Abstract:
A method comprising the following steps: preparing in a vacuum a dry form ( 18 ) of an active principle, as well as a liquid ( 22 ), and drawing this liquid into the dry form, by the action of the vacuum to obtain an injectable preparation. The device comprises a gastight syringe ( 19 ) to condition under vacuum the dry form, a reservoir ( 12 ) containing the liquid ( 22 ) and a cap ( 29 ) forming a connector between the syringe and the liquid reservoir, the injection needle ( 25 ) of the syringe being driven into the septum ( 24 ) of the cap ( 29 ). The invention enables a preparation which is directly injectable by an automatic rehydration step to be obtained; indeed, after activation, the extemporaneous preparation is automatic since the device elements move by themselves under the action of the liquid which is drawn by suction into the volume under vacuum containing the solid formulation ( 18 ).

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This is the 35 USC 371 national stage of international application PCT/FR97/00989 filed on Jun. 4, 1997, which designated the United States of America. 
     FIELD OF THE INVENTION 
     The present invention provides a process for preparing an injectable pharmaceutical preparation, a device for implementing said process and the product obtained by implementing the process by means of the device. 
     BACKGROUND OF THE INVENTION 
     It is known that injectable forms are immediately bioavailable and constitute a potential passive mode of administration for the patient and an ideal treatment in urgent cases. 
     Another important reason for the development of parenteral forms is the use of active principles (AP) which are degraded and/or not significantly absorbed by the oral route. 
     Of all these AP which, for various reasons, require an injectable form, many of them are unstable in aqueous media, whether in solution, suspension or dispersion. 
     In order to avoid hydrolysis and all the physico-chemical problems associated with a liquid presentation (precipitation, aggregation, adsorption, crystallisation), a presentation is often used in which the AP is preserved in a solid, dried or freeze-dried form. 
     The preparation of the liquid form required for injection then takes place extemporaneously, just prior to injection. 
     This preparation consists in hydrating the solid form with the liquid medium for solubilisation or suspension of the AP. 
     Traditionally, this operation is carried out in a sealed bottle which contains the solid form. The liquid is introduced into the bottle by a syringe, the needle of which is capable of piercing a stopper-septum. 
     The liquid form is then recovered in the syringe so that it can be injected. 
     The time required for this delicate operation and the risks of contamination it involves led experts in medical technology to devise devices for making extemporaneous preparation simpler and more reliable, and for using the fewest possible components. 
     Along such lines, the patents EP-A-0 664 136, DAIKYO SEIKO, EP-0 599 649 PHARMACIA, WO-95 11051 disclose a bicompartmental or “by-pass” syringe which combines in the same syringe the liquid medium and the solid form which will be directly rehydrated in the syringe before injection. 
     Similarly, certain producers propose devices which combine the bottle with the syringe and control the satisfactory execution of the preparation (French patents DEBIOTECH 2 705 898, 2 715 311, 2 717 086). 
     Certain faults in the traditional systems are not, however, solved by said new devices, which pose problems of loss of preparation in their dead volumes, which do not render rehydration automatic and static but keep it manual and dynamic, that is, the flow of liquid and the transfers after hydration displace the solid form and, in particular, the AP. The injectable form does not, therefore, necessarily have the same distribution or homogeneity as the dry form. This constitutes a problem, particularly in the case of suspensions. 
     The fact that preparation is dynamic and carried out manually may lead to important differences depending on the operator, the speed with which he acts, the manner in which he loads the liquid and controls the evacuation of the air. Finally, the force with which the solid AP is hydrated is likely to lead to a relatively substantial emulsion of microbubbles of air. 
     The time allowed for solubilisation or suspension and agitation of the liquid medium determines the homogeneity of the preparation. 
     In the case of suspensions, poor homogeneity or the onset of sedimentation may lead to dose and administration problems. 
     The object of the invention is to propose a process for overcoming these various disadvantages. 
     SUMMARY OF THE INVENTION 
     According to the invention, the process for preparing an injectable preparation is characterised in that a dry form of an active principle under vacuum and a liquid are prepared, and said liquid is introduced into the dry form by suction by virtue of the action of the vacuum in order to form the said injectable preparation. 
     The process of preparation and packing under vacuum according to the invention avoids the above-mentioned problems (dead volume, manual activation, injectability) and at the same time the problems of injected liquid formulation (homogeneity, degassing). 
     According to a characteristic of the process, the dry form under vacuum occupies the same volume as the final form obtained after automatic hydration by a corresponding, exactly pre-determined volume of liquid. 
