CA2116031C - Dual-chamber injection cartridge - Google Patents
Dual-chamber injection cartridge Download PDFInfo
- Publication number
- CA2116031C CA2116031C CA002116031A CA2116031A CA2116031C CA 2116031 C CA2116031 C CA 2116031C CA 002116031 A CA002116031 A CA 002116031A CA 2116031 A CA2116031 A CA 2116031A CA 2116031 C CA2116031 C CA 2116031C
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- Canada
- Prior art keywords
- chamber
- constriction
- cartridge
- piston
- liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/24—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic
- A61M5/2448—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic comprising means for injection of two or more media, e.g. by mixing
Abstract
An injection cartridge of the dual-chamber type having a front chamber (2) for a solid component (11) and a rear chamber (3) for a liquid component (5) of an injectable preparation, said chambers being separated by a front piston (4), is provided with a constriction (8) of the cartridge barrel (1) close in front of the front piston (4). The front piston (4) is prevented by the constriction (8), from being inadvertently displaced forward, but on application of an increased force, may be urged into and through the constriction (8) while overcoming the resistance offered by the constriction (8). Said constriction (8) has such a shape that the barrel (1) of the cartridge has a noncircular cross section at the place of the constriction (8), and the front piston (4) will be deformed when it passes through the constriction (8), such that a bypass connection for liquid from the rear chamber (3) to the front chamber (2) is established. A method for manufacturing an injectable preparation of a pharmaceutically active agent for storage in the injection cartridge.
Description
'O 94/01150 ~ . PCT/SE93/00558 ;~~..~~~~1 Dual-chamber infection cartridge The present invention refers to injection cartridges of the_.dual-chamber type. More specifically, it refers to improvements in injection cartridges of the dual=
chamber type, whereby sterility of the components in the cartridge may be assured.
Injection cartridges of the dual-chamber type have found a very wide use in the administering of injec-table preparations which are not stable as a solution or dispersion in a liquid phase. As examples of such preparations may be mentioned certain protein compounds and hormones, such as growth hormones. These prepara-tions are provided in a dry form, which is mixed with a liquid phase, usually water or an aqueous solution, immediately before the administering.
An injection cartridge of the dual-chamber type is generally shaped as a tubular barrel, which is divided into a front chamber and a rear chamber by means of a front piston. The front chamber contains the dry compo-nent of the injectable preparation, and is closed at its front end by a closure which permits the establish-ment of a liquid~connection with the outside. Such a closure may be in the form of a rubber septum which may be pierced by a hollow needle for withdrawing or expelling a liquid mixture from the front chamber. The rear chamber is filled with the liquid component of the injectable preparation, usually water or an aqueous solution, and is closed at its rear end by a rear piston.
When the injectable preparation is to be prepared, pressure is applied on the rear piston to move it forward. This pressure is transmitted through the ~ essentially incompressible liquid to the front piston, _ such that this piston is also moved forward. By this forward movement, the front piston activates a bypass connection, such that the liquid in the rear chamber can flow over into the front chamber by the action of WO 94/01150 PGT/SE93/0055$ s '" i ;~li~ti~l .
chamber type, whereby sterility of the components in the cartridge may be assured.
Injection cartridges of the dual-chamber type have found a very wide use in the administering of injec-table preparations which are not stable as a solution or dispersion in a liquid phase. As examples of such preparations may be mentioned certain protein compounds and hormones, such as growth hormones. These prepara-tions are provided in a dry form, which is mixed with a liquid phase, usually water or an aqueous solution, immediately before the administering.
An injection cartridge of the dual-chamber type is generally shaped as a tubular barrel, which is divided into a front chamber and a rear chamber by means of a front piston. The front chamber contains the dry compo-nent of the injectable preparation, and is closed at its front end by a closure which permits the establish-ment of a liquid~connection with the outside. Such a closure may be in the form of a rubber septum which may be pierced by a hollow needle for withdrawing or expelling a liquid mixture from the front chamber. The rear chamber is filled with the liquid component of the injectable preparation, usually water or an aqueous solution, and is closed at its rear end by a rear piston.
When the injectable preparation is to be prepared, pressure is applied on the rear piston to move it forward. This pressure is transmitted through the ~ essentially incompressible liquid to the front piston, _ such that this piston is also moved forward. By this forward movement, the front piston activates a bypass connection, such that the liquid in the rear chamber can flow over into the front chamber by the action of WO 94/01150 PGT/SE93/0055$ s '" i ;~li~ti~l .
the forward movement of the rear piston, to be mixed with the solid component of the injectable preparation.
