentially mechanically engaged cap 22. Since this reservoir is open at its two ends, its other end 23 is closed by a piston and valve closure 24. The piston and valve closure 19 comprises a central recess 25, and the piston and valve closure 24 comprises a central recess 26, both of which are intended to receive corresponding end projections 27 and 28 of the transfer bar member 15.

The piston and valve closure 24 comprises a pre-cut slit 31 (cut) which serves as a valve for receiving the transfer bar member 15. The piston and valve closure 19 is also provided with a pre-cut slit 33 (cut) serving as a valve that is intended to pass the other end of the transfer bar member

15th

It will be appreciated that, with the exception of several construction details, the elements described above are identical to those described with reference to FIG. However, it will be appreciated that the proximal reservoir 13 is housed within the first tubular element 40, the proximal end of which is provided with a protective cap 41 on it, and that the distal reservoir 11 is housed inside the second tubular element 42 partially inserted inside the first tubular element. element 40 ,. In the storage position shown in FIG. 6, the two tubular elements 40 and 42 define a substantially cylindrical housing within which the device 10 as shown in FIG. First

To activate the device, the second element 42 is provided with a series of teeth 43 which can be disposed on the entire circumference of the element or only on a predetermined area of the circumference. These teeth are intended to cooperate with at least one pliable tongue 44 formed within the sidewall of the element 40 to exert predetermined braking forces to control the relative axial displacement of the two stopping members 40 and 42 preventing the reverse movement of the second element. 42 when it is inserted into the first element 40.

Fig. 7 shows the activation and preparation phase of the mixture of the two components. At this stage, the tubular member 42 has been pushed inwardly 14a of the tubular member 40, resulting in the displacement of the distal canister toward the proximal canister. This results in the penetration of both ends of the transfer rod into the slots forming the corresponding piston and valve caps, the displacement of the piston and valve caps 24 axially into the proximal reservoir, and the solvent leakage into the chamber 20 containing the lyophilisate 12. At the end of this activation phase of the substances or constituents of the therapeutic substance terminated and the substance is ready for use.

Fig. 8 illustrates the final stage of preparation, which consists of degassing or de-bubbling the device, in which case the device is equipped with a needle 45 for injecting the reconstituted therapeutic agent. The second tubular member 42 has been fully pushed into the interior of the first tubular member 40, the distal reservoir in which the lyophilisate is dissolved has been completely degassed, and the pressure exerted on the bottom 17 of the distal reservoir by a suitable pushbutton 46 allows the piston and valve closure 19 to slide. the solution contained in said distal reservoir. As a result, the plunger and valve caps function as a plunger that forces the solution through the channel 16 of the transfer bar member 15 toward the injection needle 45.

At the end of the use phase shown in FIG. 9, the pushbutton 46 fully pushes the distal canister toward the proximal end of the device so that the piston and valve shutter 19 is fully inserted into the distal canister and nearly all of the injectable drug substance solution is removed. In addition, it is apparent that the second cylindrical member 42 has been fully inserted into the first cylindrical member 40 and that the teeth 43 interact with the flexible tongue 44 to block the two members relative to each other to prevent any return of the second member to its initial position. Due to the presence of these devices, the device is guaranteed to be unfit for reuse.

Fig. 10 to 13 show a variant which can be considered as an improvement of the device shown in FIG. 1 to 4 and corresponding to what may be referred to as the primary container. The device shown in FIG. 10, in the storage state, substantially corresponds to the connection of the primary container shown in FIG. 1, with its distal reservoir 11, its proximal reservoir 13, and its transfer bar member 15 mounted at least partially, at least during storage, within a cylindrical body or housing 60. This housing 60 is preferably formed of a molded synthetic material. It comprises at its front end a region of lesser thickness 61 which can be easily perforated by a needle as shown in FIG. 12. In addition, it will be appreciated that the transfer bar member comprises an inner channel 16, which is preferably formed by a hollow cannula of molded metal.

Fig. 11 shows the device 10 in the final stage of activation, when the solvent 14 has been transferred through the transfer bar member 15 to the chamber 20 of the distal reservoir 11 for dissolving the lyophilisate.