     According to an embodiment of the process of the invention, a layer of excipient is added to the dry form, said layer being used subsequent to the injectable preparation as a liquid piston in order to push the other layers and to reduce the losses of active principle during injection. 
     According to another embodiment of the process of the invention, the dry form is packed in a syringe fixed to an automatic rehydration device; in order to prepare the dry form, a liquid containing the active principle is frozen, a specific quantity of excipient solution is added to the surface of the frozen liquid, this excipient solution is frozen, the whole unit is freeze-dried so as to obtain, between the piston of the syringe and the solid of active principle under vacuum, a volume of freeze-dried product containing only the excipient which, after automatic rehydration and movement of the piston in order to empty the syringe, occupies a dead volume at the bottom of the syringe and of the injection needle at the end of injection. 
     This process of preparation and packing leads to automatic rehydration: it is sufficient for the user to activate the device for the liquid to restore the solid form to the state it was in prior to drying or freeze-drying. Activation of the device consists in bringing into contact the liquid volume and the solid volume under vacuum. After activation, extemporaneous preparation is automatic, that is, the components of the device move solely under the action of the liquid which is drawn by suction by the vacuum under which the solid formulation is placed. 
     This property of vacuum packing is independent of the operator, and hydration leads to an immediate return to the situation of the liquid form prior to drying or freeze-drying. 
     The solid form and active principle remain static during this hydration, that is, they are not displaced by the liquid. 
     This immediate preparation is thus directly injectable without the need to agitate it, transfer it or expel the air before injection. 
     This process of preparation and packing may use certain devices or containers currently available, provided that they ensure that the form under vacuum is kept under vacuum until rehydration. The component(s) of the device must allow this rehydration whilst avoiding contact with the ambient air. 
     This feature also leads to certain specific devices or components for this process of preparation and packing. These devices and components will be described below. 
     The techniques for vacuum packing the solid form in the device and the packaging are derived from existing techniques (blood sampling tube, packing under a plastic film). This vacuum packing of the solid form and of the AP is, moreover, capable of replacing inert gas blanketing (nitrogen) and improving the stability of the preparation particularly at high temperatures (thermal insulation) and the compatibility with the container (contact insulation). 
     The above-mentioned advantages of the process and of the devices of the invention, which will be explained below, are particularly important for certain preparations: 
     For a solid, readily solubilised preparation, the advantage is that of obtaining immediately a degassed liquid preparation without air bubbles. 
     For a solid preparation which is more difficult to solubilise, either due to its viscosity or due to the time required for solution, the formulation under vacuum avoids the emulsion of air in the liquid, simplifies and accelerates solubilisation. 
     For a suspension and, more especially, for a sustained-release suspension of microspheres (Decapeptyl 3.75 B.1), the formulation under vacuum avoids the problems of dehomogenisation and the risks of precipitation, hence blocking off whilst reducing the time required for reconstitution. 
     The pharmaceutical preparation under vacuum and the preloaded device make it possible to reduce considerably the dead volume and hence the losses of active principle. 
     Finally, for a dispersion and more particularly for semi-solid forms, the very high viscosity of the hydrated form makes it practically indispensable to use a process of preparation and packing under vacuum for the dry form. 
     The non-liquid or semi-solid aqueous form obtained after hydration under vacuum is, moreover, likely to have salting out properties which are different to and better than those of a form hydrated in air. The fact of not having trapped air in the dispersion makes it possible to reduce the volume for the same quantity (which improves salting out) and avoids rupture of the in situ depot structure which may also modify salting out. 
     The process, packing and devices are described here for aqueous liquid forms. It goes without saying that the whole of the invention applies with the same advantages to liquid forms (solution, suspension or dispersion) which are reconstituted from a mixture of water-organic solvent, from an organic solvent, or from other liquids such as injectable oils. 
     The speed of the process of preparation and its realisation in a hermetic packing compensates for the viscosity or the risks of evaporation of certain liquids. 
     The device for implementing the process according to the invention is characterised in that it comprises means of vacuum packing a dry form, means of packing an extemporaneous rehydration liquid, and of connection between these means in order to add, by suction, the liquid to the dry form. 
     According to a preferred embodiment, the means of vacuum packing the dry form are a gastight syringe and the means of packing liquid are a reservoir containing a piston. 
     The syringe is preloaded with the solid form under vacuum, the packing of which allows immediate injection after hydration without agitation, and avoiding the transfer of the solution or suspension through a needle from the preparation reservoir of the liquid to the syringe. 
     Another advantage of the vacuum-packed devices is that it is thus possible to reduce the volumes of the reservoirs of the liquid and solid whilst increasing the precision of the volume injected. 
