Injection cartridges and method for injection from this

FIELD OF THE INVENTION The present invention relates to an injection cartridge for parenteral injection or infusion. In particular, the present invention relates to the improvement of injection cartridges which enable a better use of the injectable formulations. The invention further relates to a method of administering a liquid composition using the injection cartridge of the invention.

Injection cartridges are widely used for the administration of injectable pharmaceutical compositions by parenteral injection or infusion. These cartridges have a number of advantages, such as being easy to handle and less risk of microbiological infection. Injection cartridges generally consist of a tubular container containing the liquid for injection. It is provided with a closure at the front end of the container which can be pierced by an outlet line such as an injection needle or cannula or an infusion tube. At the rear end of the cartridge, it is sealed with a plunger which can be moved forward to drive the composition to be injected out of the cartridge via an outlet line. This type of injection cartridge is called a single-chamber injection cartridge.

Two-chamber injection cartridges are also known. Such cartridges are used for injectable formulations which are not sufficiently stable when ready for use. The space in the charge between the front closure and the rear piston is divided into two chambers, which are separated by a movable wall. The anterior chamber generally comprises a solid component of the composition to be injected and the posterior chamber a liquid component thereof. The cartridge is provided with a bypass connection at a predetermined location within the interior wall of the cartridge so that the liquid component can bypass the movable separating wall and flow into the front chamber for mixing with the solid component. If a forward pressure is applied to the rear piston, this pressure is transmitted by the fluid and forced by the movable wall forward, and when this wall is in the bypass position, fluid will flow around the wall to mix with the component in the anterior chamber. . In this way, the two components are mixed together just before injection and there is no time for the ready-to-use preparation to degrade. Once all of the fluid has been transferred to the front chamber, the rear piston strikes the movable wall and, as they move forward, work together as a single piston to expel the mixed formulation from the cartridge.

U.S. Pat. No. 4,439,184 discloses a two-dose syringe with two chambers which are intended to form two separate liquid bodies in succession. In a preferred embodiment, a lubricant anti-infective agent and a lubricant anesthetic are used to prepare the urethra for catheterization. The lubricating properties of both materials make it easier for the catheter to slide into the urethra.

The design of single-chamber and dual-chamber injection cartridges is well known to those skilled in the art and therefore need not be described in further detail.

When administration of the liquid composition from the injection cartridge is completed and the rear piston is in the forward position, there is still a certain dead space with respect to the piston in the front portion of the cartridge and in the discharge line. This dead space can be significant, especially if a tube of some length is placed between the outlet and the needle or cannula. This is a disadvantage and means that some of the drug is not used by the patient. This disadvantage is even more serious when it comes to highly expensive pharmaceutical compositions such as hormones or certain peptides.

Many attempts have been made to overcome this disadvantage. One solution was to draw some blood back into the cartridge after the injection was completed and then inject it back into the patient by flushing the outlet duct. However, this practice is not highly recommended as there is a risk that components of the blood that are very sensitive to the surface may be damaged or coagulated and form lumps. Alternatively, the syringe containing the pharmaceutical composition was removed and replaced with a syringe containing a rinsing fluid such as physiological saline to complete the injection. This is a complicated and time-consuming procedure and increases the risk of infection.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome these deficiencies and to provide an improved injection cartridge comprising a container having an outlet at the front end of the cartridge and a front chamber closed by a movable wall, a rear chamber behind the movable wall. which is closed by a front piston, a by-pass connection is provided at the wall of the filling container, and various compositions are disposed within the container.

The substance of the injection is the solid component of the composition in the front chamber, the liquid component of the composition in the back chamber, and an auxiliary chamber behind the rear chamber in which rinsing fluid is located, this chamber is closed by a rear piston there is an additional bypass connection at its wall, the two bypass connections are arranged so that one bypass connection at the tank front, the other bypass connection is formed at the rear end of the front chamber in the container wall.

Preferably, the volume of the Rinse Liquid in the filling is at least twice the combined volume of the space in front of the front piston and the space in the discharge line.

Preferably, the bypass connection is either located at the front end of the filling in the outer wall or as a channel in the inner wall of the filling, or as a variant of the inner wall.

Preferably, the injection cartridge has a tube and an injection needle to expel the composition to be injected.

Preferably, the solid component is a lyophilized human protein.

Preferably, the movable wall between the front and rear compartments is made of butyl rubber and the container is made of glass.

