Abstract:
The present invention relates to a needleless injection device ( 1 ) comprising a reservoir ( 3 ), obturated by an upstream stopper ( 4 ) and a downstream stopper ( 5 ) between which a liquid active principle ( 6 ) is accommodated, and a receptacle ( 7 ) comprising at least one injection conduit ( 8 ), said receptacle comprising a cavity ( 10 ) whose height is equal to the distance travelled by the downstream stopper before each injection conduit is opened, —the height of the cavity in millimetres being between a minimum height and a maximum height, respectively defined by the following relationships, •minimum height=3, •maximum height=15×exp. (−(V/9) 2 )+10, where V is the initial speed of ascent of the pressure profile expressed in bar per microsecond, —the ratio between the length of each injection conduit and the height of the cavity being between 1 and 2.

Description:
TECHNICAL FIELD OF THE INVENTION 
       [0001]    The technical field of the invention is that of prefilled, disposable needleless injection devices, operating with an energy source such as, for example, a gas generator and used for intradermal, subcutaneous and intramuscular injections of a liquid active principle for therapeutic use in human or veterinary medicine. 
         [0002]    The active principle consists of a more or less viscous liquid, a liquid mix, or a gel. The active principle may also be a solid in solution in a solvent suitable for injection, or consist of a powdery solid suspended at a certain concentration in an appropriate liquid. The particle size of the active principle must therefore be compatible with the diameter of the ducts to avoid blocking them. 
       BACKGROUND OF THE INVENTION 
       [0003]    As used in the present application, the term ‘liquid active principle’ constitutes the generic definition covering all the previously mentioned embodiments of the active principle. 
         [0004]    Needleless injection devices comprising a reservoir of liquid active principle already exist in tube form and have been the subject of patents. For example, the patent application FR 2 853 837 may be cited, which relates to a needleless injection device comprising an injection nozzle and a tube intended to receive a liquid active principle to be injected, said tube being fixed to said nozzle with the help of connecting means. 
         [0005]    The person skilled in the art traditionally seeks to minimize or even eliminate the risks of damaging, on the one hand, the tube containing the liquid active principle and, on the other hand, the downstream stopper in the specific ‘double stopper’ configuration described, in particular, in the patent application WO 01/58512. Said configuration is characterized by the presence of a column of liquid delimited, on the one hand, by the side wall of the tube and, on the other hand, by an upstream stopper and a downstream stopper, between which the liquid active principle is housed. Under the effect of the gas generation, said column moves in the tube until the downstream stopper comes into contact with the base of a receptacle located in the nozzle so as to free the injection ducts in order to expel said active principle. However, when the downstream stopper hits the base of said receptacle, it creates a shockwave that will propagate through to the tube and the intensity of which is a maximum at the end of said tube which is in contact with the nozzle. In a ‘double stopper’ configuration, the downstream stopper and the glass tube are the two most stressed elements during the operation of the needleless injection device. The latter must consequently be shaped in such a way that the speed of impact of the downstream stopper in the receptacle is less than the limit speed acceptable for the mechanical strength of the components of said injection device. In addition, it is known that the time separating the opening of the injection ducts and the start of the output of the jet from the injection ducts must be longer than the attenuation time of the pressure oscillations generated by the opening of the injection ducts. 
         [0006]    In the technical literature of the field in question it is traditionally mentioned that it is necessary to apply, to the liquid active principle to be injected, on the one hand a high pressure between 200 and 500 bar in order to pierce the skin, and on the other hand a constant or decreasing pressure through to the end of the injection in order to ensure the transfer of the liquid active principle, the final values generally being between 40 and 250 bar. 
         [0007]    However, there is a major stake in reducing the operating pressures so as to construct strong and economical needleless injection devices, more particularly for single-use devices or the consumable parts, such as the injection nozzle, of reusable devices while guaranteeing good reproducibility of injections. 
