FR2799643A1 - Syringe for preparing solutions, suspensions or dispersions, has separate compartments for solid and liquid components prior to injection - Google Patents

Abstract

The present invention relates to a method of packaging in a cylindrical reservoir usable in a single-dose or multi-dose syringe intended for the extemporaneous preparation of a solution, a suspension or a dispersion. Said method is a conditioning method inside a cylindrical tank closed on one side by an injection piston blocked in its movement in said tank, characterized in that the elements to be conditioned are introduced inside said reservoir on the side of said injection piston before said reservoir is closed by said piston, said reservoir being a tube or a cartridge previously closed on the other side.

Description

<U> Packaging method in a cylindrical reservoir usable </ U> <U> in a syringe </ U> <U> or </ U> multidose <U> destined <B> to </ B> the preparation < The present invention relates to a device for the extemporaneous preparation of a solution of a suspension or a dispersion of a suspension, or a dispersion. , for example of injectable formulations preferentially according to a process of reconstitution under the action of the so-called vacuum ("Vacuum Automatic Control") subject of an earlier French patent application no. <B> 96/06886. </ B The present invention also relates to a process for preparing and conditioning said formulations in said devices according to which will then close the reservoir of said devices containing the solid part said formulation by the piston side, opposite <B> to </ B> its injection or <B> to </ B> its release after reconstitution.

According to the invention, the device is preferably used as a device which part of the formulation is packaged under vacuum and another consists of the liquid part of the final preparation, each of them being conditioned a separate reservoir forming part of said device.

In therapeutic and exemplary preparations, more particularly the case of injectable forms, it is sometimes useful, preferable or even essential to separate the constituents. The device and the method forming the subject of the present invention are more particularly concerned with the cases in which a part of said constituents is in a non-liquid form and another in a liquid form. In particular, they can be applied to any lyophilizate of injectable solutions, a powder or any other solid form vacuum-packed so that, after reconstitution, they can form a liquid. , a gel or an injectable pasty form.

<B> A </ B> As an example of a form illustrating the interest of this invention, and without this being linutative vis-à-vis other possible applications, we can retain the injectable forms in which a part is in dry or solid form and another is the liquid injection vehicle.

More specifically, the solid part will generally contain the active ingredient and may be a freeze-dried form and the injection vehicle may be an aqueous preparation intended to moisturize the dry form before injection. The objective is then to reconstitute a solution or a suspension or an injectable dispersion.

This type <B> of injectable form is widespread and the reasons why <B> are </ B> used rather than a mixed liquid form are well known.

In particular, the problems of stability or constituent compatibility in the liquid mixture may be mentioned. If such a separate liquid solid packaging makes it possible to improve certain points such as for example the conservation of the formulation over time <B> at </ B> a temperature compatible with its routing and storage, the fact remains that it is an arrangement that poses many specific problems, particularly related to the existence of the two subsets.

The traditional solution for this type of preparation is the packaging in a vial of the solid or freeze-dried form, which is hydrated at the time of use by transfer from an injection syringe of the liquid medium <B> to </ b>. using a needle <B> to </ B> through the vial stopper. Once hydrated, the formulation is generally recovered by the same needle in said syringe. This syringe may have been previously loaded liquid <B> to </ B> from a vial or a first vial or it may be a syringe pre-filled with the liquid phase of the mixture.

This relatively complicated operation moves the constituent elements of the formulation several times and presents risks of contamination (or contact with the needle) both for the user and the recipient patient. The variability of results and therefore of the treatment administered remains significant according to imponderable parameters such as the skill or the practice of the operator.

a number of technical solutions at the device level have therefore been developed to try to simplify this preparation and / or reduce the risks. Some solutions remain fairly close to the standard process from multi-element packaging and only seek to reduce risk or problem. This is particularly the case of technical solutions which an intermediate element is added between the bottle and the syringe to simplify the injection and recovery of the liquid. For example, there may be mentioned Becton Dickinson's Monovial device or Baxter's Vial-Mate device.

Although this approach does not simplify the extemporaneous preparation and does not fall into the category of pre-filled containers or syringes, it especially has the eyes of the pharmaceutical industry the merit of not changing the primary packaging into a bottle of the solid form synonymous with a perfectly validated and known filling and processing method, using existing equipment.

<B> It </ B> exists, though <B>, </ B> other more radically innovative device approaches to simplify this problem that usually calls <B> to </ B> a packaging or pre syringe - filled. One can, for example, mention the use of bi-compartmental syringes generally equipped with deviations or by-pass at which the mobile separations existing between the two parts of the same reservoir can be deactivated. <B> A </ B> by way of example, mention may be made of Hypack liqui-dry syringes from Becton Dickinson or Lyoject syringe from Vetter. In this case, the mobile separation is a piston which, at the time of rehydration, will move with respect to a deflection made in the wall of the syringe.

This elegant solution has the advantage of reducing the elements of the injectable <B> to </ B> a single unitary device. In its basic version, this solution may present risks of error or false manipulation during the reconstitution operation; however, some improvements can significantly reduce these risks.

The major disadvantage for the pharmaceutical industry of such a device remains linked to the conditioning in one and the same reservoir of two constituents, one of which is liquid and the other solid and which usually do not have the same mode at all. treatment and / or sterilization especially when the solid is prepared by lyophilization. Another disadvantage in this case is related to the size or volume occupied by the bi-compartment in the freeze-dryer which, given the portion of the tank then provided for the liquid part, may be twice as large. only in separate tanks.

<B> A </ B> this is added the risk of stability linked <B> to </ B> the proximity and possibility of contact between the two parts of the tank <B> to </ B> through the mobile separation or piston.

Faced <B> to </ B> this problem, other <B> approaches of '</ B> packaging in a single device were attempted in which the packaging is, this time, realized in two distinct tanks .

<B> A </ B> as an example, in this sense, PCT patent application WO 94/13344 (Meyer), which describes a device in which the liquid solvent is packaged in a cartridge which can be standard and the second part of the formulation (which may be a lyophilisate) is contained in a specific tube right <B> to </ B> closed bottom. The pistons called "shutters-piston-valves" are particular including the tube piston which has grooves for pre-positioning lyophilization, also synonymous with dead volume.

device is designed to be fully assembled, which involves performing this operation in aseptic or considering a liquid-solid joint post-sterilization that may be incompatible with one of the phases or with the current guidance of some guidelines . In this, this device does not solve the problem of conditioning, and therefore of unitary treatment of bi-compartments.