HU 219 112 Β

The invention further relates to a method of dispensing a composition from an injection cartridge, comprising filling a container with a bypass connection with one component of a composition and separating it with a movable partition, and then loading the other component of the composition into the container. The essence of the process is that the first component of the composition is a solid component, the second is a liquid component, this liquid component is sealed with a front piston, and then a flushing fluid is filled into an auxiliary chamber formed behind the liquid component and closed by dispensing. pushing and pushing the rear piston through the bypass which is located at the end of the front of the tank, the solid component is mixed with the liquid component, the blended components are squeezed out and the flushing fluid is expelled from the container by means of an additional bypass located at the container front.

The essence of the process is to rinse the outlet duct from the remainder of the formulation using a physiological saline solution as a liquid in the auxiliary chamber.

Preferably, the composition to be injected is expelled through a tube and an injection needle.

Preferably, the volume of the flushing fluid in the filling is selected to be at least twice the combined volume of the space in front of the front piston and the space in the outlet duct.

Preferably, the injection medium is a two-chamber injection containing a solid component, namely, a lyophilized human protein.

The invention will be described in more detail with reference to the figures, which illustrate an exemplary embodiment of an injection cartridge according to the invention.

Figure 1 shows a known injection cartridge prior to injection.

Figure 2 shows the known injection cartridge after the injection has been administered.

Fig. 3 shows an injection cartridge similar to Figs. 1 and 2, but modified to be flushed before injection.

Figure 4 shows the injection cartridge after the injection has been given, but before the flushing has started.

Figure 5 shows an injection cartridge during rinsing. Figure 6 shows the injection cartridge after completion of rinsing.

Figure 7 illustrates a dual-chamber injection cartridge of the present invention prior to being ready for injection.

Figure 8 illustrates a dual-chamber injection cartridge of the present invention, ready for injection.

Figure 9 shows a dual chamber injection cartridge according to the invention after the composition to be injected has been returned to the anterior chamber.

Figure 10 shows a dual-chamber injection cartridge according to the invention in an intermediate position after returning the composition to be injected.

Figure 11 shows a two-chamber injection cartridge according to the invention as the flushing fluid flows into a chamber formed behind the movable wall.

Figure 12 illustrates a dual-chamber injection cartridge of the present invention, ready for injection.

Figure 13 shows a dual chamber injection cartridge according to the invention at the time of injection.

Figure 14 shows a dual chamber injection cartridge according to the invention, after injection but prior to rinsing.

Figure 15 shows a dual chamber injection cartridge according to the invention after rinsing has been completed.

In the drawings, the injection cartridge is shown schematically, since the details of the injection cartridge are well known to those skilled in the art. Identical parts are denoted by the same reference number.

Figure 1 schematically shows a single chamber known injection cartridge at which injection of the composition to be injected has just begun. The injection cartridge is provided with a reservoir filled with a liquid for injection. The chamber filled with this composition 2 is closed by a plunger 3 at its rear end. The cartridge is provided with an outlet conduit 4 at its front end, and in the embodiment shown, this outlet conduit 4 is connected to a tube 5, which in turn is connected to an injection needle or cannula 6. A device 7, such as a surgical tape, is disposed near the needle 6 to secure the needle 6 to the patient's skin. The injection of formulation 2 has just begun, as indicated by the slightly advanced position of the plunger 3 and the drop of formulation 8.

Figure 2 shows the known injection cartridge after administration. The piston 3 is in the foremost position in the container 1 and substantially all of the injectable composition 2 is expelled from the cartridge. However, there is a certain amount of composition 2 left in the dead space formed by the outlet conduit 4 and the tube 5. This amount cannot be used by the patient and is essentially lost. This loss can be economically significant if very expensive injectable formulations such as growth hormones and certain peptides are administered. As mentioned above, there has been no satisfactory way to remedy this deficiency.

Figure 3 shows a similar single-chamber injection cartridge modified to be flushed before administration of the formulation.

As can be seen from the foregoing, the injection cartridge has a reservoir 1 containing a liquid injectable formulation 2 and the chamber containing this formulation is closed at the rear end by a front piston 3. Also at the front end of this filling

There is a 112 Β outlet that is connected to a 6 needle or cannula 5 via a tube.