       SUMMARY OF THE INVENTION 
       [0008]    It has been surprisingly observed that the subject of the present invention precisely enables excellent needleless injection results to be attained with pressure profiles with initial values between 50 and 150 bar, preferably between 70 and 100 bar, i.e. values clearly lower than those commonly accepted in the field considered. 
         [0009]    More precisely, the subject of the present invention relates to a needleless injection device comprising an energy source such as a gas generator, a reservoir blocked by an upstream stopper and a downstream stopper between which a liquid active principle is housed, and an injection nozzle equipped with a receptacle and with at least one injection duct, said receptacle containing a cavity with a height equal to the distance covered by the downstream stopper before opening each injection duct, characterized in that it is shaped such that:
       the height of the cavity in millimeters is between a minimum height and a maximum height respectively defined by the following equations:       
 
         [0000]      •minimum height=3 
         [0000]      •maximum height=15×exp(−( V/ 9) 2 )+10       where V is the speed of the initial increase in the pressure profile expressed in bars per microsecond;   the ratio between the length of each injection duct and the height of the cavity is between 1 and 2.         
         [0013]    The speed of the initial increase in pressure will be understood to involve the calculation of dP/dt throughout a period of time going schematically from 0 to 0.5 millisecond. 
         [0014]    In addition, with a needleless injection device according to the invention it is possible to obtain pressure profiles that are not necessarily flat or uniformly decreasing, in contrast to what is commonly accepted today in the literature. 
         [0015]    Even if several parameters such as the number and the diameter of the orifices in the injection ducts, or the quantity of liquid active principle, play a part in controlling the injection depth, a crucial advantage of the invention lies in the fact that the large variety of permitted shapes of pressure profile, depending on the type of energy source used, ensures fine and optimized management of the injection depth. 
         [0016]    Moreover, another considerable advantage of a needleless injection device according to the invention is the fact that it has been observed that the final pressure has no influence on performance as long as it is greater than 20 bar, which should be compared with the final values of 40 to 250 bar commonly accepted in the literature. 
         [0017]    Advantageously, the minimum height of the cavity in millimeters is defined by the following equation: 
         [0000]      •minimum height=12×exp(−( V/ 18) 2 )+4. 
         [0018]    Again advantageously, the maximum height of the cavity in millimeters is defined by the following equation: 
         [0000]      •maximum height=14×exp(−( V/ 9) 2 )+9. 
         [0019]    Preferably, the ratio of the length of each injection duct and the height of the cavity is between 1.1 and 1.6. 
         [0020]    Again preferably, the needleless injection device according to the invention is shaped in such a way that the time for an increase in pressure to 80 bar is schematically between 0.2 and 2.0 milliseconds. 
         [0021]    Advantageously, the energy source consists of a pyrotechnic gas generator equipped with a pyrotechnic charge and an ignition system. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS  
         [0022]    The invention will be better understood with the help of the detailed description set out below with regard to the appended drawing in which: 
           [0023]      FIG. 1  is a schematic longitudinal cross section view of a needleless injection device according to the invention; 
           [0024]      FIGS. 2 to 5  show examples of pressure profile curves obtained as a function of the velocity of the energy source used. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0025]    A needleless injection device  1  according to the invention, as generally shown in  FIG. 1 , comprises a body  2  in which a reservoir  3  containing a liquid active principle  6  is housed. 
         [0026]    An injection nozzle comprising a receptacle  7  is positioned at the downstream end of the body  2 , the injection system being conventionally covered by an outer protection (not shown) to ensure the asepsis of the injection device  1 . 
         [0027]    A pyrotechnic gas generator  70  containing a pyrotechnic charge  72  is fixed by being screwed to the upstream end of the body  2  by means of a connecting member  71  which bears on the reservoir  3 , the seal being ensured by a circular O-ring. 