Depending on the very broad industrial development of certain filling processes around reservoirs or standard contents and known requirements of aseptic preparation or usual post-sterilization, it would be highly desirable to be able, in this case, to formulate in two subunits. , have a device simplifying and securing the extemporaneous preparation while allowing the use of standard treatments of subsets existing tanks. This requires the use of a pre-filled device to avoid problematic transfers. For some very fragile or sophisticated products, it is important to avoid the agitation and displacements created by these transfers.

another aspect of the problem related to mixing operations two parts of the formulation and degassing (with <B>. </ B> risk of contamination depending on the importance and time of contact with the environment) explains the search for devices in which this mixture is simplified and, if possible, made without opening 'alable on the outside, or even devices in which the degassing could be avoided.

the way in which the reconstitution is carried out and in particular its speed of realization and the losses related to the transfer and the degassing remain, whatever the device, random parameters which can enter dissimilar results.

French Patent Application No. 96/06886 describes a method according to which this reconstitution becomes automatic after activation under the action of vacuum and in which the degassing operation is simply suppressed.

The Applicant has now invented advantageous devices which satisfy <B> to </ B> all of these <I> desiderata, </ I> for example in the form of a "syringe" arrangement very close to that commonly known that allows to preserve the same therapeutic gestures and to use the most traditional reservoirs. These devices and arrangements are characterized in that the non-liquid part of the formulation to be injected packaged into the body of the syringe and the liquid reconstitution part is packaged at <B> to </ B>. in a reservoir that can form the piston injection rod of the syringe. These arrangements are made, in particular, from conventional reservoirs, by applying the preparation and conditioning method which constitutes the other part of the invention and which consists of filling and close from the rear at the piston.

Similarly, the transfer system between the two parts is provided by a needle, a tube or a rod which has the particularity of entering the non-liquid reservoir through the piston that will serve <B> to </ B> the injection of the reconstituted form.

These devices, according to the invention, furthermore have a locking means of said injection piston allowing the implantation of said transfer system in said piston <B>; </ B> said blocking means can then be deactivated, thus releasing said injection piston. Finally, the device may have a mechanism by which, after penetration into said piston, said transfer system is removed prior to injection to regain sealing of the reservoir containing the formulation to be injected.

This withdrawal will, for example, according to the device detailed later, combined with unlocking injection piston.

A number of other more specific applications, derivative or corollary devices according to the invention will be specified in the more detailed descriptions which follow.

The devices and methods that are the subject of the present invention can function advantageously by using a reconstitution method that directly allows a prior degassing injection. Once reconstituted, the formulation is immediately usable <B> at </ B> atmospheric pressure without risk of overpressure (or depression) <B>; </ B> no risk, therefore, nebulization or accidental throwing of the product at the moment of its connection with the injection needle. This, combined with the absence of degassing, eliminates important problems such as contamination in contact with the surrounding environment and the risk of accidental punctures, since the needle no longer has <B> at </ B > be manipulated in the open air before implantation. This needle <B> can even advantageously be connected to the reconstituted formulation only after having introduced it into the body, which makes it possible to practice the vein test simply by visualizing the other end of the needle after implantation. . One of the most conventional tanks corresponding to the existing standardization requirements is the cartridge or cartridge of injection, terminated at one end by a conventional piston and at the other by a closed neck, pa # a lid or septum or by a cap and set by a metal cap.

Similarly, devices according to the invention can advantageously use such standard carpules for their two tanks as well as existing pistons and plugs. filling conditions and sterility treatment for their two tanks can be exactly the same as those usually applied <B> to </ B> this type of container.

Thus the device according to the invention provides a new and simple solution that responds among others to the issues, problems and needs mentioned above.

In addition, the use of the automatic rehydration system vacuum is in itself a direct integrity check of the primary packaging containing the active ingredient, <B> to </ B> know the tank or carpule. Its operation VAC a unique pledge, that the asepsis of the tank was well preserved during storage. This control may be associated with the use of a secondary vacuum packaging which will ensure the same control for the entire device and possibly allow to relay the vacuum control on storage duration.

The following descriptions (general or more precise <B> to </ B> from the figures) are only some advantageous examples of embodiments of the device according to the invention, which may be implemented according to other specificities also. covered the invention. In addition to a possible detailed device, some other alternatives will be presented.

This device, according to the invention, can be applied with some minor modifications but still according to the same mechanical principles <B> to many variations in the field of injectable as in other therapeutic areas. Some clarifications concerning these other possible applications such as, for example, the use of a pen-injector, will be given according to their relationship with the inventive matter.

In the example described and according to an advantageous embodiment of the invention, the device is presented with a total separation of the two tanks, <B> to </ B> namely that containing the non-liquid elements (here freeze-dried) and the one containing the liquid elements (here aqueous medium resuspended). In other words, there is no relationship by physical element between the two tanks before use.

Said reservoirs can also advantageously be packaged separately and individually. However, as will be specified, it is possible to envisage device in an arrangement in which the two subassemblies are associated or even included in the same package.

The process aspect of the invention relates to the specificities of the preparation and packaging related to the use of standard tanks and that allows the use of the device, especially around freeze-drying.

Even if device of the invention could be realized with other types reser-see and in particular with glass tubes, in the advantageous embodiment of the device described in detail, it will therefore be used, as reservoirs, two standard carpules, by example of capabilities <B> 2.25 </ B> and <B> 3.15 </ b> mi.

The carpule containing the non-liquid part, here the lyophilizate, constitutes a proximal reservoir located <B> to </ B> inside said device and directly in contact with the exit zone of the injection needle. It is in this proximal reservoir, which in general contains the active principle of the preparation, that the formulation <B> to </ B> inject is reconstituted, which is then, in terms of arrangement, in an equivalent mode <B> to </ B> the traditional use of injection carpules, exactly opposite the double-pointed needle.

The carpule containing the liquid part or aqueous injection medium constitutes distal reservoir of the device. It is located <B> at the other end of the injection device and also serves as a piston rod during the injection of the preparation by the syringe it forms with the assembly. It therefore penetrates more or less deeply <B> to </ B> inside the body of the syringe device and <B> to </ B> inside the proximal carpule.

<B> 1 1 </ B> Between these two carpules are the different parts or elements of the connecting mechanism, which can be fixed on the <B> the </ B> piston of the proximal carpule. The set is preferably arranged <B> to </ B> within a plastic body that guides or controls some of the functions and protects the glass tanks.

This outer element which constitutes the body of the injection syringe forms the device, will preferably be of cylindrical shape, for its lower part and will include the finger rest of said syringe in its upper part. Each part may be a separate sub-element assembled <B> to </ B> the other at the time of assembly. The lower part of this cylindrical body may also have a function of supporting and guiding the cartridge and the injection piston during lyophilization and vacuum packaging operations.

The proximal end of said lower portion will support the injection needle which may be prefixed as shown later or, more conventionally, mounted on a base which will be fixed on said proximal end. Advantageously, this end may therefore constitute a third outer element attached to the lower part.