     In fact, the absence of air makes it possible to fill completely the compartment containing the solid. The volume contained in the liquid compartment may be calculated exactly in order to occupy the volume left empty in the preparation plus losses of the device. But this volume may also be in excess because it is the volume of the empty space in the solid that will determine exactly the quantity of liquid required for rehydration. 
     The device containing the rehydration liquid is advantageously contained in an leakproof reservoir, the volume of which may fall freely as the liquid is transferred to the reservoir of the solid form under vacuum. 
     This may be obtained easily, in particular, with a cartridge or with a pre-filled syringe, the piston of which moves with the movement of the liquid. 
     The reservoir may also be composed of a pre-filled flexible plastic bag, the flexible walls of which will follow the movement of the liquid. 
     The connecting element of the liquid and the vacuum shielded from the ambient air may be composed of a septum, a gate, valve or tap. 
     One of the characteristics of the method and of the devices is to reduce the dead volumes. This is achieved not only by reducing the volume of the connecting components (liquid-vacuum) or injection components (needle-syringe) but also by virtue of the static rehydration process which makes it possible to occupy the dead volumes with liquid without active principle, and hence without loss of injection. 
     Thus, the connecting component and/or the needle may be loaded with liquid without active principle in order to eliminate losses. 
     Moreover, it is possible, by virtue of the same static process, to provide the “liquid piston” without active principle mentioned above, which will occupy the dead volumes of the injection syringe and of the needle after administration, thus making it possible to reduce even further the losses of active principle. This is simply obtained by adding, after freezing the liquid formulation containing the active principle, a calculated volume of a solution of excipient such as mannitol, which will be frozen and freeze-dried at the same time as the formulation. By virtue of static and rapid rehydration, the two liquids, once re-formed, will hardly mix at all and the liquid without active principle will be able to push all the liquid with active principle out of the syringe and the needle (like a “liquid piston”), which will avoid losses. 
     In all cases (solution, suspension or dispersion), once the solid form has dried or freeze-dried, if the syringe is closed on the injection side by the connecting component, the needle or a septum, the piston is placed under vacuum with or without a blocking system, for example, inside the freeze-dryer. If the syringe is open, it can be vacuum-packed at the time of packaging under plastic film. 
     Even if the packing of the closed syringe is carried out beforehand under vacuum, it will be best then to pack this syringe under vacuum in such a way that the packaging, and not the syringe, ensures air-tightness during storage. This constitutes a double safety mechanism and also facilitates monitoring of the integrity of the packaging prior to use (opening). 
     The product or final form obtained after hydration of the solid may take one of the three forms below: 
     1) Solutions 
     The active principle combined, for example, with mannitol, is solubilised in water for injectable preparation; the solution is distributed by volume inside the syringes; the syringes are frozen and freeze-dried according to a conventional process and the solid freeze-dried product is vacuum-packed with the syringe, whether or not the syringe has been fixed beforehand to the other components of the extemporaneous rehydration device. 
     2) Suspensions 
     In the case of sustained-release microspheres, for example, the dose of microspheres is weighed into the syringe. The volume of dispersion liquid is added. The microspheres are then dispersed mechanically in the liquid. Ultrasonics are preferably used for this dispersion operation. The dispersion is then frozen rapidly, preferably in liquid nitrogen to obtain a homogeneous dispersion of the microspheres in the frozen liquid. The liquid contains the matrix of the freeze-dried product, for example, mannitol. Freeze-drying is carried out to obtain a solid in which the microspheres are suspended by the matrix in the ideal state of homogeneous dispersion of the liquid. 
     This solid, whether or not it is combined with the components of the automatic device for extemporaneous rehydration, is then vacuum-packed. 
     3) Dispersion 
     In the case of a semi-solid implant, for example, the semi-solid Autogel BIM 23014C, the active principle is weighed out inside a gastight metered-dose syringe. 
     The product obtained by implementing the process and device according to the invention comprises a dry form for parenteral administration and vacuum-packed inside an injection device also containing a liquid volume, ready to be mixed by suction with the dry form in order to reconstitute the injectable preparation. 
     The dry form may be a freeze-dried form or a powder obtained after removal of a solvent. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     Other features and advantages of the invention will become apparent during the description that follows, given with reference to the attached drawings which illustrate a certain number of embodiments thereof by way of non-limiting examples. 
     FIG. 1 is an elevation of a gastight syringe containing an active principle. 
     FIG. 2 illustrates the compression of the active principle in the syringe of FIG.  1 . 