The container 1 is stretched backwards and comprises an auxiliary chamber filled with flushing fluid 9, the rear end of which is closed by a rear piston 10. In addition, 11 bypass connections are provided near the front end of the charge. The bypass connection 11 can be arranged in a number of ways well known to those skilled in the art. For example, it may consist of a channel located in the inner wall of the container 1, or it may be formed by other modifications of the inner wall of the container. All bypass connections can also be called "negative" types, in which the interior of the cartridge is constricted so that the piston 3 is deformed when in this position. The main purpose of this bypass connection is to ensure that the piston 3 does not completely block the inner wall when in the position of the bypass 11.

Figure 4 shows a single-chamber injection cartridge, substantially when the entire composition to be injected has been expelled from the cartridge. The front piston is the

In container I, it is in the foremost position, but there is still a small amount of injectable composition 2 in the dead space formed by the outlet conduit 4, the tube 5 and the bypass connection 11. In its uppermost position, the front piston 3 is located at the bottom by-pass connection such that a passageway for fluid flow is formed from the chamber behind the front piston 3 into and around the dead piston 3.

Figure 5 shows a single-chamber injection cartridge after rinsing has begun. The rear piston 10 then moves forward such that the flushing fluid 9 is a

It flows through a bypass connection II around the front piston 3 and out into the dead space formed by the outlet conduit 4 and the tube 5, thereby expelling the injection composition 2 previously present in this dead space through the injection needle 6 or cannula to the patient. .

Figure 6 shows a single-chamber injection cartridge after the entire rinsing fluid has been expelled from the cartridge. The rear piston 10 then strikes the front piston 3 and the outlet conduit 4 and tube 5 contain essentially only rinsing fluid 9. Essentially, the entire formulation 2 to be injected is now injected through the injection needle or cannula 6 with most of the flushing fluid 9 as shown by the droplet 12.

Fig. 7 illustrates a dual chamber injection cartridge according to the invention having a tubular container 21 divided into a front chamber 22 and a rear chamber 23. The front chamber 22 contains the solid component 24 of the composition for injection, and the rear chamber 23 contains the liquid component 25 of the composition for injection. The front chamber 22 and the rear chamber 23 are separated by a movable wall 26. The rear chamber 23 is closed at the rear end by a front piston 27. A circumferential connection 28 is provided in the inner wall of the filling container 21. At the front end of the cartridge, an outlet conduit 29 is provided through which the composition to be injected may be expelled. The outlet line 29 is connected to an injection needle or cannula, either directly or by means of a tube as shown in FIGS. . For the sake of simplicity, these details are illustrated in pages 7-15. FIGS.

The above-mentioned features of the dual-chamber injection cartridge of the present invention are well known in the conventional dual-chamber injection cartridges.

The reservoir 21 of the injection cartridge of the invention extends behind the front piston 27 to form an auxiliary chamber 30. This chamber 30 is filled with rinsing fluid 31 and is closed at the rear end by a rear piston 32. In addition, a circumferential connection 33 is provided at the front end of the charge.

Fig. 8 shows a dual chamber injection cartridge according to the invention after the rear piston 32 has been moved forward with the movable wall 26 at the bypass connection 28 and a portion of the liquid component 25 flowing from the rear chamber 23 to the front chamber 22. Thus, the liquid component 25 is admixed with the solid component 24 to dissolve or suspend it to form a ready-to-use injection. The flushing fluid 31 is still enclosed in the auxiliary chamber 30 between the front piston and the rear piston 32.

Figure 9 shows a dual chamber injection cartridge according to the invention after the entire liquid component 25 has been forced into the front chamber 22 to form the injectable composition 34 together with the solid component 24. The front piston 27 now strikes the movable wall 26 and the rear chamber is temporarily non-existent. Due to the movement of the rear piston 32 and the front piston 27, the auxiliary chamber 30 moves forward with the rinsing fluid 31, but otherwise remains intact.

Fig. 10 shows a dual chamber injection cartridge according to the invention after the rear piston 32 and consequently the front piston 27 and the movable wall 26 have been further moved forward so that the front piston 27 and the movable wall 26 cover the bypass connection 28. The latter is inactive in this situation.

All. Fig. 4A shows a dual chamber injection cartridge according to the invention after the rear piston 32 has been moved forward with the front piston 27 in the bypass position. As the rear piston 32 moves forward, the flushing fluid 31 begins to flow around the front piston 27 and into the space between the movable wall 26 and the front piston 27, thereby restoring the rear chamber 23 and filling it with flushing fluid 31. The injectable composition 34 thus moves forward in the front chamber 22 but otherwise remains intact.