The device is therefore presented later with a specific solution of pre-assembled needle and cap-lock that avoids the risk of activation before reconstitution of the formulation. <B> It </ B> is obviously possible to use this device with any other needle and in particular needles not pre-mounted, for example those of the conventional type used on injectors or pens <B> to </ B> carpules.

Similarly, depending on other applications (perfusion, ophthalmology, <B> ...), </ B> the device could be associated <B> with </ B> a transfer connector or needle, a drop dispenser or a spray.

On the distal side, the detailed solution keeps the liquid cartridge as a piston rod. In the case, for example, of a pen-injector, the body assembly of the device may constitute the proximal portion of the injector and it is possible to consider removing the distal cartridge after reconstitution and replace it with the mechanism dosing said pen, which would close the body of the device.

This solution is particularly advantageous because of the precision of the total reconstituted dose and the small volume in the pen-injector, without distal carpule or bi-compartmental carpule, which makes possible the use of the device according to the VAC method, thus making it possible to reduce the case of a lyophilisate in the simple and classical case of a solution.

For the sake of clarity and logical sequence of operations in a chronological order, after the general figure of the detailed device according to the invention with the following figures, we will describe, as a first step, methods of filling and packaging (some aspects of which constitute the second part, that is to say the preparation process of the invention), before specifying the device of the invention which is derived therefrom. These methods correspond to the assembly of the device of the invention which is derived allow to specify said device and the functions of the elements that <B> the </ B> constitute. Finally, we will finish in the figures, by the description of the use of said device.

Specific and specific device represented by the following figures is only one possible solution for producing the device and method according to the invention, which in no way limit the general scope of said invention.

For example, the so-called latch elements represented hereinafter could be replaced by a key system or side pin capable of locking the vacuum-packed cartridge piston not only on its glass base but also on the surrounding plastic sheath. Said key could be unlocked (or unpinned) after reconstitution according to the VAC method. For reasons of convenience and space in the freeze dryer, said key system could be provided with a removable or independent grip or activation handle.

even if one of the advantages of the devices, according to the invention, in terms of filling, sterilization and conditioning, can be the physical separation two reservoirs, it is all <B> to </ B> makes it possible to assemble them beforehand, either after sterilization (in aseptic) or before sterilization (with a post-sterilization of the whole). In the case of the assembled solution, the liquid cartridge can be provided with a locking / unlocking device in the body of the syringe which prevents its accidental manipulation. It can also ensure (for example by a seal) the aseptic closure of the body of the syringe.

In the solution represented by the figures, it is also possible to provide a device or element which protects the membrane or the septum of the carpule, which is of the type <B> -off, </ B> or else a system, for example retractable on the tube, which will protect this septum until the introduction of the neck into the syringe body. Similarly, on the side of this body and for example at the fingerrest, it is possible to provide a protection, removable or pierceable, for example, which protects the asepsis of the transfer needle.

Finally, the device is presented in a pre-assembled needle solution. <B> It </ B> is possible to design the device, according to the invention, simply equipped with a cap on the proximal side of the head of the carpule <B>; </ B> cap which will be removed after reconstitution of the mixing, and replaced by a needle whose mounting by its base can ensure the piercing of the membrane or cap of the carpule. This piercing may be achieved either by a double-pointed needle or a plastic tip, the base element whose channel will be connected to the needle. In order to specify the general part of the invention in terms of device and method of preparation and packaging, following the detailed example will be presented other possibilities and their treatment process will be summarized .

A solution, adaptable to aseptic treatment and lower volumes will be evoked. A simplified and adaptable solution for small volumes and pen-injectors will also be described. Finally, an alternative solution <B> to </ B> the detailed solution in which some automatisms of the mechanism are abandoned in favor of a general simplification. <B> A </ B> each time, the specific method of the invention will be specified. Figgres <B> <U> 1 to 13 </ U> </ B> <B> 1 </ B> represents a general view of the device of the invention after installation of the piston rod formed by the cartridge of liquid and before activation.

Figures 2 and <B> 3 </ B> schematize the conventional filling process around the standard cartridge containing the liquid phase, and its specific assembly to be subsequently used in the device of the invention.

Figures 4 <B> to 6 </ B> illustrate the steps of conditioning the solid phase formulation in a standard cartridge and in the particular case of a dispersion form in a lyophilisate.

Figure <B> 7 </ B> represents the assembly steps of the proximal part of the device around the solid or freeze-dried form.

Figures <B> 8 </ B> and <B> 9 </ B> describe, after association of the two subsets of the device <B> (to </ B>) know the body of the syringe containing the solid and the syringe rod the cartridge of the liquid), the automatic VAC reconstitution and the operating mechanism of the device of the invention.

Figure <B> 10 </ B> represents the injection into the body of the reconstituted formulation into the device of the invention.

figure <B> 11 </ B> represents a device alternative around another transfer mechanism usable in aseptic.

Figure 12 illustrates a simplified device for small volumes and for pen-injectors <B>. </ B> Finally, Figure <B> 13 </ B> represents the application of the simplified device in the case of the formulation and volume of the previously detailed device. <U> Detailed Description of </ U> Rigures The figure represents a precise or specific form of the device for producing a medicinal solution or suspension, a solution of peptides or proteins, for example, or an injectable suspension of microspheres PLGA allowing the release prolonged of an active principle (forms retard), according to the VAC method, <B> to </ B> from basic reservoir elements, here, carpules. In particular, the figure <B> 1 </ B> represents this device before reconstitution, once installed the distal cartridge acting piston rod and reconstituting said device in a very similar appearance <B> to </ B> a syringe classic. This version corresponds to <B> at </ B> the solution for 2 ml maximum volume <B> to </ B> inject <B>; </ B> the distal reservoir can be more or less filled and determine the reconstituted volume .

This syringe device comprises a first container <B> II </ B> constituted by the cartridge in which is stored a solvent or aqueous medium 12, a second container <B> 13 </ B> consisting of the cartridge in which the solid form or lyophilisate 14 is vacuum packed, 4 transfer elements, <B> to </ B> know upper key <B> 15, <B> lock 16, </ B> lower key <B > 17 </ B> and the transfer needle <B> 18, </ B> and finally a sheath <B> 19 </ B> where the <B> 13 </ B> tank is and where , <B> to </ B> the distal end, the reservoir <B> 11 </ B> acting as a piston rod and on which is fixed, <B> to </ B> the proximal end, l injection needle 20. It will be noted that the lyophilizate 14 which corresponds in the example <B> to a microsphere suspension (delay form) may be replaced by any lyophilizate of injectable solutions, a powder or any other solid forms packaged under vacuum such that they can form, after reconstitution, a liquid, a gel or a pasty form that can be used in said device.

The first container <B> 11, </ B> forming reservoir or distal cartridge and piston rod of the syringe, will preferably be stored and packaged <B> to </ B> from the rest of the syringe, for example in an individual package . All the rest of the device can advantageously be packaged together in a second package.