When all of the liquid in the rear chamber has been made to flow over into the front chamber, the front face of the rear piston will abut the rear face of the front. piston. On further forward movement of the rear piston, the two pistons will act as one single piston to expel the mixed injectable preparation from the front chamber through the liquid connection mentioned above. Alternatively, the front chamber may serve as a reservoir for the mixed injectable preparation, and portions thereof may be withdrawn through said liquid connection.
The bypass connection for the liquid from the rear chamber to the front chamber may be arranged as a channel in the interior wall of the barrel of the car-tridge. This channel is exposed by the front piston on its movement forward, to afford a liquid connection between the two chambers. Other arrangements are also possible.
When the injectable preparation is prepared from the two 'components, the injection cartridge is usually placed in a holder device provided with means for applying the pressure on the rear piston. The holder device may also be provided with means for metering and administering doses of the mixed injectable prepara-tion:
The design and function of injection cartridges of the dual-chamber,type,is well-known to those skilled in the art, and need not be described here in more detail.
Also, a number of the above-mentioned holder devices , are well-known, and some of them are commercially available.
In the manufacture of injection cartridges of the dual-chamber type, it is of course of the utmost importance that sterility is maintained, so that no risk of microbial contamination of the injectable pre-O 94!01150 , . PC.'T/SE93/00558 ~~ .1.~ ~ U ~ ~.
When all of the liquid in the rear chamber has been made to flow over into the front chamber, the front face of the rear piston will abut the rear face of the front. piston. On further forward movement of the rear piston, the two pistons will act as one single piston to expel the mixed injectable preparation from the front chamber through the liquid connection mentioned above. Alternatively, the front chamber may serve as a reservoir for the mixed injectable preparation, and portions thereof may be withdrawn through said liquid connection.
The bypass connection for the liquid from the rear chamber to the front chamber may be arranged as a channel in the interior wall of the barrel of the car-tridge. This channel is exposed by the front piston on its movement forward, to afford a liquid connection between the two chambers. Other arrangements are also possible.
When the injectable preparation is prepared from the two 'components, the injection cartridge is usually placed in a holder device provided with means for applying the pressure on the rear piston. The holder device may also be provided with means for metering and administering doses of the mixed injectable prepara-tion:
The design and function of injection cartridges of the dual-chamber,type,is well-known to those skilled in the art, and need not be described here in more detail.
Also, a number of the above-mentioned holder devices , are well-known, and some of them are commercially available.
In the manufacture of injection cartridges of the dual-chamber type, it is of course of the utmost importance that sterility is maintained, so that no risk of microbial contamination of the injectable pre-O 94!01150 , . PC.'T/SE93/00558 ~~ .1.~ ~ U ~ ~.
paration will arise. However, this has been a problem with the prior art injection cartridges of the dual-chamber type.
In the prior art process for manufacture, the empty cartridges are provided with the front piston in place.
The barrel of the cartridge is shaped as a cylindrical tube, which may be shaped as a bottleneck at its front end to receive the closure, which usually consists of a rubber septum and a metal capsule having an opening in its middle. The front chamber is filled with a solution of the solid component of the injectable preparation, and the cartridge with its contents is then subjected to a freeze-drying process to evaporate the solvent and afford the component in a dry solid form. The front end of the cartridge is then closed with the closure means, and the rear chamber of the car~:ridge is filled with the liquid component of the injectable preparation and is closed by insertion of the rear. piston.
All these operations must be carried out under aseptic or sterile conditions to assure against conta-urination by microorganisms. The finished cartridge cannot be heat sterilized by autoclaving, as this would degrade the sensitive solid component of the injectable preparation. The most critical of these operations is the filling of the cartridge containing the solid component with the liquid component, and the sealing of the rear chamber with the rear.piston. In this opera-tion, there is a considerable risk of microbial conta-mination.
_ It would be preferable to be able to fill the car-tridge with the liquid component in the rear chamber and seal this chamber as a first step and then steril-ize this assembly by autoclaving, and subsequently fill the front chamber with the solution of the solid compo-vent and carry out the freeze-drying step. However, this has not been possible, due to the fact that the cartridge with the liquid component in the rear chamber ~ j~ ~ ~ J 1 PCT/SE93/00558 ~
In the prior art process for manufacture, the empty cartridges are provided with the front piston in place.