Figure 12 shows a dual chamber injection cartridge according to the invention after the rinsing fluid 31 has been forced into the posterior chamber 23. The rear piston 32 then collides with the front piston 27 and the two pistons then function as a single piston while the previous auxiliary chamber 30 is gone.

HU 219 112 Β

Fig. 13 shows a dual chamber injection cartridge according to the invention after the front piston 27 and the rear piston 32, and consequently the movable wall 26, have been moved forward so that the front chamber 22 is now completely filled with the composition 34 to be injected. This composition 34 can now be expelled from the cartridge via the outlet conduit 29 to begin administration. The bypass 28 is now inactive.

Figure 14 shows the dual chamber injection cartridge of the present invention after the entire composition 34 to be injected has been expelled from the cartridge and administered to the patient. However, some of the composition 34 remains in the dead space of the cartridge opposite the movable wall 26 and in the outlet conduit 29 and possibly in the tubing (not shown), which also leads to an injection needle (not shown).

When movable wall 26 is in its foremost position, it is located at the position of the front bypass connection 33 which thereby becomes active and allows the flushing fluid 31 to bypass the movable wall 26 and to flow out into its opposite dead space. As the front plunger 27 and the rear plunger 32 continue to move forward, the flushing fluid 31 is forced through the bypass 33 and is expelled through the outlet conduit 29 to displace the remainder of the injectable composition 34 through the injection needle or cannula. Thus, it can be seen that the total amount of the composition to be injected can be administered to the patient and there will be no loss.

Figure 15 shows a dual chamber injection cartridge according to the invention after the entire amount of flushing fluid 31 has been expelled through the outlet line 29. The movable wall 26, the front piston 27 and the rear piston 32 now collide with one another and the bypass connection 33 is inactive. The filling from the filling is completed.

Injection of the composition for injection and subsequent rinsing from a single-chamber injection cartridge and preparation, administration and rinsing from a two-chamber injection cartridge are performed by applying the 3 front plungers (Figs. 3-6) or 32 rear plungers (7-15). Figures 1 to 4) are forced forward by means of a piston rod. Such a piston rod may be moved forward by a simple axial forward thrust, a screw mechanism, or a combination of the two. Various arrangements for the purpose are well known to those skilled in the art and need not be described in further detail.

The operation of the dual chamber injection cartridge according to the invention is as follows.

The injection cartridge is generally shipped to the user in the condition described with reference to Figure 7. When the filling is prepared for injection, the user applies a feed pressure to the rear piston 32 by means of a suitable piston rod (not shown). This pressure is exerted by the substantially non-compressible liquid component 25 in the rear chamber 23 and the flushing fluid 31 in the auxiliary chamber 30 so that both the movable wall 26 and the front piston 27 are forced forward. When the movable wall 26 reaches the position of the bypass connection 28, the latter becomes active and allows the liquid component 25 to flow around the movable wall 26 and mix with the solid component 24 in the front chamber 22. The solid component 24 is then dissolved or dispersed in the liquid component 25 to form the injectable composition 34.

When the front piston 27 has moved so far forward that the entire amount of the liquid component 25 has been transferred to the front chamber 22, the front piston 27 strikes the movable wall 26. As the rear piston 32 moves forward, the front piston 27 and the movable wall 26 will move forward together until the front piston 27 reaches the bypass position 28. The latter now becomes active again so that the flushing fluid 31 can flow around the front piston 27. As the rear piston 32 continues to move forward, the front piston 27 remains in place while the movable wall 26 is forced forward and the flushing fluid 31 bypasses the front piston 27 to fill the space between the movable wall 26 and the front piston 27. When the total amount of flushing fluid 31 is forced into this space, the rear piston 32 strikes the front piston 27 and, during further forward movement, these two pistons function as a single piston.

As the two pistons 27 and 32 move forward, the movable wall 26 expels the mixed injectable composition 34 through an outlet line 29 which is connected to an injection needle or cannula, optionally by a tube. The injection needle or cannula is attached to the patient and injection of the composition 34 can begin.