The carpule <B> 11 </ B> of the first container which contains the liquid medium 12 is closed <B> at both ends in a standard manner. <B> A </ B> its proximal end, the medium For example, a closure membrane 21 or a closure disk 21 fixed to the neck of the cartridge by crimping a capsule 22 pierced at its center and which may, for example, be metallic. This solution equivalent <B> to </ B> that used among others in dental carpules will include an overflow filling avoiding all air bubbles <B> to </ B> inside the liquid. <B> A </ B> its distal end, the carpule <B> Il </ B> is closed by a piston <B> 23 </ B> which may be a conventional injection piston, for example rubber or polybromobutyl. This piston has an internal thread where the piston rod is usually attached.

In the case of the device, this screw thread 24 serves to bolt the short bleed stem <B> 25 </ B>, which will activate the "take-off" rehydration of the piston <B> 23 </ B> and purge the transfer needle <B> 18, </ B> by filling, after piercing the membrane 21. length of said rod will be a function of the volume of the liquid in the carpule <B> 11. < It will protrude from this cartridge a length allowing the translation of the piston <B> 23 </ B> over a distance at least sufficient to the displacement of the quantity of liquid necessary <B> to </ B> the purge.

This first container <B> 11 </ B> additionally affixed <B> to </ B> the glass distal end the carpule, a finger rest <B> 26. </ B> This support finger is the area where the thumb presses during extemporaneous activation or reconstitution operations. <B> It </ B> can have the following different functions <B>: </ B> it finishes the carpule <B> 11 </ B> like any syringe <B>; </ B> in its function of piston rod of the device, it avoids during the pressure of the thumb, does not create a cavitation by the displacement of the piston <B> 23, <B> to </ B> using small openings or leaks located under the bearing zone and communicating with the interior of the carpule <B> 11, </ B> in rear of the piston provides a grip when unlocking the second container <B> 13, </ B> after reconstitution through a rearwards movement of the assembly <B> 11. </ B> Finally, presses -digt can be used <B> to </ B> lock or lock the piston <B> 23 </ B> and its bleed rod <B> 25 </ B> backwards to prevent 'they can not be removed from carpule <B> Il </ B> or that the bleed rod is unscrewed.

second element of the device forming the body of the syringe is articulated around the carpule <B> 13 </ B> containing the solid or lyophilized part 14 of the vacuum-packed formulation. This carpule <B> 13 </ B> can also be closed <B> at </ B> both ends in a standard way. The proximal end facing the injection needle may be blocked by a membrane or lozenge. According to an advantageous embodiment allowing a standard lyophilization treatment, it will be closed by a plug <B> 27 </ B> engaged in the neck of the carpule. This cap <B> 27 </ B> can ensure a better sealing of the closure and the maintenance of the vacuum in the carpule <B> 13; </ B> it will eventually reduce the dead volumes of the injection cartridge < B>; </ B> it can, finally, be used as conventional plugs vials freeze-dried forms, that is to say be prepositioned after filling the medium then releasing slits or leaks for the elimination of liquids, by sublimation during lyophilization and can then stop the carpule under vacuum in the freeze dryer according to a usual mechanism. This standard possibility is, however, not that which is described in the packaging method according to the invention. This packaging method according to the invention constitutes a new advantageous embodiment in that it allows to pre-seal the carpule at the level of its neck, for example with a standard membrane or pad, set by a metal ring, then fill and lyophilize it from the back before filling it with its usual injection piston. Thus, the closing elements are all <B> to </ B> made standard <B>; </ B> one operates with ease on the side of the widest opening and one avoids any dead volume.

The membrane or the cap <B> 27 </ B> are crimped on the neck by a cap 28 which may be metallic. The internal bevel of the injection needle 20 will connect the <B> formulation to the needle, <B> to </ B> through this membrane or plug, at the time of injection.

at its other end, the container <B> 13 </ B> is plugged by a piston <B> 29 </ B> which may be a standard piston of rubber or polybromobutyl cartridges. This piston <B> 29 </ B> has an internal screw pitch <B> 30 </ B> or any other type of fastening capable of securing it with a part of the bolt <B> 16 </ B> forming the mechanism locking - unlocking with keys <B> 15 </ B> and <B> 17. </ B>

for example, the bolt base <B> 16 </ B> is screwed into the piston screw thread <B> 29. </ B> <B> 16 </ B> as well as the top and bottom keys are hollow <B> to </ B> contain, circulate and <B> to </ B> control the movement of the transfer needle <B> 18 </ B> when <B> of </ B> activation by transfer of the liquid. It is the carpule <B> 11 </ B> in its function of piston which will activate all of this mechanism of transfer by the part of its collar which will be there connected. The bolt <B> 16 </ B> has, <B> at </ B> its other end, support arms that will rest on the glass base of the distal end of the carpule <B> 13 < / B> in locking position. These bases prevent the pressure generated by vacuum in the cartridge from driving the piston towards the bottom, around the support arms of the lock articulates the lower key This key is free in the locked position. When activated, by pressing the upper key <B> 15, </ B> this lower key is secured <B> to </ B> the proximal part of the upper key. <B> A </ B> at this time, the latch arms of the <B> 16 </ B> latch block the squeeze movement, making it impossible to move the cartridge assembly <B> 11 </ B> further transfer to the rear.

During this withdrawal movement, the lower key <B> 17 </ B> will release latch <B> 16 </ B> by clamping the latch arms and locking the transfer mechanism to then inject. Transfer needle <B> 18 to </ B> Inside the transfer mechanism and more precisely the upper <B> 15, </ B> has a base <B> 31 </ B> whose role is to clipper the <B> 18 </ B> needle in the <B> key 15 </ B> only after filling the needle with the liquid 12 and before piercing the piston <B> 29. </ B>

For a completely reliable operation of the activation, the length, the diameter and the type of bevel, side carpule and piston side, can be optimized so that the needle of transfer enters systematically, first <B> to < / B> across the membrane 21 of the carpule <B> 11 </ B> only then, <B> to </ B> through the piston <B> 29. </ B> For example, the needle may be finer carpule side <B> 11 </ B> with a longer, more penetrating bevel.

Similarly according to the same objectives, as well as to guarantee more sealing during penetration into the vacuum chamber, the membrane 21 may be thinner than the bottom of the piston <B> 29. </ B> The latter will present a sufficient thickness <B> to </ B> ensure tightness when penetrating the needle <B> 31 </ B> and, in particular, greater thickness <B> to </ B> the bevel length of this needle, piston side <B> 29. </ B>

The rear release mechanism also allows, after rehydration VAC, to remove the needle <B> 1 8 </ B> from the piston <B> 29. </ B> When injecting, the needle < B> 18 </ B> will remain locked in the upper key <B> 15 </ B> and locking the mechanism by removing or tightening the latch arms <B> 16, </ B> will prevent the needle <B> 18 < / B> to rewind piston <B> 29. </ B>

This set of carpules plus transfer elements is contained in the casing or sheath <B> 19 </ B> which forms the body of the syringe. According to a preferred mode of arrangement of said sheath, it consists of three subassemblies locked or clipped into each other at the time of assembly.