     FIG. 3 illustrates the placing under vacuum of the active principle of the syringe of FIG.  2 . 
     FIG. 4 is a longitudinal elevation of the syringe of FIG. 3 connected to a liquid reservoir by way of a valve, the latter being in the closed position. 
     FIG. 5 illustrates the suction of the liquid into the syringe containing the solid after the valve has been opened. 
     FIG. 6 represents a complementary phase of mixing between the liquid and solid by suction of said mixture into the reservoir initially filled with liquid. 
     FIG. 7 illustrates a loading stage of a small syringe from the syringe previously filled and separated from the second syringe. 
     FIG. 8 is a view of the small syringe of FIG. 7 ready to be connected to a liquid reservoir. 
     FIG. 9 is a view of the syringe of FIG. 8 connected to a liquid reservoir with an interposed valve. 
     FIG. 10 is a view of the whole syringe-liquid reservoir unit of FIG. 9 packed under vacuum. 
     FIGS. 11 to  14  illustrate the successive stages of implementation of a first embodiment of the process and device according to the invention. 
     FIGS. 15 to  17  are elevations similar to FIGS. 11 to  14  illustrating the implementation of a second embodiment of the device according to the invention. 
     FIGS. 18 to  21  illustrate the implementation of a third embodiment of the process and device according to the invention. 
     FIG. 22 is a longitudinal elevation of a fourth embodiment of the device according to the invention. 
     FIGS. 23 to  25  show the successive stages of the preparation and vacuum packing of a fifth embodiment of the device according to the invention. 
     FIGS. 26 to  29  are longitudinal elevations and partial sections illustrating the implementation of a sixth embodiment of the device according to the invention. 
     FIGS. 30 to  32  are longitudinal elevations illustrating the implementation of a seventh embodiment of the device according to the invention. 
     FIGS. 33 to  36  are views illustrating the implementation of an eighth embodiment of the device according to the invention. 
     FIGS. 37,  38  and  39  illustrate the successive stages of implementation of a ninth embodiment of the syringe device according to the invention. 
     FIGS. 40,  41  and  42  are partial elevations illustrating three possible variants of execution of the embodiment of FIGS. 37 to  39 . 
     FIG. 43 is a partial section and elevation of a tenth embodiment of the device according to the invention. 
     FIG. 44 is a view similar to FIG. 40 of an eleventh embodiment of the device according to the invention. 
     FIG. 45 is a longitudinal section and partial elevation of a twelfth embodiment of the syringe device according to the invention. 
     FIG. 46 is a longitudinal section and partial elevation of a thirteenth embodiment of the packing device provided by the invention. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     With reference to FIGS. 1 to  10 , a description will first be given of an embodiment of the process for preparing an injectable preparation according to the invention, and of the rehydration device under vacuum for implementing said process. 
     An active principle  3  is loaded into a syringe  1 , fitted with a tap or valve  2  in the position of its injection needle, said active principle having been weighed and brought to a volume approximating or equal to that occupied by the semi-solid form by pressure of the piston  4  (FIG. 2) of syringe  1  before or after application of a vacuum. In FIGS. 2 and 3, it may be assumed, for example, that the active principle  3  is compressed by the piston borne by its spindle  5 , prior to application of a vacuum, which operation is carried out at the stage of FIG.  3 . Spindle  5  is fitted with a piece  26  for retaining the piston  4  resting on the end of syringe  1 , and this because of the vacuum in the volume of the active principle  3 . 
     Active principle  3  may be pretreated in order to adjust to the final volume and/or to promote subsequent hydration. It is thus possible to calculate its particle size distribution by grinding; spray-drying or by freeze-drying to a determined concentration. 
     Metered-dose syringe  1  containing the active principle under vacuum  3  is then connected (FIG. 4) by the leakproof valve  2  with the same syringe  6  containing a volume  7  of liquid for rehydration of the solid  3 , for example, water. This liquid volume  7  is contained in the syringe  6  by the piston  8  and the spindle  9  of this syringe. 
     Then valve  2  is opened (FIG. 5) with the result that the liquid  7  passes into the solid  3  by suction under the action of the vacuum, plus, possibly, by a mechanical action on the piston  8 . The retaining piece  26  may then be removed. 
     The preparation is thus first mixed in syringe  1 , then it is mixed again immediately or after a hydration period by the backward and forward motion from one syringe to the other (FIG.  6 ). This backward and forward motion is obtained by mechanical action on piston  8  and on piston  4 , for example, with a syringe push or a hydraulic press. 