The barrel of the cartridge is shaped as a cylindrical tube, which may be shaped as a bottleneck at its front end to receive the closure, which usually consists of a rubber septum and a metal capsule having an opening in its middle. The front chamber is filled with a solution of the solid component of the injectable preparation, and the cartridge with its contents is then subjected to a freeze-drying process to evaporate the solvent and afford the component in a dry solid form. The front end of the cartridge is then closed with the closure means, and the rear chamber of the car~:ridge is filled with the liquid component of the injectable preparation and is closed by insertion of the rear. piston.
All these operations must be carried out under aseptic or sterile conditions to assure against conta-urination by microorganisms. The finished cartridge cannot be heat sterilized by autoclaving, as this would degrade the sensitive solid component of the injectable preparation. The most critical of these operations is the filling of the cartridge containing the solid component with the liquid component, and the sealing of the rear chamber with the rear.piston. In this opera-tion, there is a considerable risk of microbial conta-mination.
_ It would be preferable to be able to fill the car-tridge with the liquid component in the rear chamber and seal this chamber as a first step and then steril-ize this assembly by autoclaving, and subsequently fill the front chamber with the solution of the solid compo-vent and carry out the freeze-drying step. However, this has not been possible, due to the fact that the cartridge with the liquid component in the rear chamber ~ j~ ~ ~ J 1 PCT/SE93/00558 ~
cannot be subjected to the vacuum applied during the freeze-drying step. The pressure prevailing in the rear .
chamber with the liquid will strive to expel the front and rear pistons from the barrel of the cartridge, and even if it is possible to secure the rear piston by some suitable holder arrangement during the freeze-drying step, this has not been possible for the front piston. Thus, during the freeze-drying step, the front piston will move forward by the influence of the,pres-sure in the rear chamber, and will push out the solu-tion of the solid component from the front chamber.
By the present invention, this disadvantage is elimi-nated. An injection cartridge of the dual-chamber type is provided, which may be subjected to a freeze-drying process while its rear chamber is filled with a liquid, without any risk of its pistons being displaced by the influence of a pressure difference between the front and the rear chamber. The pressure difference is usual-ly about one atmosphere or one bar (1013 millibars, to be exact), which corresponds to the case when the con-tents of the front chamber is freeze-dried under vacuum conditions, while the rear chamber is filled with a liquid at atmospheric pressure. In such a case, there is consequently~a vacuum in front of the piston and essentially atmospheric pressure behind the piston.
Small deviations in this pressure differential are possible, mostly dependent on the temperature of the liquid in the rear chamber and on the ambient pressure of the atmosphere.
Thus, the present invention refers to an injection cartridge of the dual-chamber type, which comprises a cylindrical cartridge barrel having a front chamber for a solid product and a rear chamber for a liquid pro-duct, said chambers being sealingly separated by a displaceable piston of a resilient material, and having an openable bypass connection'for liquid from the rear chari~ber to the front chamber and a pierceable sealing closure of the front end of the front chamber. What characterizes the invention is that in the cartridge barrel is arranged a constriction such that said cartridge barrel has a non-circular cross-section at said constriction, and 5 that before said liquid bypass connection has been opened, said separating piston is situated close to the rear of said constriction, such that said constriction exerts a resistance against a forward displacement of said piston, such that said piston is prevented from moving forward when there is a vacuum in front of the piston and essentially atmospheric pressure behind said piston, and that said piston during a displacement forward through said constriction while overcoming said resistance is deformed such that said liquid bypass connection is established.
The invention further refers to a method for manufacturing an injectable preparation of a pharmaceutically active agent suitable for storage in a dual-chamber injection cartridge as defined above, said method being characterized by the steps of A. filling the rear chamber of said injection cartridge with the liquid component of the preparation;
B. sealing said rear chamber and optionally subjecting said injection cartridge to a heat sterilization;
C. charging a solution of said pharmaceutically active agent in the front chamber of said injection cartridge;
D. subjecting said injection cartridge to a freeze-drying process; and E. sealing said front chamber of said injection cartridge.
5a In the preferred embodiment of the invention, the front and rear chambers are separated by a displaceable piston which is prevented from being displaced during the freeze-drying step. By the application of additional force, however, the piston may be deformed sufficiently to pass through said constriction and, by be-WO 94/01150 PCT/SE93/0055$
r~~~~~~
chamber with the liquid will strive to expel the front and rear pistons from the barrel of the cartridge, and even if it is possible to secure the rear piston by some suitable holder arrangement during the freeze-drying step, this has not been possible for the front piston. Thus, during the freeze-drying step, the front piston will move forward by the influence of the,pres-sure in the rear chamber, and will push out the solu-tion of the solid component from the front chamber.