The main or central part of the sleeve <B> 19 </ B> contains the carpule <B> A </ B> its distal end is fixed the end of the sheath <B> 32 </ B> which may include The end of the syringe or handle <B> 33. </ B> This end may, in addition, have the mechanism of locking and locking towards the rear of the carpule <B> 13 </ B> of the transfer mechanism, thus preventing any withdrawal after assembly.

<B> A </ B> the proximal end of the central part <B> 19, </ B> attaches the end or plug of the sheath It is on this end that is fixed, in the version of the figure <B> 1, </ B> the injection needle 20 at its base <B> 35. </ B> It is also at the end that can be fixed the cap or protective cap of the needle <B> 36. </ B> This solution makes it possible to realize a fully equipped device and in particular <B> to </ B> injection needle - mounted without having any problem with the length and the position of said needle during conditioning of the formulation. In the version presented, this cap is blocked by a lock <B> 37 </ B> that holds the head of carpule <B> 13. </ B> In this way, the cap <B> 36 </ B> can not be removed or the carpule <B> 13 </ B> be connected <B> to the injection needle 20 before the transfer mechanism has been fully realized that is to say until At the withdrawal, after hydration VAC, the other specific functions of certain elements of the set will be specified in the description of the figures that <B> y </ B> correspond.

An essential variant of the figure <B> 1, </ B> when used for a multidose system of the pen-injector type, could be the attachment of interchangeable needles at the end cap of the sleeve 34 which would close then the pen-injector end. In this version, during removal after reactivation, the carpule <B> Il </ B> could be removed and replaced by a conventional mechanism-dosing and injection that would be fixed, by its container, on the sheath <B > 19 </ B> or <B> to </ B> its end <B> 32, </ B> for example, by screwing. This container of the dosing and injection mechanism would thus close the pen injector in its distal portion.

In the same way that the vacuum in the cartridges ensures integrity control, it will be possible to vacuum package the entire part of the syringe body of the device and thus obtain the same control, with the advantage of thermal insulation and better stability or inertia. This vacuum of the package may, for example, be greater than the vacuum cartridge <B> 13 </ B> to ensure the relay, or a double security, the duration of storage.

The figure shows a conventional process for filling the carpule <B> 11 </ B> containing the liquid part of the formulation. The piston <B> 23 </ B> is previously installed and its positioning in the tube of the carpule <B> 11 </ B> detern-fine exactly liquid volume of reconstitution. This liquid volume 12 is added, according to a conventional method that can be performed on automatic machines. The carpule <B> 11, </ B> when filled <B> at </ B> its edge into the neck, is then sealed by a cartridge 22 containing for example a membrane 21, in a manner also classic and automatable . This process, which can be performed by overflow, avoids the presence of gas <B> to </ B> inside the sealed cartridge.

Figure <B> 3 </ B> shows the installation on the cartridge <B> Il </ B> of the purge rod <B> 25 </ B> for example by screwing on the piston <B> 23. </ B> The finger rest <B> 26 </ B> is then attached or clipped onto the glass base of the cartridge tube. It will be able, thus, to prevent any withdrawal of the piston <B> 23 </ B> and the rod <B> 25 </ B> and to avoid the dismantling of said rod <B> 25. </ B> The assembly as well assembled can be classically sterilized for example by autoclaving. FIG. 4 schematizes a comparison between a conventional freeze-drying bottle and a device according to the invention, in what constitutes a part of the invention corresponding to the freeze-drying and conditioning process from the rear or distal part opposite to the proximal side of the invention. injection and carpule neck. In a conventional bottle <B> A, </ B> the plug 40 is pierced with holes and slots allowing positioning on the neck before lyophilization and its closing by pressing the shelves the freeze-dryer. The purpose of the device according to the invention is to allow such freeze-drying either with a conventional flask of the type <B> A </ B> but with a standard carpule <B> 13 </ B> as represented in B. To do this, as we explained above, it is possible to use a cap on the neck of the cartridge <B> 13 </ B> equivalent, smaller, to the cap 40 of the bottle <B> A. </ B> In this case, the transfer mechanism where at least one lock member attached to the piston <B> 29 </ B> is pre-positioned <B> to the distal end of the tube of the carpule <B> 13 </ B> and lyophilization is done through the cervix opening. This solution removes the lyophilizate from the heat exchange rack and partially isolates it by the piston <B> 29 </ B> thus making the process more difficult. In addition, it complicates the filling by the narrow neck and it does not allow filling <B> to 100 </ B> the solution of the process of the invention shown here, in particular to optimize and facilitate the filling of the carpul < B <'> <<B> 13 </ B> and to facilitate all operations on preparation of lyophilisate, it operates in a different way. The carpule is previously sealed with its cap <B> 27 </ B> by a capsule <B> 28 </ B> (see figure <B> 1); </ B> it is filled with preparation <B> to </ B> lyophilize by its large distal opening and thus to the bottom of the neck. <B> It </ B> is thus possible to use all standard carpules to <B> y </ B> condition a freeze-dried form even the smallest, and also to operate all possible arrangements of the future freeze-dried, such as, for example, the filling of two successive layers either because they are incompatible, or because the second serves <B> to </ B> avoid dead volumes of injection. The injection piston <B> 29 </ B> will plug the capsule at the end of lyophilization <B> </ B> unlike the stopper 40, it is not equipped with leaks or openings synonymous with dead volume and it is not prepositioned on the glass base of carpule <B> 13 </ B> but on a cartridge holder <B> 19 </ B> in this inverted position, which serves as a guide. This carpule support may advantageously be the central part of the sleeve <B> 19 </ B> or body of the syringe. The advantage is to have, here, a perfectly cylindrical shape that will save the maximum space in the freeze-dryer as well as the total filling of the effective volume of the carpule <B> 13. </ B> The sheath <B> 19 </ B> in its distal part has zones of clips with the part <B> 32 </ B> of the body of the syringe which will serve, here, <B> to </ B> the time of maintenance to the piston <B> 29 </ B> and opening <B> to </ B> the carpule during lyophilization. The piston <B> 29 </ B> is pre-mounted in this distal portion of the sleeve <B> 19 </ B> at least with part of the transfer mechanism, <B> to </ B> know, here, the bolt <B> 16 </ B> and the lower key <B> 17. </ B> This guiding of the sheath <B> 19, </ B> once the assembled device, will serve, here, blocking or stop at the movement of the carpule <B> 13 </ B> in the body of the syringe.