     Once homogeneous, the mixture is distributed immediately, or after a rest period, inside small syringes such as  11  of the injection device by volumetric metering from one of the two mixing syringes  1  and  6  which are large in size. If the quantity and precision of metering into each syringe  11  does not allow direct distribution from the syringe for preparation of the mixture, particularly if the mixing syringe  6  corresponds to a large volume, an intermediate syringe of smaller diameter is used for distribution. 
     Syringe  11  may be, for example, one such intermediate syringe. The contents of the large syringe  6  are thus distributed in several intermediate syringes  11  of smaller capacity, each of them then being emptied in a final step into several small syringes of small capacity. 
     For example, from a batch prepared in 200 ml syringes  6 , it is possible to use ten 10 ml syringes in order to load single 0.2 ml doses to the final syringes. 
     The final syringes  11  or  12  filled with semi-solid  13  and fitted with their pistons  14  and their spindles  15  (FIG. 8) are then freeze-dried and vacuum-packed, then combined (FIG. 9) with an automatic device  16  for extemporaneous rehydration. This device  16  may itself be a syringe containing the liquid  17  and connected to syringe  11  or  12  by a leakproof valve  2 . 
     Finally, the device thus obtained (FIG. 9) is packed in a vacuum packaging  18  ready to be used for an injection of the injectable preparation which will be obtained by mixing the liquid  17  and the solid  13  by suction by virtue of the action of the vacuum under which the solid  13  is placed. 
     In the embodiment of FIGS. 11 to  14 , the dry form  18  is packed in a syringe  19  fixed to an automatic rehydration device  21  containing a volume  22  of liquid, composed of a reservoir containing a piston  23 . The freeze-dried product or solid  18  is pre-loaded under vacuum inside syringe  19  before the syringe is connected with the liquid reservoir  21 . The means of connection between reservoir  21  and the syringe  19  are, in the example shown, composed of a connection  29  comprising a septum  24  in which is inserted the end of an injection needle  25  of syringe  19 . The syringe is also fitted with a piece  26  keeping the spindle  27  and its piston  28  in a suitable position, in view of the vacuum under which the solid  18  is placed. The whole device is vacuum-packed in a flexible packaging  31 . 
     In order to obtain the injectable preparation from the device of FIG. 11, the packaging  31  is first removed, then the syringe  19  is pushed by its spindle  27  so as to insert the needle  25  in the septum  24  (FIGS. 12,  13 ). When the end of the needle  25  penetrates the volume of liquid  22 , said liquid is sucked by the vacuum prevailing in the solid  18  with which it mixes without altering the volume occupied by the solid  18 , whilst the piston  23  slides in the direction of syringe  19 . After which the user removes piece  26 , the reservoir  21  and the cap-septum  29  (FIG.  14 ), and the syringe  19  is ready for use for the injection of the preparation which it contains. 
     In the example illustrated in FIGS. 15 to  17 , the freeze-dried product or solid  18  pre-loaded under vacuum into syringe  19  is connected to the liquid reservoir  21  (here a cartridge as in the example of FIGS. 11 to  14 ) by way of a valve  31 , for example, of the quarter-turn type. Syringe  19  is vacuum-packed in a flexible packaging  32  and fixed to a connector  33  in communication with the liquid reservoir  21 , the connector  33  being fitted with valve  31 . 
     Extemporaneous rehydration preparation then consists in opening valve  31  so that the liquid  22  passes automatically, by suction, from cartridge  21  to syringe  19  (FIG. 16) whilst the piston  23  of cartridge  21  travels towards syringe  19 . Cartridge  21  and tap  31  (FIG. 17) of syringe  19  are then disconnected in order to fix injection needle  25  to said syringe, the mixture obtained in syringe  19  then being ready to be injected. 
     In the embodiment of FIGS. 18 to  21 , the syringe  34  is vacuum packed in a flexible packaging  35  and fixed to a connector  36  in communication with liquid reservoir  37  composed of a cartridge. The connector  36  serves to pierce the plastic packaging  35  (FIG. 19) and to fix syringe  34  to the reservoir of liquid (water)  37 . 
     The connector  36  is pierced with an axial channel  39  such that the piercing of the plastic packaging  35  by the connector  36  brings into communication the volume of liquid  38  with the solid dry form  41 , which operation draws into the latter, via connector  36 , the liquid  38  (FIG.  20 ), the piston  23  accompanying the displacement of the liquid  38 . The reservoir  37  thus empties automatically to rehydrate the solid  41 . It is then disconnected from syringe  34  (FIG. 21) and the injection needle  25  is fitted to syringe  34 . 