By the present invention, this disadvantage is elimi-nated. An injection cartridge of the dual-chamber type is provided, which may be subjected to a freeze-drying process while its rear chamber is filled with a liquid, without any risk of its pistons being displaced by the influence of a pressure difference between the front and the rear chamber. The pressure difference is usual-ly about one atmosphere or one bar (1013 millibars, to be exact), which corresponds to the case when the con-tents of the front chamber is freeze-dried under vacuum conditions, while the rear chamber is filled with a liquid at atmospheric pressure. In such a case, there is consequently~a vacuum in front of the piston and essentially atmospheric pressure behind the piston.
Small deviations in this pressure differential are possible, mostly dependent on the temperature of the liquid in the rear chamber and on the ambient pressure of the atmosphere.
Thus, the present invention refers to an injection cartridge of the dual-chamber type, which comprises a cylindrical cartridge barrel having a front chamber for a solid product and a rear chamber for a liquid pro-duct, said chambers being sealingly separated by a displaceable piston of a resilient material, and having an openable bypass connection'for liquid from the rear chari~ber to the front chamber and a pierceable sealing closure of the front end of the front chamber. What characterizes the invention is that in the cartridge barrel is arranged a constriction such that said cartridge barrel has a non-circular cross-section at said constriction, and 5 that before said liquid bypass connection has been opened, said separating piston is situated close to the rear of said constriction, such that said constriction exerts a resistance against a forward displacement of said piston, such that said piston is prevented from moving forward when there is a vacuum in front of the piston and essentially atmospheric pressure behind said piston, and that said piston during a displacement forward through said constriction while overcoming said resistance is deformed such that said liquid bypass connection is established.
The invention further refers to a method for manufacturing an injectable preparation of a pharmaceutically active agent suitable for storage in a dual-chamber injection cartridge as defined above, said method being characterized by the steps of A. filling the rear chamber of said injection cartridge with the liquid component of the preparation;
B. sealing said rear chamber and optionally subjecting said injection cartridge to a heat sterilization;
C. charging a solution of said pharmaceutically active agent in the front chamber of said injection cartridge;
D. subjecting said injection cartridge to a freeze-drying process; and E. sealing said front chamber of said injection cartridge.
5a In the preferred embodiment of the invention, the front and rear chambers are separated by a displaceable piston which is prevented from being displaced during the freeze-drying step. By the application of additional force, however, the piston may be deformed sufficiently to pass through said constriction and, by be-WO 94/01150 PCT/SE93/0055$
r~~~~~~
coming deformed, will allow the liquid to pass by and enter the front chamber to be mixed with the solid, pharmaceutically active component.
Through the injection cartridge and the method of the , present invention, it has for the first time become possible to freeze-dry the solution of the active agent in the front chamber of the cartridge while the liquid component of the injectable preparation is already present in the rear chamber. This brings about con-siderable advantages, as has been described in the foregoing.
Preferably, the constriction has such a shape that the cartridge barrel has an oval or a dumbbell-shaped cross-section at the site of said constriction.
In the drawings, Figure 1 shows a sectional view of an injection cartridge of the invention with a liquid filled into its rear chamber. Figure 2 shows the same cartridge with a solution of the solid component filled into the front chamber. Figure 3 shows the same car-tridge during the freeze-drying process. Figure 4 after completion of the freeze-drying process. Figure 5 shows the same cartridge-during the displacement forward of the front piston and the opening of the liquid bypass connection. Figures 6 and 7 show two different shapes of the constriction in cross-sectional views. In the drawings, like parts have the same reference numbers.
Figure .1 is a schematic longitudinal sectional view of an injection cartridge according to the invention.
The cartridge comprises a barrel 1, which is divided into a front chamber 2 and a rear chamber 3 by means of a displaceable front piston 4. The rear chamber 3 con- , tains a liquid 5 and is sealed at its rear end by a -~ displaceable rear piston 6. The liquid is primarily sterile water or a sterile aqueous solution. However, other types of liquids, such as emulsions or suspen-sions are also possible. At its front end 7, the car-tridge barrel 1 is shaped to receive a closure of a 'O 94/01150 PC T/SE93/00558 ,:,.~~~~~~I
known type, such as a rubber septum and a metal capsu-le. As such a closure is well-known to those skilled in the arx, it is not shown in the drawing.