         [0028]    The body  2  of the injection device  1  comprises two diametrically opposite windows in order to view the liquid active principle  6  contained in the reservoir  3 . Downstream of the body  2 , in a suitably shaped bore, the receptacle  7 , which will be described in more detail below, is shrunk on. The reservoir  3  bears on the receptacle  7  and is centered in the downstream part of the body  2 , an intermediate transparent material  9  being positioned around said reservoir  3 . Upstream, the body  2  receives the connecting member  71  which is centered around the end of the reservoir  3 . The latter essentially consists of a glass tube closed at both ends by a movable upstream stopper  4  and a movable downstream stopper  5 , these being elements conventionally used in needleless injection devices and obtained by molding elastomers compatible with the liquid active principle  6  for a long duration, for example chlorobutyl or bromobutyl whose Shore hardness is schematically set between 45 and 70. These elements may receive surface treatments, in particular to facilitate their movement in the tubular reservoir  3 . At rest, each element has a diameter about 10% greater than the internal diameter of the reservoir  3  and a height schematically between 0.5 and 0.8 times this diameter. Once engaged, each element has, due to the deformations it undergoes, a height of between around 0.6 and 1.0 times the internal diameter of the reservoir  3 . 
         [0029]    In this exemplary embodiment, the receptacle  7  is implemented by a part of cylindrical-conical outer shape which comprises a central cavity  10  in which the downstream stopper  5  will come to be housed. On its periphery the receptacle  7  comprises three injection ducts  8  uniformly offset in relation to each other. The diameter of the central cavity  10  is equal to that of the reservoir  3 , and its free height is equal to that of the downstream stopper  5 . When the latter has reached the base  7   a  of the receptacle  7  due to the actuation of the pyrotechnic gas generator  70 , each injection duct  8  is then brought into communication with the liquid active principle  6  by means of an inlet  8   a,  said liquid active principle  6  flowing with a speed corresponding to the pressure transmitted by the upstream stopper  4 . 
         [0030]    More precisely, the height of the cavity  10  in millimeters is chosen so as to be between a minimum height and a maximum height respectively defined by the following equations: 
         [0000]      •minimum height=3 
         [0000]      •maximum height=15×exp(−( V/ 9) 2 )+10 
         [0000]    where V is the speed of the initial increase in the pressure profile expressed in bars per microsecond. The speed of the initial increase in pressure will be understood to involve the calculation of dP/dt throughout a period of time going schematically from 0 to 0.5 millisecond. In addition, each injection duct  8  is shaped so that the ratio of the length of said injection duct  8  to the height of the cavity  10  is between 1 and 2. 
         [0031]    According to a preferred embodiment, the height of the cavity  10  in millimeters is between a minimum height and a maximum height respectively defined by the following equations: 
         [0000]      •minimum height=12×exp(−( V/ 18) 2 )+4 
         [0000]      •maximum height=14×exp(−( V/ 9) 2 )+9 
         [0000]    and the ratio of the length of each injection duct  8  to the height of the cavity  10  is between 1.1 and 1.6. 
         [0032]    Even if several parameters such as the number and the diameter of the orifices in the injection ducts  8 , or the quantity of liquid active principle  6 , play a part in controlling the injection depth, it should be properly understood that a large variety of pressure profile shapes is available. 
         [0033]    Indeed, with reference to  FIGS. 2 to 5 , it will be noticed that just as much for a pyrotechnic charge  72  of high intensity, the pressure profile of which is shown in  FIG. 2  and characterized by a time for an increase in pressure to 80 bar of around 0.2 millisecond, as for other pyrotechnic charges  72  of medium, low, or very low intensity, the pressure profiles of which are shown in  FIGS. 3 to 5  and which are characterized by a time for an increase in pressure to 80 bar of around 0.5 millisecond, 1.0 millisecond and 2.0 milliseconds respectively, it is possible to obtain different pressure profiles for a given intensity according to the type of primer  73  chosen to initiate the pyrotechnic charge  72 . By way of illustration, in each of the configurations shown in  FIGS. 2 to 5 , two examples of different pressure profile curves are plotted. The preferred pressure profile curve with the lowest final pressure is shown with a continuous line and the pressure profile curve with the highest final pressure is shown with a dotted line. 