     In the embodiment of FIG. 22, the device comprises a syringe  42  connected by a cap  43  to a cartridge-septum  44  containing the liquid  45 . The syringe  42  containing the solid (dry form  46 ) is fitted with an injection needle  47  introduced and kept in place inside the cap  43  in a packing  48  made of a flexible material such as an elastomer, which keeps needle  47  in place inside the cap  43 , opposite the septum  49 . The needle  47  is then ready to be inserted in the septum  49  to bring about the passage of liquid  45  into the syringe  42  and thus the rehydration of the solid of active principle  46 . 
     In the embodiment of the device illustrated in FIGS. 23 to  25 , the syringe  51  is provided with an injection needle  52  engaged in a cap  53  inside of which it is able to slide in order to bring into communication the interior volume of syringe  51  containing the solid  54  with the reservoir or cartridge  55  containing the liquid  56 . These two elements are prepared independently and then combined in an extemporaneous rehydration device (FIGS. 24 and 25) by fixing the cap  53  with the end  55   a  of cartridge  55  by means of a suitable connection  57  (FIG.  25 ). 
     The whole unit is vacuum-packed in a flexible packaging  58 , ready for use after removal of this packaging  58 , insertion of the needle  52  in the end  55   a  and suction of the liquid  56  into the solid  54 . 
     The needle  52  is inserted in septum  53   a  which it pierces completely at the moment of rehydration under vacuum of solid  54  by liquid  56 . 
     In the device illustrated in FIGS. 26 to  29 , the process to which the invention relates provides for the addition to the dry form  58  of a layer of excipient  59  which is used subsequent to the injectable preparation as a liquid piston to push the other layers and reduce the losses of active principle during injection. 
     The device comprises, apart from syringe  61  containing the solid active principle  58 , a reservoir  62  containing a piston  60  and the rehydration liquid  63  and a cap-septum  64  blocking off the reservoir  62  on the side of syringe  61  and in which is engaged the injection needle  25 . The syringe  61  is fitted with piece  26  for retaining its piston  65  and its spindle  27 , the piece  26  resting against the end of the body of the syringe. 
     According to the process, after freezing of the liquid containing the active principle and prior to freeze-drying or drying, a specific quantity of solution of excipient such as mannitol is added to the surface of the frozen liquid. This volume is in turn frozen and the whole unit ( 58 ,  59 ) is then freeze-dried. A volume  59  of freeze-dried product containing only the excipient (mannitol) is thus obtained between piston  65  and the solid  58  of active principle under vacuum. This volume  59 , after automatic and static rehydration by piercing of the septum  64  by the needle  25  (FIG. 27) and separation of the reservoir  62 , will be used to push the liquid form  66  of active principle. At the end of injection, the volume  59  occupies the dead volumes  59   a  (FIG. 29) at the bottom of the syringe  61  and of needle  25 . 
     Thanks to liquid piston  59 , practically any loss of active principle is avoided, this being an important advantage because of the cost of the active principle. 
     The embodiment of the device illustrated in FIGS. 30,  31  comprises a liquid reservoir composed of a flexible bag  67  containing the volume of rehydration liquid  68 . The bag  67  is connected to a syringe  69  by a stopper  71  fitted with a septum  72  ready to be pierced by needle  25 . The syringe  69  containing the solid formulation  74  is vacuum-packed in a flexible envelope  73 . The needle  25  allows, by pressure on the piston  28 , the formulation under vacuum  74  to be connected with its volume of rehydration liquid  68  (FIG.  31 ). 
     Once mixing has taken place, the packaging envelope  73  is removed, the bag  67  is separated and the stopper-septum  71  removed, the syringe  69  then being ready for use (FIG.  32 ). 
     In the embodiment illustrated in FIGS. 33 to  36 , the device comprises a syringe  75  packed in a vacuum packaging  76  and a reservoir  77  of liquid  78  fitted with a stopper  70 . The injection needle  25  forming a connector by way of its support  79  is introduced beforehand into a cartridge-reservoir  77  through stopper  70 . The reservoir  77  may be connected to syringe  75  by piercing packaging  76  by way of the connection  79  (FIG.  34 ). 
     Once this operation has been carried out, the volume of liquid  78  and the solid formulation  81  are brought into communication, with the result that the liquid is drawn into syringe  75  (FIG.  35 ). After which it is sufficient to remove the cartridge  77 , its stopper  70 , and the plastic packaging  76  in order to render the syringe  75  ready for use (FIG.  36 ). In this embodiment, the needle  25  and its support  79  form the connector proper, the needle  25  being introduced beforehand into the stopper  70  of cartridge  77 . 