Fig. 12 shows the phase of degassing of the syringe obtained by adding a needle 62 pre-mounted on the base 63 and protected by a protective cap 64. FIG. It will be appreciated that the distal reservoir 11 has been pushed toward the proximal end of the device to vent the air contained in the chamber 20 of said distal reservoir after the mixture has been formed.

Fig. 13 shows the device at the end of use. Obviously, the cap 64 has been refitted at the end of the needle guard and to prevent the attendant from accidentally injuring her. Finally, the distal and proximal reservoirs are inserted into each other and lie entirely within the housing 60, preventing any reuse of the syringe, since it is impossible to pull the distal reservoir rearwardly without breaking the housing. If this operation could be carried out, the safety achieved by effectively disconnecting the piston and valve shutters and the transfer rod member from each other, as explained with reference to the device description of FIG. 1 to 4.

Fig. Figures 14 to 18 show another embodiment derived from the previous embodiment in which the housing 60 has been replaced by a housing 60 ^l longer than the housing 60. To this housing 60 'is attached a pressure cap 70 as well as a dispensing mechanism 7i which is itself known under the name PEN and the like. The device 10 comprises, as in the previous example, the main elements which are the distal reservoir 11, the proximal reservoir 13 and the operating rod member.

15. FIG. 14 in the storage phase. Fig. 15 shows the activated state. Fig. 16 shows an activated device equipped with a dispensing mechanism 71. FIG. 17 shows an activated device equipped with a dosing mechanism and equipped with a syringe 72. FIG. 18 shows the device at the end of use.

Fig. 19 and 20 illustrate a device adapted for use for ophthalmological purposes. It will be appreciated that in this embodiment, the proximal reservoir 13 is formed from a single piece molded plastic with the housing 60, which generally comprises said proximal reservoir and partly, at least during storage, the distal reservoir 11. The housing 60 is extended by an eye drop applicator formed by a protrusion 54, substantially identical, at least in function, to the protrusion described with reference to FIG. This protrusion could also be in the form of a nebulizer for nasal application. The sealing and sterile closure of the device during the storage phase shown in FIG. 19, and the activation phase shown in FIG. 20 is secured by a protective cap 53. The use phase is shown in FIG. 21. The end of use is shown in FIG. It will be appreciated that the distal reservoir 11 is fully inserted into the interior of the housing 60, ensuring that the device will not be reused.

Fig. 23 shows an enlarged detail of the piston and valve shutters 24 and the corresponding end of the transfer bar member provided with its central channel in the storage position. In this position, the end 15a of the actual transfer rod member is inserted into the first region 24a of the piston and valve closure 24, which insertion is designed so as to provide a perfect seal and sterile obstruction due to the resilient compression that is produced at the surface 15b. Also in this position, the end 16a of the channel 16, which is defined by a planar section substantially perpendicular to the axis of the channel, is also supported by the inlet of the slot 31 which forms the valve of the piston and valve closure 24.

As mentioned above, the valve is kept tightly closed by compressing a relatively large mass surrounding its closing portions. The opening of this closure does not occur, as in many known systems, under the effect of the pressure exerted by the liquid being pushed through the channel 16, but by the mechanical pressure of inserting the end 16a into the channel. Thus, the tightness between the walls of the channel 16 and the closing portions of the slot 31 is maintained and the central recess 26 of the piston and valve closure 24 never contacts the components of the two reservoirs or the reconstituted substance.

Fig. 24 shows an enlarged detail similar to FIG. 23, but showing the piston and valve shutters 19 in a storage condition. As in the previous case, the second end 15c of the transfer rod member 15 is inserted into the central recess 32 of the piston and valve shutters 19 and the channel end 16c is supported on the inlet of the slot 33 serving as the valve function. Tightness and sterility are provided at the level of the surface 15d, due to the compression exerted by the mass of the piston and valve closure 19 at the end 15c of the transfer bar member in the respective region. Likewise, a seal is provided between the end 16c of the channel 16 and the closing portions of the slot 33 when this end is inserted into said slot.