After the administration is complete, the movable wall 26 is in the foremost position in the reservoir container 21 and substantially all of the injectable composition 34 is expelled from the container. However, a certain amount of composition 34 may remain in the dead space formed by the space opposite the movable wall 26, the outlet conduit 29, and the connecting tube or injection needle. This part cannot be utilized by the patient unless the special measure according to the invention is applied.

At the forward position of the movable wall 26, it is at the position of the front bypass connection 33 such that a flow path for the flushing fluid 31 is provided around the movable wall 26. The additional forward thrust exerted on the one-piece pistons 27 and 32 forces the flushing fluid 31 to flow out of the movable wall 26 through the outlet conduit 29 and the associated tube and needle or cannula. Meanwhile, the rinsing fluid 31 will deliver the remainder of the composition to be injected to the patient and at the same time flush the outlet 29 and the tube. Thus, there will be no loss of product for injection. When the entire amount of rinse liquid 31 has been expelled from the cartridge, the operation is complete.

The injection cartridge is generally housed in a holding device to facilitate its use when administering an injection. Such holding means are also generally5

It is known to a person skilled in the art. The filler according to the invention does not require any particular modifications to these supports. Small adjustments may be necessary to accommodate the front bypass and the larger length of charge, but these are within the skill of the art. The materials used to make the injection cartridges of the present invention are the same as those used for conventional injection cartridges, such as glass and various plastics and rubbers. Thus, in the case of a filling having an anterior chamber containing a liquid composition and an auxiliary chamber containing a rinsing fluid, the anterior piston may be made of a resilient material, preferably of rubber. When the fill according to the invention is used for lyophilization to form the solid component, the movable wall between the front chamber and the rear chamber is made of a resilient material with low water vapor permeability. Suitable materials include butyl rubber, preferably halobutyl rubber, such as chlorobutyl or bromobutyl rubber. When the fill according to the invention is used for lyophilization, the fill container should be made of a rigid material to better withstand the low pressure and temperature used for lyophilization. The right material is glass.

It is important that the volume of the rinse fluid is sufficient to thoroughly rinse the dead spaces and transfer any remaining product to be injected for injection into the patient. It has been found that the volume of the flushing fluid is at least twice, but preferably three times, the combined volume of the space in the injection filler in front of the front piston or in the outermost position of the movable wall and the outlet into the injection needle or cannula. This gives a thorough rinsing effect.

The injection cartridge of the present invention can be used with any injectable formulation which has been found to be suitable for the conventional injection cartridge. For example, therapeutic proteins and peptides may be mentioned. However, the advantages of the invention are more pronounced when very expensive formulations are to be administered, such as those produced by recombinant DNA technology. Typical examples include growth hormones, certain peptides, anticancer drugs, vaccines, interleukins, monoclonal antibodies, tissue plasmin activators (tPA), erythropoietin (EPO), urokinase, streptokinase, low molecular weight heparins, and human proteins. More specifically, the human proteins are shown in Table VIII. factor IX. factor III or antithrombin III, produced by recombinant DNA technology. The elimination of losses in such formulations is of great economic importance.

Suitable liquid injectable formulations include solutions containing human protein, such as Form VIII. factor IX. factor III, antithrombin III, with at least one stabilizer, such as a surfactant. A suitable solid component of an injectable preparation may comprise a lyophilized human protein, preferably VIII. factor produced by recombinant DNA technology.

The injection cartridge of the invention is preferably used for parenteral administration, such as subcutaneous, intramuscular or intravenous injection, most preferably intravenous injection. Preferably, the injection cartridge of the present invention is used to rinse the outlet conduit connected to a tube and injection needle or cannula, thereby rinsing substantially the entire composition for injection. The injection cartridge of the invention is used to administer any human protein, preferably lyophilized protein.

The method of administering a liquid composition of an injection syringe of the present invention is generally employed by parenteral administration, such as by intramuscular or intravenous injection, most preferably by intravenous injection. Preferably, the method of administering the liquid composition is used to rinse the outlet conduit connected to a tube or injection needle or cannula so that each composition to be injected is flushed out. The method of administering the liquid composition of the invention is preferably suitable for administration of any human protein, preferably lyophilized protein.

The rinsing fluid may be any liquid which is compatible with the composition to be injected and does not cause any adverse effect when administered to a patient. Many such liquids are known to those skilled in the art, for example, physiological saline solutions.

The invention has been described above with reference to the Examples, but it will be understood by those skilled in the art that many changes may be made therein without departing from the subject matter of the invention.