According to the invention, the barrel 1 of the cartridge is provided with a constriction 8, and the front piston 4 is situated close or preferably imme-diate to the rear of said constriction 8. Thus, the constriction 8 prevents any inadvertent displacement forward of the front piston 4. .
The barrel 1 of the cartridge is usually made from glass or a plastic material, and the constriction may be arranged by pinching the barrel with a suitable pin-ching tcol while the barrel material has been saftened by heating. The constriction may also be arranged by securing a ring-shaped constricting piece inside the barrel at a suit4r. ie position, if softening by heat is not suitable.
Figure 2 is a schematic sectional view of the same injection cartridge, where the front chamber 2 has been filled with a solution 9 of the solid component of the injectable preparation. Prior to the filling of the solution in the front chamber, the cartridge with the liquid component enclosed in the rear chamber 3 has been subjected to a heat sterilizing process to render it sterile before the solution 9 is filled into the front chamber 2. Such a sterilizing process is possible in a pressure autoclave, where the pressure counteracts the tendency of the liquid 5 in the rear chamber 3 to expand under the influence of the heat and displace one or both of the front piston 4 and the rear piston 6.
Figure 3 shows a schematic longitudinal sectional . view of the same injection car~.ridge while it is sub-jected to a freeze-drying process. The liquids 5 in the rear chamber and 9 in the front chamber are here frozen, and vapour escapes from the frozen solution 9, as is shown by the arrow 10.
As the freeze-drying is carried out under vacuum, the WO 94/01150 ~ .~ ~;'~;r.i: e~
pressure prevailing in the rear chamber 3 strives to displace the front piston 4 forward and the rear piston 6 rearSaard. However, the constriction 8 prevents the displacement forward of the front piston 4, while the rear piston 6 is held secure by a clamping device of a known type (not shown). Thus, nothing of the contents of the rear chamber 3 escape from said chamber.
Figure 4 shows a schematic sectional view of the same cartridge after the freeze-drying process has been completed. The solution in the front chamber 2 has been evaporated to give a solid residue 11, which is the solid component of the injectable preparation. The frozen liquid 5 in the rear chamber has thawed into its liquid state. Also, the front chamber has been sealed by a suitable closure (not shown) at its front end 7.
This is usually carried out inside the freeze-drying chamber after completion of the freeze-drying process, by the use of suitable equipment, which is known to those skilled in the art.
After the vacuum in the freeze-drying chamber has been released, the cartridge may betaken out. Its contents in the two chambers 2 and 3 is now completely sterile, and the cartridge may be stored until it is to be used for administering one or more injections, or for the preparation of an injectable preparation to be withdrawn from the cartridge.
Figure 5 shows a schematic longitudinal sectional view of the injection cartridge of the invention when the liquid in the rear chamber is to.be mixed with the solid component in the front chamber. A forward pressure is applied on the rear piston 6, as is sym- , bolized by the arrow 12. This pressure will be trans-mitted through the essentially incompressible liquid 5 to act on the front piston 4. At a sufficiently high pressure on the rear piston 6, the front piston 4 will overcome the resistance of the constriction 8 in the barrel 1 and will be urged into said constriction. This 'O 94/01150 . PCT/SE93/00558 ~.t.~~~~~
will be possible because the front piston 4 is manu-factured from a suitably resilient material, such as rubber. When the front piston 4 is urged into the con-striction 8, it will be deformed, and will strive to-y adapt to the cross-section of the constriction 8.
However, as said cross-section is non-circular, the resilience of the piston material is not sufficient to allow the piston 4 to adapt completely to the cross-section. Instead, leaks will occur between the deformed piston 4 and the interior wall of the barrel 1, to afford a bypass liquid connection from the rear chamber 3 to the front chamber 2. Thus, the liquid 5 will flow from the rear chamber 3 into the front chamber 2 under the influence of the pressure 12 acting on the rear piston 6, bypassing the deformed front piston 4, as is shown by the arrows 13. The liquid component 5 will new be mixed with the solid component il to dissolve it or disperse it into the injectable preparation.
When the rear piston 6 has been moved forward so far that it abuts the front piston 4, all of the liquid component 5 has been transferred to the front chamber 2. Further pressure on the rear piston 6 will make the two pistons 6 and 4 act like one single piston and will urge them through the constriction 8 out into the front chamber 2. This is possible because of the resilience of the material of the pistons 4 and 6, and after the two pistons have passed through the constriction 8, .
they will revert to their undeformed state and will seal against the interior wall of the barrel 1. They will then act like one single piston in the front chamber 2 for expelling the mixed injectable prepara-tion through a liquid connection which has been opened through the closure of the front end 7. This liquid connection can consist of a hollow needle, which may be pointed at both ends for directly administering the preparation to a patient, or which may be connected to a tube, which at its other end is connected to a needle or cannula for injection or infusion to a patient. Such arrangements are well-known to those skilled in the art, and are therefore not shown in the drawing.