     In the embodiment represented in FIGS. 37 to  39 , the vacuum packing and rehydration device for the injectable preparation comprises a syringe  81  with a needle  116  enveloped by a stopper  110 . This syringe comprises two compartments  82 ,  83  containing respectively the liquid  82   a  and the solid formulation  83   a.  These compartments are delimited by a first piston  84  integral with an activating spindle  85  and by three other independent pistons  86 ,  87 ,  88  juxtaposed between the piston  84  and the injection orifice  89 . These three pistons  86 - 88  are independent, that is, not fixed together. 
     The syringe  81  is loaded with a liquid containing the active principle  83 . The preparation is then freeze-dried and the freeze-dried product  83   a  is vacuum-packed in the bottom of the syringe with the three flat and independent pistons  86 ,  87 ,  88 . The volume of rehydration liquid  82   a  is then added to syringe  81  then the piston  84  with its spindle  85 , positioned behind the liquid  82   a  as for a bicompartmental syringe. Piston  84  is made of a standard non-rigid rubber. 
     Drawing on piston  84  by means of its spindle  85  causes suction of the three flat pistons  86 - 88  (FIG. 38) which pivot and bring into communication the solid  83   a  and liquid  82   a  forms. During this suction and the sliding of piston  84 , the solid and liquid forms mix and are mixed by the movement of pistons  86 - 88 . The liquid (for example, water) passes automatically into the solid and reconstitutes the preparation to a liquid of the active principle, which may then be immediately injected (FIG.  39 ). 
     This system avoids the specific by-pass syringe and may be implemented by means of a standard syringe. 
     A flat positioning of the three independent pistons  86 - 88  in the syringe could prevent good mixing of the liquid/freeze-dried product but the arrangement of the three pistons avoids this risk. The maximum angle of rotation of the pistons is in relation to the distance between the pistons at rest. Said pistons are sufficiently close to one another to avoid a 90° rotation, and as soon as the two chambers  82 ,  83  communicate, the pistons  86 - 88  no longer undergo a force likely to displace them to the extent that they come into contact with the injection piston  84 . 
     However, for greater security, it is possible, as a variant, to provide between the pistons  86 - 88  flexible bonds which join them in pairs. These bonds may be centred, such as bonds  120  and  121  (FIG. 40) or asymmetrical: bonds  122 ,  123  (FIG. 41) or situated on the same side of the axis of the syringe  81 : bonds  124 ,  125  (FIG.  42 ). 
     Such arrangements make it possible to fix the pistons by a flexible bond, whilst leaving each piston free to pivot. 
     The device represented in FIG. 43 comprises a syringe  91  pre-filled with solid under vacuum  92 , a cartridge  93  containing the liquid  94  and fitted with a septum  95 , and a connector  96  in communication between syringe  91  and the reservoir  93 . The injection needle  25  is introduced into connector  96 , ready to perforate septum  95 . 
     As soon as the terminal bevel of needle  25  is inserted in septum  95 , the solid form  92  and the liquid form  94  are brought into communication and the liquid  94  is sucked into the dry formulation  92  of the syringe  91 . 
     In the embodiment of FIG. 43 shown in FIG. 44, the piston  97  of the liquid reservoir  93  is fitted with a spindle  98  after the liquid  94  has been introduced into said reservoir  93 , this arrangement having the advantage of avoiding any risk of faulty handling. 
     In the embodiment of FIG. 45, the device comprises a syringe  99  of the two-compartment type  101 ,  102  separated by a central by-pass  103  obtained by a local lateral recess of the wall of the syringe leading to an increase in the cross section at that location. One of the two compartments, namely compartment  101  having to contain the rehydration liquid  101   a,  contains two independent pistons  104 ,  105  between which the liquid may be placed. 
     The process for implementing the injectable preparation by means of this device is as follows. 
     Into the compartment  102  contained between the by-pass  103  and the injection needle  25 , a liquid is loaded and frozen, said liquid containing the active principle  102   a,  and a solution of excipient  106  is added at by-pass  103  and then in turn frozen. The excipient may be a cold dilute solution of mannitol. The whole unit is freeze-dried under vacuum, the first piston  104  is arranged on the excipient under vacuum  106 , the second compartment  101  is filled with liquid  101   a,  the second piston  105  is placed on liquid  101   a,  the spindle (not shown) of the second piston  105  is installed. 
     By means of this second piston  105 , a pressure is exerted which crushes the excipient freeze-dried under vacuum  106 , with the result that the first piston  104  slides and reaches the level of by-pass  103 ; the liquid  101   a  then passes automatically via the by-pass  103  into the first compartment  102  and rehydrates the solid under vacuum  102   a,  and finally the preparation ready to be injected is obtained. 