It will further be appreciated that for the two piston and valve shutters 19 and 24 shown in FIG. 24 and 23, the ends 15a and 15c on either side of the transfer bar member 15 are harpoon-shaped, provided with engaging stops to ensure a relatively firm connection of the transfer bar member and the piston and valve caps during the storage phase. Due to this shape of the spear, these ends 15a and 15c form engaging stops and coupling means which allow to define the exact position of said piston and valve caps within the device.

Fig. 25 shows the piston and valve caps 24 of FIG.

in the device activation position. The end 15a of the transfer bar member has been moved inside the central recess 26 and the end 16a of the channel 16 has been pushed through the pre-cut slot 31. This figure shows clearly how the sealing and sterility zones are maintained at this stage.

Fig. 26 shows the piston and valve caps 19 of FIG.

in the activation phase. Here, the end 15c of the transfer bar member 15 is pushed inside the central recess 32, and the end 16c of the channel 16 is pushed through the pre-cut slot 33. As in the above case, the leakage and sterile obstruction zones are maintained at this stage.

Fig. 27 to 30 show various accessories or peripheral formations intended to be connected to the device 10 for a particular use of the device. Specifically, FIG. 27 is an enlarged detail of the end of the device 10 as shown in FIG. 12, wherein the needle 62 mounted on the base 62 is protected by a protective cap 64.

Fig. 28 shows another embodiment in which the transfer needle 62a is protected by a solid synthetic resin guard 80, wherein the needle is furthermore covered by a flexible sheath 81.

This sheath 81 serves to prevent dew (re-spraying) of the device from operating inside the medical staff.

protection of the secured bent on itself, to another needle 62a. fabric equipment,

Indeed, such a reservoir, such as transfusion due to a slight overpressure, 10 may occur which may be dangerous to spray by avoiding the vagina 81, which is flexible as the successive transfer needle of the constituent substance inside the device 10 at the time of bag connection through the dusting. as a consequence and which is inserted into the corresponding extension of the blood bag and then expands upon removal and disconnection to close the device 10.

Fig. 29 shows a device equipped with a housing 60a having substantially the same functions as the housing 60 shown in FIG. 10. At the end of the housing there is provided an extension 60b having the shape of an outer sleeve cone of the Luer system and making it possible to attach accessories such as a needle carrier, a plug-in connection element of the Luer system, etc.

Fig. 30 is similar to FIG. 29, but the adapter 60b is replaced by a plug-in adapter 60c in the shape of a Luer cone.

The following figures schematically show the movement phases of assembly and construction of the device 10 and its components in various cases in the figures, i. when the distal reservoir is intended to contain a lyophilisate, a more or less viscous liquid or powder. Fig. 31 shows the distal reservoir 11 disposed in the housing 90. It is understood that this clamped arrangement is possible due to the cylindrical shape of the reservoir. Fig. 32 shows the filling of the distal reservoir 11 by means of a solution to be lyophilized.

Fig. 33 shows the pre-deposition phase of the piston and valve shutters 19. FIG. 34 shows the lyophilization phase during which steam and gases can escape through grooves 91 formed in the lower region of the piston and valve closure 19. It is evident that the energy transfer is easy relative to the flat bottom of the vial, promoting homogeneous ice crystal formation and almost complete drying of the lyophilized product . Fig. 35 shows the sealing phase of the distal reservoir. This closure takes place by inserting the piston and valve shutters 19 through a thrust member 92, which may be formed directly by the ceiling of the lyophilization chamber within which the march occurs.

Fig. 37 shows the deposition phase of the piston and valve shutters 19, which is done automatically by sucking the device inside the distal reservoir in which the vacuum is and then mechanically to adjust the final position. Fig. 37 shows the return of filled containers to cartridges 90. It will be understood that these processes are carried out by standard procedures, widely used in the pharmaceutical industry.

In the case where the active substance contained in the reservoir 11 is a liquid and not a lyophilisate, the process is simplified because it contains only the filling phase shown in FIG. 32, the pre-deposition of the piston and valve caps shown in FIG. 33 and finally fitting the piston and valve caps, possibly by means of a suitable push button which allows degassing within the reservoir.