Figures 6 and 7 show two embodiments of the 5 constriction 8 in the barrel 1 of the injection cartridge of the invention. The figures are cross-sectional views along the lines A-A in figure 5.
In figure 6, it will be seen that the constriction 8 of the barrel 1 of the injection cartridge has an oval 10 cross-section. The front piston 4 is deformed to adapt to this cross-section, but its resilience is not sufficient to adapt completely, and spaces 14 will form between the piston 4 and the interior wall of the barrel 1. These spaces 14 will serve as bypass connections to afford a passage of liquid from the rear chamber 3 into the front chamber 2.
Figure 7 shows an embodiment where the constriction 8 has a cross-section which is essentially shaped like a dumbbell. When the front piston 4 is deformed and strives to adapt to this shape, spaces 15 are formed which allow the passage of liquid from the rear chamber 3 into the front chamber 2.
Other shapes of the cross-section of the constriction 8 are also possible. What is important is that the cross-section should not be circular. A piston which is deformed to adapt to a circular cross-section having a smaller diameter will still seal against the interior wall, and will not give any spaces for a bypass flow of liquid.
The shape and size of the constriction 8 and the shape and resilience of the pistons 4 and 6 should be selected such that the front piston in its initial position close to the rear of the constriction cannot overcome the resistance of said constriction by the action of only the pressure differential during the freeze-drying step. When additional force is applied on the piston, however, it should be able to pass through the constriction while being deformed, and be able to revert to its original shape and resilience after having passed through said constriction.
These parameters may be determined by one skilled in the art by routine experiments, once the basic inventive idea has been understood.
Thus, the constriction 8 and the front piston 4 should be constructed in such a way that the force necessary to push the piston 4 into the bypass zone formed by the constriction 8 (FoPe~) is greater than the force arising from the pressure difference between the two faces of the piston 4 during the freeze-drying process (Fl,,o). This pressure difference reaches a maximum value (0P) of about 1013 millibars (about one atmosphere or 10 N/cm2), which usually occurs in the secondary stage of the freeze-drying process, provided that the rear chamber is closed at the same pressure and temperature as is used in the secondary drying. The necessary force can then be calculated with knowledge of the interior diameter (Di) of the cartridge barrel:
Fopen > Fl,,o = L1P,~,~ x Diz x II/4 However, the value of Fopen should not be too high, as this will make the handling of the injection device inconvenient when the components are to be mixed. In practice, this sets a useful interval for the value of FoPen. An example: If the interior diameter of the barrel is 1.5 cm, the value of Fl,,o will be about 17.7 N. If the maximum necessary force for convenient handling of the device is set to about 25 N, the constriction should provide an intermediate FoPe" value of, lla say, about 20 N. The selection of a suitable size of the constriction in connection with suitable dimensions and materials of the front and rear pistons 4 and 6 is well within the competence of a person skilled in this art.
For the readying of the cartridge by mixing the two WO 94/01150 PCT/SE93/0055$
~.L1~~~1 components into the injectable preparation and the subsequent administering of one or more doses of said preparation, the injection cartridge is usually placed in a holder device; Such holder devices of various w designs are known to those skilled in the art, and need not be described here in greater detail. They usually comprise a piston rod for moving the rear wall forward to establish the liquid bypass connection, and a metering device for the subsequent metering out of_ doses of the injectable preparation for administering to the patient. A number of such devices are intended to be used by a patient for administering injections to .
Many such devices are of a disposable type, himself.
such that an emptied cartridge cannot be taken out from the device without breaking said device, thus making it impossible to use the device more than once. This is an important safety feature.
In NO-A-80 841 is disclosed a tubular ampoule comprising two chambers which are separated by a stopper positioned in a liquid component and which is closed at one end by a movable wall. The separating stopper provides a-complete seal between the two chambers while it is positioned in the constriction, and it may be pushed out into the chamber containing the solid component by applying pressure on the movable wall closing the other end of the ampoule. Once pushed out into the chamber, the stopper lies loose in the chamber and cannot serve as a piston for expelling the mixed preparation from,the ampoule, as it does not seal , against the interior wall of the barrel. The movable wall at the other end of the ampoule is only displaced a short distance sufficient to push out the stopper from the constriction, so that a connection is estab-lished between the two chambers, and there is no question of establishing a temporary bypass connection for a liquid. Also, the opposite end of the ampoule , from the movable wall is closed permanently, and there ", ,1 .L i.~ '~ c~
is no arrangement of a pierceable closure at this end.