This freeze-drying <B> à </ B> back has, therefore, a number of advantages while allowing a standard process with good contact with the cold source, Figure <B> 5 </ B> illustrates the performing a specific packaging operation of a formulation <B> to </ B> lyophilize made in a carpule according to a method equivalent <B> to </ B> that traditionally used with a bottle. In <B> A, </ b> the carpule <B> 13 </ B> is washed and siliconized, in B, it is crimped by its capsule and membrane, in <B> C, </ B> it can be installed on a lure taking the form of the vial 40, in <B> D </ B> and <B> E, </ B> the constituents of the mixture are easily introduced by the base, at F and <B> G, < It will be possible to make all equivalent treatments to the bottle with the same guarantee of height to the outside. Here, is schematized an ultrasound treatment. In the same way, the mixture (vortex) or the suspension could be added vigorously before freezing.

Figure <B> 6 </ B> represents a carpule <B> 13 </ B> filled with the <B> </ B> mixture to lyophilize, frozen or not. In <B> A, </ B> this carpule <B> 13 </ B> is introduced into the sheath <B> 19 </ B> which serves as a support. In B, all stages of the lyophilization cycle are normally carried out in the lyophilizer. In <B> C, </ B> at the end of lyophilization, and still under vacuum, the piston <B> 29 </ B> is introduced <B> to </ B> inside the tube of the carpule <B> 13 </ B> by conventional pressure in the freeze dryer on the <B> 16 latch. At this time, the lyophilizate is completely isolated from the outside by the lips of the piston <B> 29 </ B> in sealed contact with the tube wall of the carpule. In <B> D, </ B> we will break the vacuum <B> to </ B> inside the freeze dryer thus ensuring a return, <B> to </ B> the atmospheric pressure. Under this pressure, the piston <B> 29 </ B> and the bolt <B> 16 </ B> will continue the descent into the tube of the capsule <B> 19 </ B> ensuring, this fact, a visual and individual control of the existence and quality of vacuum carpule. This positioning of the piston will stop there by the support of the latch arm <B> 16 </ B> on the cartridge The sealed element, thus constituted, is then an integral device according to the invention.

The figure shows the following assembly operations of said device. <B> A, </ B> based on the <B> D </ B> element of Figure <B> 6, </ B> are assembled the other parts of the transfer mechanism. ie, the upper key <B> 15 </ B> in which is pre-mounted the transfer needle <B> 18. </ B> This upper key may have a clip crown for the head of the taller carpule around the needle to protect it during its handling. In B, for example, the proximal portion or stopper of the sheath 34, which previously includes the injection needle 20 and the cap <B> 36, is fixed by clipping. </ B> In <B> C, </ B> Finally, the third part of the body of the syringe <B> is fixed to the distal part of the sheath <B> 32. </ B> This part, the body of the syringe, can then be individually wrapped. and be post-sterilized, for example by gamma-irradiation.

Figure <B> 8 </ B> represents the reconstitution steps of the formulation contained in the device of the invention. In <B> A, </ B> the carpule <B> 11 </ B> is introduced into the body of the syringe. B, the reconstitution is activated by pressing on the bleed rod <B> 25. </ B> The first operation is then the piercing of the disk 21 and then the filling of the needle. <B> C </ B> and according to the same action of pressure on the rod, it operates, finally, piercing the piston <B> 29. </ B> moment, the gesture is then blocked and the preparation is automatically reconstituted with descent of the piston <B> 23 </ B> in the tube of carpule <B> 11. </ B>

figure <B> 9 </ B> represents first, <B> to </ B> from step <B> C </ B> of the figure <B> 8, </ B> in the unblocking by removal of the piston rod constituted by the cartridge <B> 11. </ B> This operation has previously been described in the operation of the transfer mechanism. It carries a little carpule <B> 13 </ B> backwards until its stop on the sheath. In this case the decapuchoning is made possible by the release of the cap at its blocking <B> 37, </ B> operated by the slight withdrawal of the head of the injection cartridge <B> 13. </ B> <B> A </ B> at this time only, the injection cartridge <B> 13, </ B> can be connected <B> to the injection needle 20.

The figure <B> 10 </ B> schematizes the injection in a mode all <B> to </ B> made standard. Since device, according to the invention, allows a preparation that does not require prior bleeding <B> to </ B> the injection, it is possible to practice, before <B> A, </ B> the injection of the needle 20 previously <B> to </ B> its connection <B> to </ B> the carpule <B> 13. </ B> This step can also serve direct vein test, for example, in case of IV or IM injection by visualizing any return blood on the side of the inner bevel of the needle before connection <B> '</ B> the formulation. In B, at the end of injection, the mechanism may be blocked to prevent any subsequent manipulation.

Figure <B> 11 </ B> represents another possible embodiment of the device, according to the invention, adaptable to treatment, in aseptic condition (especially filling) and lower volumes. The implementation of this device requires no aseptic assembly after closure in the freeze dryer, the device and its constituent elements then being isolated from the outside.

During the lyophilization process, according to the invention, the <B> 13 </ B> lyophilizate cartridge is installed <B> at </ B> inside the sheath <B> 19 </ B> which is, then , positioned proximally around the neck of the carpule it is the holder of and bearing <B> at </ B> its distal end, the <B> 16 </ B> closed <B> at </ B> one end by the piston <B> 29 </ B> and <B> to </ B> the other end by a film 41 with <B> to </ B> inside the transfer needle <B> 31. </ B> At the end of freeze drying, the tank is closed by the piston <B> 29 </ B> by pressing on the lock <B> 16 </ B> and thanks to the guides of the sheath <B> 19 </ B> (not shown). The device is then permanently locked by the sleeve head <B> 27 </ B> and the finger rest <B> 33. </ B>

The treatment of the liquid carpule <B> It </ B> is similar <B> to </ B> the example detailed previously. At the moment of use, the <B> 11 </ B> carpule is introduced <B> to </ B> through film 41. It connects and purges the needle <B> 31 </ B> before drilling piston <B> 29 </ B> for hydration VAC.

Once this is done, the lock <B> 16 </ B> is unlocked by pressing the arrow zone of the scabbard <B> 19, </ B> causing the breaking of thin walls and the clipping of arms that will hold the lock. and then bend the needle <B> 31 </ B> allowing it to be removed from the piston <B> 29. </ B> The injection needle can then be installed on the head <B> 27 </ B> and the injection is made by the carpule <B> 11 </ B> serving as a rod to the piston <B> 29. </ B>

FIG. 12 illustrates another representation of the device, according to the invention, of the backpacking process of a solid form and of its rehydration process <B> to </ B> through the injection piston of the device.