Fig. 38-44 show filling of the distal reservoir with powder. Specifically, FIG. 38 of the reservoir 11 housed in the container magazine 90. FIG. 39 shows the filling of the reservoir 11 with a dose of powder, the doses being contained in the buckets 93 mounted on the feed system of the wheel type 94 used in the pharmaceutical industry. Fig. 40 shows the pre-deposition phase of the piston and valve shutters 19 accompanied by a degassing phase by means of a suction nozzle 95 of suitable shape. For this purpose, the adapter comprises a cannula 96 which is inserted through the slot 33 of the piston and valve closure. Upon retraction of the tool, the distal grips 21 are loosely supported on the transfer plate 97 from where they protrude in an aligned fit for subsequent processing, as shown in FIG. 41st

Fig. 41 shows the distal reservoir 11 with its piston and valve shutters 19, preloaded as it emerges from the transfer plate 97 of FIG. 41. This phase of vibration of the powder is necessary to ensure that it is deposited on the bottom of the reservoir. The precise fit of the piston and valve caps 19 within the distal reservoir 11 is accompanied, as shown in FIG. 43, by aspirating the gases lying over the powder, through the cannula 96 described with reference to FIG. FIG. 44 shows a distal reservoir 11 with a suitably disposed piston and valve closure. The powder is wiped from the walls of the reservoir when the piston and valve caps are fitted due to the pressure exerted on these walls. Despite this, a decontamination phase is still necessary, consisting in the removal of powder residues on the inner and outer walls of the distal reservoir.

Fig. 45 to 54 show the assembly of a device 10 specifically intended for ophthalmic use. Fig. 45 shows a proximal reservoir 12 housed in a box container 100. This reservoir corresponds to the reservoirs described above, in particular those described above with reference in particular to FIG. 5 and FIG. 19-22. FIG. 46 shows the filling phase of the reservoir 13 by means of a liquid 14, which may be a solvent or diluent, as mentioned above. Fig. 47 illustrates the deposition phase of the piston and valve shutters 24 within the reservoir 12. After these various operations, the reservoirs 13 are refolded in the container cartridges 100 (see FIG. 48). As in the aforementioned case, this tight arrangement is possible only because of the fact that the reservoirs have a cylindrical shape without roughening and especially without protruding flanges.

The containers 12 stored in the container may be stored for more or less long periods and possibly subjected to processing such as sterilization. This phase is shown in FIG. 49. FIG. 50 shows a reservoir 90 into which distal reservoirs 11 are received. FIG. 51 illustrates the placement of the transfer bar member 15 in the proximal reservoir 13.

Fig. 52 illustrates a final assembly phase consisting in mounting the distal canister 11 on a transfer bar member 15 that has been pre-positioned inside the proximal canister 13. FIG. 53 shows the visual inspection phase of the pre-assembled device 10. FIG. 54 shows a fully assembled and inspected device originating from the processes described above.

Obviously, all of these processes can be carried out in standard equipment, widely used in the pharmaceutical industry, and do not need any particular machine to assemble the various components of the equipment. To facilitate this assembly and reduce costs, the number of rearrangements, in particular the number of transitions from the rearranged to the rearranged and vice versa, is minimized.

Fig. 55 to 62 show a method for preparing the proximal reservoir 13 and fitting the transfer bar member 15. The empty reservoir 13 is stored as shown in FIG. 55, into the container magazine 100. FIG. 56 shows the phase of placing the piston and valve shutters 24 inside the reservoir 13. FIG. 57 shows the filling phase of solvent or diluent 14. FIG. 58 shows the lid of the reservoir, i. fitting the cap 22. FIG. 59 depicts the return of the containers 13 to the container 100 for storage or subsequent processing such as sterilization.