Therefore, the disclosure of NO-A-80 841 will not lead a person skilled in the art to the present invention.
The injection cartridge of the present invention is manufactured from previously known materials, such as glass or plastics, and in a conventional way. As stated above, the dimensions of the constriction and the material and dimensions of the pistons are selected such that a suitable resistance is achieved against the forward movement of the pistons through the constric-tion It must be ensured that the front piston is not inad~rertently displaced during the freeze-drying , process or the heat sterilizing process, but that it may be displaced against the resistance of the con-striction by the application of a reasonably greater force, at the same time as it is temporarily deformed to affc~-d the bypass liquid connection.
The injection cartridge of the present invention may be used for any injectable preparation which is unstable in its ready-mixed state and which must be prepared immediately before use by mixing a solid and a liquid component. It is especially suitable for the prepara-tion and administering of such preparations as solu-tions or dispersion of hormones, such as human growth hormone, and other proteins which are easily degraded ' in an aqueous solution.
Through the present invention, it has been made possible to provide an injection cartridge of the dual-chamber type, which can be subjected to a heat-steri-lizing process and a freeze-drying process while the liquid component is present in the rear chamber of the cartridge, without any risk of inadvertent displacement of the front piston separating the front and the rear chamber. This will considerably decrease the risk of contamination by micro-organisms during the manufacture ' and preparation of the cartridges. Also, the injection cartridges of the invention do not require any impor-WO 94/01150 -~ . PCT/SE93/00558 ~~~J~~~
taut modification of the freeze-drying equipment con-ventionally used. This makes the invention advantageous from an economical point of view.
Furthermore, through the bypass arrangement of the invention, there will be no neea xor a pypass cnanne~
arranged in the wall of the cartridge, so that there will be no external projection from the barrel of the cartridge. This makes the cartridge take up less space in a holder device, which may therefore be made simmer and less bulky, so that it will be easier for a patient to carry around.
In the foregoing specification, the invention has primarily been described with reference to the embodi-ments shown in the drawings. However, a person skilled in the art will realize that other embodiments and modifications are possible within the scope of the annexed claims.
Through the injection cartridge and the method of the , present invention, it has for the first time become possible to freeze-dry the solution of the active agent in the front chamber of the cartridge while the liquid component of the injectable preparation is already present in the rear chamber. This brings about con-siderable advantages, as has been described in the foregoing.
Preferably, the constriction has such a shape that the cartridge barrel has an oval or a dumbbell-shaped cross-section at the site of said constriction.
In the drawings, Figure 1 shows a sectional view of an injection cartridge of the invention with a liquid filled into its rear chamber. Figure 2 shows the same cartridge with a solution of the solid component filled into the front chamber. Figure 3 shows the same car-tridge during the freeze-drying process. Figure 4 after completion of the freeze-drying process. Figure 5 shows the same cartridge-during the displacement forward of the front piston and the opening of the liquid bypass connection. Figures 6 and 7 show two different shapes of the constriction in cross-sectional views. In the drawings, like parts have the same reference numbers.
Figure .1 is a schematic longitudinal sectional view of an injection cartridge according to the invention.
The cartridge comprises a barrel 1, which is divided into a front chamber 2 and a rear chamber 3 by means of a displaceable front piston 4. The rear chamber 3 con- , tains a liquid 5 and is sealed at its rear end by a -~ displaceable rear piston 6. The liquid is primarily sterile water or a sterile aqueous solution. However, other types of liquids, such as emulsions or suspen-sions are also possible. At its front end 7, the car-tridge barrel 1 is shaped to receive a closure of a 'O 94/01150 PC T/SE93/00558 ,:,.~~~~~~I
known type, such as a rubber septum and a metal capsu-le. As such a closure is well-known to those skilled in the arx, it is not shown in the drawing.
According to the invention, the barrel 1 of the cartridge is provided with a constriction 8, and the front piston 4 is situated close or preferably imme-diate to the rear of said constriction 8. Thus, the constriction 8 prevents any inadvertent displacement forward of the front piston 4. .