<B>. </ B> the rear lyophilization process, according to the invention, is practiced carpules <B> 13 </ B> previously capped and installed in a lower support (not shown) indexed to the upper support (not shown) piston <B> 29 </ B> and lock <B> 16. </ B> In lyophilization, the piston <B> 29 </ B> and its lock <B> 16 </ B> are introduced into the carpule <B> 13. </ B> Another preferable solution, according to the method of the invention is to replace these indexed lower and upper supports by individual supports (21) for each carpule. These individual supports can then fulfill the function of the decoy as described in the figure <B> 5. </ B> In addition, these supports can be directly used in the freeze-dryer and can constitute the base of a packaging made with the support upper single piston (22) piston <B> 29 </ B> and bolt <B> 16. </ B>

After lyophilization, the lower (21) and upper (22) individual supports are closed again to constitute in the freeze-dryer the packaging of the carpule.

The liquid carpule <B> II </ B> is prepared as previously described, it may have a purge rod but not necessarily a finger rest. A sleeve 43 and a piston rod 42 may also be part of the device. Two injection needles 20 (represented here in their cap) of the type of disposable pen-injector needles (for example Becton Dickinson's Micro Fine) are also required <B > to </ B> its use. In the case of using this device as a single dose syringe, the carpule <B> 11 </ B> is introduced into the sheath <B> 19 </ B> as shown in FIG. 12, a needle 20 is fixed and rehydration is performed by piercing the piston <B> 29 through <B> 16. </ B>

The sleeve <B> 19 </ B> is then separated from the carpule <B> Il </ B> and the bolt <B> 16 </ B> is unscrewed thanks to <B> at </ B> the base of the needle 20 and then thrown into the cap. The sheath <B> 19 </ B> may have lateral openings allowing the release of the carpule <B> 11 </ B> and its reuse for the injection of the reconstituted preparation into the carpule <B> 13 </ B> thanks to <B> to </ B> the addition of a piston rod 42 on the piston <B> 29 </ B> and <B> to </ B> the second needle 20.

In the case of using this device as a multidose penultimate cartridge carpule <B> 11 </ B> is introduced into the proximal part of the pen that could symbolize <B> '</ B> the sheath <B > 19, </ b> a needle 20 <B> y </ B> is fixed and rehydration and removal of the <B> 16 </ B> lock on the <B> 13 </ B> carpule is practiced as previously. The carpule <B> 13 </ B> then replaces the carpule <B> 11 </ B> in the proximal part of the pen for a conventional use of it as with the carpules of products in solution.

Figure <B> 13 </ B> shows a simplified application of the device according to the invention in case of an equivalent formulation (in volume and composition) <B> to </ B> that of the detailed example. The device can thus operate with the same carpules <B> 11 </ B> for the liquid part of the formulation 12 and <B> 13 </ B> for the freeze-dried part 14 that those represented in the figure <B> 1. < / B>

essential difference is at the connector lock <B> 15 </ B> which is screwed injection piston <B> 16 </ B> and consists of one piece. No editing operation <B> at </ B> this level is necessary before sterilization. Similarly, it is possible to avoid packaging before gamma-irradiation.

The <B> 13 </ B> carpule is installed before lyophilization in the <B> 17 </ B> sheath, which will serve as a guide when closing the <B> 16 piston. </ B> The syringe head <B > 18 </ B> is the base of the needle <B> 19. </ B> It can be sealed with the cap 20 on the sleeve <B> 17 </ B> for example thanks <B> to </ B> an O-ring between the <B> 13 </ B> cartridge and the <B> 17 sleeve. </ B>

In this case, no packaging is necessary and the device is closed between the cap and the connector lock <B> 15. </ B> The fingerrest 21 can be clipped on the distal portion of the sleeve <B> 17 . </ B>

The use of this device, according to the invention, consists in fixing a standard needle 22 type disposable needles for pen-injector (for example Becton Dickinson's Micro Fine) on the thread of the sheath containing the <B> 11 </ B> liquid cartridge or, as shown here, on the single screw thread <B> 23 </ B> attached <B> to </ B> the <B> Il carpule . </ B> The assembly is then inserted into the connector lock <B> 15 </ B> then <B> to </ B> through the piston <B> 16 </ B> by pressing the bleed rod 24. After rehydration VAC, the carpule is removed by unscrewing with the transfer needle 22 and the lock <B> 15; </ B> another solution is <B> to </ B> lengthen the latch holding arms on the carpule so <B> to </ B> cliper arm of the connector lock <B> 15 to </ B> its level, only after disappearance of the needle in said lock. The carpule-lock connector assembly is then unscrewed from the piston. A piston rod, which may be the cap 20, is attached to the piston to practice the injection. The invention thus relates first of all to a device of the syringe type actuated by a piston for reconstituting a preparation, in solution, in suspension or in dispersion in the form of a syringe. a liquid <B> to </ B> inside a reservoir closed by a piston and forming part of the body of said syringe, characterized in that the non-liquid part of said preparation is previously conditioned <B> to </ B> inside said reservoir of said syringe and that the liquid portion of said preparation is previously separated from said reservoir and said syringe, wherein the reconstitution of said preparation is carried out transfer of said liquid portion <B> to </ B> through said piston of said reservoir.

According to preferred embodiments of the invention, said device may additionally have at least one of the following additional characteristics: <B> 1) said liquid and said non-liquid are conditioned to </ B> inside conventional injection tanks such as tubes or glass cartridges <B>; </ B> said device has the characteristic <B> 1) </ B> and is furthermore a single-dose syringe or multidose of the pen-injector type <B>; </ B> the transfer during said reconstitution is performed <B> to </ B> through a tip, a channel, a tube or a hollow transfer needle introduced into said piston < B>; </ B> said piston has a locking mechanism on said reservoir preventing its depression before and during said reconstitution of said preparation, said locking mechanism being optionally also able to be the <B> connector of said liquid part on said reservoir-of said syringe <B>; </ B> said device f has the characteristic 4) described above and said locking mechanism is screwed on said piston <B>; </ B> said device has the characteristics 4) or <B> 5) </ B> and said locking mechanism can be deactivated, preferably after the reconstitution of said preparation <B>; </ B> said device has the characteristic <B> 6) </ B> and the deactivation of said locking mechanism also corresponds to the withdrawal of said transfer needle said piston <B>; </ B> said liquid portion is in a container for <B> activating said transfer in said reservoir of said syringe <B> to </ B> through said locking mechanism <B </ B> said device has the characteristic <B> 8), </ B> said container then further serving as an injection pin to said piston said device has the characteristic <B> 9), </ B> said conventional tanks being glass carpules <B>; <B> 1 </ B> said liquid is packaged in a resin a piston whose piston is activated by a short rod making it possible to initiate the movement of said piston and to purge said needle or channel or tube before injection into said reservoir of said non liquid <B>; 12) said device has the characteristic <B> 11), </ B> said tank of said liquid being further equipped with an end avoiding its closure by the thumb of hand <B> 13) </ B> said non-liquid part in said tank is vacuum-packed 14) said device has the characteristic 12), said liquid part said second tank also automatically controlling, by its volume, the reconstituted volume of said preparation <B> 15) </ B> said device possesses the characteristic <B> 13) </ B> or the characteristic 14), the reconstitution being operated automatically by pressing on said second tank <B>; </ B> <B> 16) </ B> said device, possibly possessing one or more characteristics selected from among characteristics <B> 1) to 15), </ B> constitutes a single injection syringe <B>; </ b> <B> 17) </ B> said device, possibly possessing one or more characteristics selected from characteristics <B> 1) to </ B> 14), constitutes a multidose syringe of the pen-injector type <B>; </ b> <B> 18) </ B> said device has the characteristic <B> 17) </ B> said second reservoir being removed after said reconstitution and replaced by the metering mechanism <B>; </ B> <B> 19) </ B> minus said reservoir of said device containing said non-liquid part then packaged under empty <B>; </ B> 20) the injection needle is prefixed and its cap blocked before carrying out said preparation.