     The advantage of the system compared with the conventional use of by-passes is to avoid non-loaded re-solution or re-suspension volumes and to make it possible to fill the wasted volumes at the by-pass, the pistons at the bottom of the syringe and of the needle with a liquid preparation without active principle, provided that the rehydrated active principle does not become mixed with the rehydrated excipient before injection. This is the case, for example with microspheres of PLGA (polylactic-glycic acids). 
     It is thus possible to load, for example, a quantity of 2 ml and more into a by-pass syringe  99  initially intended only for 1 ml. 
     The device illustrated in FIG. 46 comprises a syringe  107  fitted with an injection needle  25  and containing a cartridge-septum  108 . This latter is fitted with a short needle  109  blocked off by insertion in an injection piston  111  of syringe  107 . The cartridge-septum  108  may contain the rehydration liquid  112  and the syringe  107  may contain the dry form  113 . 
     The cartridge-septum  108  is fitted with a piston  114  and a spindle  115  of sufficient length to be able to use the cartridge-septum  108  as a spindle of the injection piston  111 . The cartridge-septum  108 , which is the equivalent of a small syringe with its short needle  109 , is pre-filled with liquid  112  and positioned in the barrel of the syringe  107 . The short needle  109  is blocked off by insertion in the injection piston  111 . Activation of the device is obtained by inserting the needle  109  of the cartridge-septum  108  in the injection piston  111 . This insertion makes it possible to pass the liquid  112  into the reservoir of the syringe  107  contained between the injection piston  111  and needle  25  and which contains the solid under vacuum  113 , which operation ends in the reconstitution of the injectable preparation. 
     In this type of embodiment, the injection piston  111  acts as a septum or barrier between the volume of liquid  112  and the solid under vacuum  113 . Thus, the device as a whole is in the same syringe  107 , and the needle  25  is not used to pierce the septum and to serve as a connecting element. 
     In order-to obtain the dry form, in the case of a semi-solid, the liquid dispersion is loaded into the syringe  107 , freeze-dried or dried and vacuum-packed with the injection piston  111 . 
     The product obtained by implementing the device and the process which have just been described in the various embodiments illustrated in the drawings comprises, in a general manner, a dry form for parental administration and vacuum-packed inside an injection device also containing a liquid volume, ready to be mixed by suction with the dry form in order to reconstitute the injectable preparation. 
     The dry form may be a freeze-dried form or a powder obtained after removal of a solvent. 
     The dry form may contain the active principle alone, or the active principle and an injectable excipient, for example, mannitol. 
     The volume containing the dry form under vacuum is equal to the volume occupied by the injectable preparation obtained after mixing the dry form with the necessary liquid. 
     The liquid may be water, or an aqueous medium, or an organic solvent with or without water, or an anhydrous liquid or injectable oil. 
     The injectable preparation obtained may be a liquid solution, or a solid suspension in a liquid, or a gel or a semi-solid dispersion. 
     The vacuum required for the process of preparation according to the invention is a vacuum sufficient to draw a stream of reconditioning liquid prior to injection (hydration or other) into the whole of the volume to be injected without leaving air bubbles, dead spaces or a zone of product that is still dry. 
     According to conventional processes for packing dry or freeze-dried injectable products, it is possible to use a “partial vacuum” of air or inert gas (nitrogen) before closing the reservoir containing the dry form in order to avoid excess pressure after stoppering. 
     This partial vacuum may be offset by stoppering with a return to atmospheric pressure, or a pressure slightly below atmospheric may be maintained in the bottle or in the syringe in order to prevent excess pressure during the addition of the liquid medium. 
     It is possible, of course, to stopper a bottle under a “total vacuum” after freeze-drying, but this does not have any advantage for reconditioning the solid apart from the precise case of the invention where the solid occupies the entire volume under vacuum, and where the liquid comes to occupy exactly this volume under vacuum directly in the injection device (syringe). 
     The partial vacuum may be between 0.9 and 0.6 atmospheres. The total vacuum may be defined as the vacuum corresponding to less than ½ atmosphere and advantageously to low pressures of {fraction (1/10)} atmosphere and less. 
     This total vacuum may also be defined as the vacuum obtained by a vacuum pump used, for example, for a freeze-dryer. A rotary pump with a two-stage valve may reach 1.10 −3  mbar or 1 μbar. 
     The vacuum used for the invention may thus be less than 100 mbar or advantageously less than 10 mbar or even less than 0.1 mbar.