         [0034]    It has been observed that it is possible, for example, to carry out completely satisfactory subcutaneous injections of 0.5 milliliter of liquid active principle  6  with a pressure of around 80 bar at the start of the injection and of 30 bar at the end of the injection, for an injection device  1  equipped with three injection ducts  8  of 250 micrometers diameter. Of course, the pressure values and the number/diameter of the injection ducts  8  are suited to the quantity of liquid active principle  6  to be injected, along with its viscosity and the desired injection depth. 
         [0035]    In this embodiment the pyrotechnic gas generator  70  acts on the upstream stopper  4  by means of a piston  11  of effective cross section equal to that of said upstream stopper  4 . Since this piston  11  is in contact with the upstream stopper  4 , there is therefore no shock or ram effect at the start of operation. This piston  11 , thanks to its sealing system, prevents the gases generated by the combustion of the pyrotechnic charge  72  from coming into contact with the upstream stopper  4 , and therefore allows possible damage thereof and gas leakage into the liquid active principle  6  contained in the reservoir  3  to be avoided. The piston  11 , of a suitable color, may also serve as an operating indicator by appearing in the viewing windows of the body  2 . 
         [0036]    At this stage we will generally describe the main elements of the pyrotechnic gas generator  70  on top of the pyrotechnic charge  72  and the primer  73 . More precisely, the pyrotechnic gas generator  70  comprises a connecting member  71  positioned around the piston  11 , and in which the pyrotechnic charge  72  is located, just above said piston  11 . The primer  73  is mounted on top of the pyrotechnic charge  72 , the combustion of which is initiated when said primer  73  is struck by a striker  74 . In the initial position, the striker  74  is held in a striker guide  75  screwed into the connecting member  71  by balls  77  partly engaged in a groove in the striker  74 . A striking device is also provided and breaks down into a pusher  78  having an enlarged groove  79  and an internal spring  76 . The pusher  78  slides on the outside of the striker guide  75 , and it is held by lugs moving in lateral grooves. This pusher  78  constitutes in this example the triggering element. 
         [0037]    Of course, to initiate the combustion of the pyrotechnic charge  72 , it is possible, without departing from the scope of the invention, to use initiation devices other than the previously described striker device. Without going into details and without seeking to be exhaustive, we mention as examples electric battery initiation devices or piezoelectric initiation devices. 
         [0038]    The pyrotechnic gas generator  70  may optionally be replaced by a gas generator consisting of a reservoir of compressed gas closed by a quick opening valve. The triggering element will open said valve, and the compressed gases from the reservoir will then be able to expand and act on the pushing means. 
         [0039]    For the use of the injection device  1  according to the invention, after having removed the asepsis cap and having placed the downstream side of said injection device  1  on the skin of the subject to be treated, the operator presses with his/her thumb the pusher  78 , which is pushed in, compressing the spring  76 . The pusher  78  moves translationally until the enlarged groove  79  of the striker  74  reaches the height of the balls  77 . On doing this, the latter balls engage under the effect of gravity in the enlarged groove  79  and thus release the striker  74  which then violently strikes the primer  73 , the initiation of which ignites the pyrotechnic charge  72 . The gases generated by the latter will, in a known manner, force the column consisting of the upstream stopper  4 , the liquid active principle  6  and the downstream stopper  5  to slide along the reservoir  3  until the downstream stopper  5  stops against the base  7   a  of the receptacle  7 . Under the effect of the deformation, the downstream stopper  5  frees the inlets  8   a  of the injection ducts  8  and therefore allows the liquid active principle  6  to be injected at high speed so as to be able to pass through the skin of the person to be treated. 
         [0040]    Although the invention has been described in connection with particular exemplary embodiments, it is obvious that it is in no way limited thereto and that it covers all the technical equivalents of the means described and their combinations if these fall within the scope of the invention.