According to a particular variant of the invention, the piston has a hollow transfer element and a locking mechanism on the reservoir. Preferably, said locking mechanism is hollow and contains said transfer member.

The invention also relates to a method of conditioning <B> to </ B> the inside cylindrical reservoir closed at least on one side by an injection piston blocked its displacement in said reservoir, characterized in that the elements <B > to </ B> conditioner are introduced <B> to </ B> inside said tank side of said injection piston before said tank is closed by said piston.

According to preferred embodiments of the invention, said method may additionally have at least one of the following additional characteristics: <b>: a) said reservoir is a tube or a cartridge previously closed on the side opposite the piston <B>; <B> </ B> </ B> <B> <B> </ B> a lyophilization before closing by said injection piston c) said cylindrical reservoir is previously introduced into a support on which said piston is previously positioned, thus allowing an opening outward of said reservoir <B> to </ B> through said support, said piston being then introduced into said reservoir by pressure and by displacement in said support which serves as a guide <B>; < <B> <b> d) </ B> said process has at least one of the characteristics <B> b) </ B> or c), said piston being then permanently positioned in said reservoir by the ambient pressure thus allowing conditioning control e) l The process has the characteristic c) or <b> d), where the support is then an integral part of the final device <B>; </ B> <B> f) </ B>. </ B> are a mixture previously vigorously agitated in said reservoir <B>; </ B> <I> g) </ B> </ B> </ B> </ B> </ B> </ B> <B> <B> <B> <B> B> b) to f), said elements being introduced and frozen separately in a layer in said reservoir before said freeze-drying <b>; h) said process optionally has one or more characteristics selected from the characteristics a ) and <B>, </ B> said cylindrical reservoir being previously introduced a support and said piston locked in another support, thus allowing an opening towards the outside of said reservoir between the two supports, said piston being then introduced into said tank by pressing and bringing said two supports <B> together; i) said method pos sede the feature h), said supports being further hermetically sealed after said approximation and constituting the packaging of said cylindrical reservoir.

All of the variants set out above represent only a part of the achievements made at the disposal of the person skilled in the art of the present description and can not limit the scope of the present invention. the present invention. The specialist will be able to adapt <B> to </ B> his specific needs the teaching that is given here.

Claims (1)

<U> Claims </ U> <B> 1. </ B> <B> <B> <B> <B> <B> <B> <B> <B> <B> <B> <B> </ B> injection piston side <B> (29) </ B> blocked in its movement in said reservoir <B> (13), characterized in that the elements <B> to </ B> condition ( 12 or 14) are introduced <B> to </ B> within said reservoir <B> (13) </ B> on the side of said injection piston <B> (29) </ B> before said reservoir is closed by said piston <B> (29), </ B> said tank being a tube or carpule <B> (13) </ B> previously closed on the other side. 2. Method according to claim 1, characterized in that <B> lyophilization is carried out before closure by said injection piston <B> (29). </ B> > <B> 3. </ B> Proce according to claim 2, characterized in that the piston <B> (29) </ B> is then permanently positioned in the tank <B> (13) </ B> by the ambient pressure, thus allowing conditioning control. 4. Proce according to claim 2 or <B> 3, </ B> characterized in that the elements <B> to </ B> condition (12 or 14) are introduced and frozen separately layered in the tank <B> ( 13) </ B> before lyophilization. <B> 5. </ B> Method according to one of claims 2 <B> to </ B> 4, characterized in that the elements <B> to </ B> condition (12 or 14) are introduced and frozen separately layered in tank <B> (13) </ B> before lyophilization. <B> 6. </ B> Process according to one of claims <B> 1 to 5, characterized in <B> - </ B> said cylindrical tank <B> (13) </ B> is previously introduced a support <B> (l 9) </ B> on which said piston <B> (29) </ B> is previously positioned, thus allowing an opening towards the outside of said tank <B> (13) through said support <B> (19); <B> - </ B> said piston <B> (29) </ B> is then introduced into said reservoir <B> (13). ) </ B> by pressing and moving in said support <B> (19) </ B> which serves as a guide. <B> 7. </ B> Method according to one of claims <B> 1 to 6, characterized in that <B> - </ B> said cylindrical tank <B> (13) </ B> is previously introduced into a support <B> (19) </ B> and said piston <B> (29) </ B> blocked, in another support <B> (19) </ B> thus allowing a opening towards the outside of said tank between the two supports <B> (19); </ B> and <B> - </ B> said piston <B> (29) </ B> is then introduced into said tank < B> (the </ B> by pressure and approximation of said two supports <B> (19). </ B> <B> 8. </ B> Method according to one of the claims <B> 6 </ B> or <B> 7, </ B> characterized in that said carriers <B> (19) </ B> then constitute a part of an injection syringe device and its packaging. <B> 9. < / B> Proce according to one of claims <B> 1 to 8, </ B> characterized in that the elements <B> to </ B> condition (12 or 14) are a mixture previously stirred very vigorously in the tank. <B> 10. </ B> Process according to one Claims <B> 1 to 9, </ B> characterized that the cylindrical reservoir is previously introduced into a support <B> (19) </ B> and piston <B> (29) </ B> blocked in other support <B> (19), </ B> thus allowing an opening towards the outside of said tank between the two supports <B> (19), </ B> said piston being then introduced into said tank by pressure and by bringing said two supports together <B> 19). </ B> <B> 11. </ B> The method according to claim 10, wherein the carriers <B> (19) </ B> are furthermore hermetically sealed after the approximation and constitute the packaging of the cylindrical tank <B> (13). </ B>