Fig. 60 shows the receptacles 13 as stored in the container 100 after an optional sterilization or similar treatment within the housing 60 as shown in FIG. These housings 60 are themselves removed from the interior of the cartridge 110 where they have been stored for assembly. Fig. 61 shows the mounting of the transfer bar member 15 on the proximal reservoir 13 previously mounted within the housing 60. FIG. 62 illustrates the mounting of the distal reservoir 11 at the other end of the transfer bar member 15 previously mounted within the housing 60. FIG. 62 shows the mounting of the distal reservoir 11 at the other end of the transfer bar member 15, previously assembled as shown in FIG. 61st

Here again, the assembly is carried out using standard means which are commonly used in the pharmaceutical industry and do not require special equipment. In addition, most of the components, and in particular the distal and proximal reservoir, as well as the housing in which the proximal reservoir is housed, are housed in the reservoirs, reducing or eliminating a series of transitions from one ordered state to another disordered state.

Claims (12)

PATENT CLAIMS An apparatus for preparing a solution, suspension or emulsion of an active therapeutic substance, of two components, one of which is in the powder, lyophilizate, liquid or paste state and the other of which is a liquid diluent or solvent, and stored in two corresponding elongated containers; a distal reservoir with a closed bottom and a proximal reservoir, characterized in that the distal reservoir (11) has a closed bottom (17) and, like the proximal reservoir (13) at one end, has an opening closed by a piston and valve cap movable axially in the corresponding reservoir, the two piston and valve shutters (19, 24) being connected by an operating rod member (15) adapted to provide a rigid, tight and sterile connection between the two piston and valve shutters (19, 24) when the device is in a first position, namely a storage position, and to define a tight and sterile connection a channel between the two containers (11, 13) when the device is in a second position, the use position, wherein the distal container (11) comprises said component in powder, lyophilizate, liquid or paste state and the proximal container (13) comprises said a liquid diluent or solvent (14), wherein the distal reservoir has a cross-section greater than the cross-section of the proximal reservoir, the piston and valve cap (19) of the distal reservoir (11) having a cross-section greater than the cross section of the piston and valve cap ( 24) of the proximal reservoir (13), wherein the ends of the transfer bar member (15) are trimmed in a plane substantially perpendicular to its longitudinal axis, and wherein said piston and valve caps have a central area provided with a slot (31, 33) strongly compressed and tight closed when the device is in the storage position, and open when the end of the transfer bar member (15) is inserted and the control is in said second position. Device according to claim 1, characterized in that it comprises a housing (60) in which the proximal reservoir (13) and at least partially the distal reservoir (11) are received. Apparatus according to claim 2, characterized in that said housing (60) is associated with a push cap (70) and a dispensing mechanism (71) for applying multiple doses. Device according to claim 2, characterized in that said housing (60) is formed integrally with a proximal reservoir (13). Apparatus according to claim 4, characterized in that said housing (60) is provided with an extension projection (54) forming an eye drop applicator or nasal spray disposed in the proximal reservoir (13). Apparatus according to claim 2, characterized in that said housing (60) consists of a first tubular element (40) and a second tubular element (42), which can be inserted into each other, wherein said first tubular element houses a proximal reservoir (13) and in said second secondary tubular element said distal reservoir (11) is received. The device of claim 6, wherein said first tubular element comprises teeth (43) and the second tubular element comprises at least two tabs (44) adapted to interact with said teeth. Apparatus according to claim 1, characterized in that said piston and valve caps (19, 24) each comprise a corresponding central recess (32, 36), said transfer rod member (15) comprising tight and sterile coupling means for coupling by said piston and valve caps (19, 24). Apparatus according to claim 1, characterized in that said transfer rod member (15) comprises stop stops adapted to abut on opposite faces of a corresponding piston and valve closure when the device is in the use position. Apparatus according to claim 1, characterized in that said piston and valve caps (19, 24) are adapted to ensure the tight and sterile closure of the corresponding receptacles (11, 13) by abutting on the inner walls of said receptacles such that said receptacles they can be stored and processed independently. Apparatus according to claim 1, characterized in that said transfer bar member (15) is adapted to provide a rigid, tight and sterile connection of said piston and valve caps (19, 24) firmly connected to said distal reservoir (11); a proximal reservoir (13). Device according to claim 1, characterized in that said proximal reservoir (13) is adapted to receive various attachments and applicators depending on the intended therapeutic uses.