The barrel 1 of the cartridge is usually made from glass or a plastic material, and the constriction may be arranged by pinching the barrel with a suitable pin-ching tcol while the barrel material has been saftened by heating. The constriction may also be arranged by securing a ring-shaped constricting piece inside the barrel at a suit4r. ie position, if softening by heat is not suitable.
Figure 2 is a schematic sectional view of the same injection cartridge, where the front chamber 2 has been filled with a solution 9 of the solid component of the injectable preparation. Prior to the filling of the solution in the front chamber, the cartridge with the liquid component enclosed in the rear chamber 3 has been subjected to a heat sterilizing process to render it sterile before the solution 9 is filled into the front chamber 2. Such a sterilizing process is possible in a pressure autoclave, where the pressure counteracts the tendency of the liquid 5 in the rear chamber 3 to expand under the influence of the heat and displace one or both of the front piston 4 and the rear piston 6.
Figure 3 shows a schematic longitudinal sectional . view of the same injection car~.ridge while it is sub-jected to a freeze-drying process. The liquids 5 in the rear chamber and 9 in the front chamber are here frozen, and vapour escapes from the frozen solution 9, as is shown by the arrow 10.
As the freeze-drying is carried out under vacuum, the WO 94/01150 ~ .~ ~;'~;r.i: e~
pressure prevailing in the rear chamber 3 strives to displace the front piston 4 forward and the rear piston 6 rearSaard. However, the constriction 8 prevents the displacement forward of the front piston 4, while the rear piston 6 is held secure by a clamping device of a known type (not shown). Thus, nothing of the contents of the rear chamber 3 escape from said chamber.
Figure 4 shows a schematic sectional view of the same cartridge after the freeze-drying process has been completed. The solution in the front chamber 2 has been evaporated to give a solid residue 11, which is the solid component of the injectable preparation. The frozen liquid 5 in the rear chamber has thawed into its liquid state. Also, the front chamber has been sealed by a suitable closure (not shown) at its front end 7.
This is usually carried out inside the freeze-drying chamber after completion of the freeze-drying process, by the use of suitable equipment, which is known to those skilled in the art.
After the vacuum in the freeze-drying chamber has been released, the cartridge may betaken out. Its contents in the two chambers 2 and 3 is now completely sterile, and the cartridge may be stored until it is to be used for administering one or more injections, or for the preparation of an injectable preparation to be withdrawn from the cartridge.
Figure 5 shows a schematic longitudinal sectional view of the injection cartridge of the invention when the liquid in the rear chamber is to.be mixed with the solid component in the front chamber. A forward pressure is applied on the rear piston 6, as is sym- , bolized by the arrow 12. This pressure will be trans-mitted through the essentially incompressible liquid 5 to act on the front piston 4. At a sufficiently high pressure on the rear piston 6, the front piston 4 will overcome the resistance of the constriction 8 in the barrel 1 and will be urged into said constriction. This 'O 94/01150 . PCT/SE93/00558 ~.t.~~~~~
will be possible because the front piston 4 is manu-factured from a suitably resilient material, such as rubber. When the front piston 4 is urged into the con-striction 8, it will be deformed, and will strive to-y adapt to the cross-section of the constriction 8.
However, as said cross-section is non-circular, the resilience of the piston material is not sufficient to allow the piston 4 to adapt completely to the cross-section. Instead, leaks will occur between the deformed piston 4 and the interior wall of the barrel 1, to afford a bypass liquid connection from the rear chamber 3 to the front chamber 2. Thus, the liquid 5 will flow from the rear chamber 3 into the front chamber 2 under the influence of the pressure 12 acting on the rear piston 6, bypassing the deformed front piston 4, as is shown by the arrows 13. The liquid component 5 will new be mixed with the solid component il to dissolve it or disperse it into the injectable preparation.
When the rear piston 6 has been moved forward so far that it abuts the front piston 4, all of the liquid component 5 has been transferred to the front chamber 2. Further pressure on the rear piston 6 will make the two pistons 6 and 4 act like one single piston and will urge them through the constriction 8 out into the front chamber 2. This is possible because of the resilience of the material of the pistons 4 and 6, and after the two pistons have passed through the constriction 8, .
they will revert to their undeformed state and will seal against the interior wall of the barrel 1. They will then act like one single piston in the front chamber 2 for expelling the mixed injectable prepara-tion through a liquid connection which has been opened through the closure of the front end 7. This liquid connection can consist of a hollow needle, which may be pointed at both ends for directly administering the preparation to a patient, or which may be connected to a tube, which at its other end is connected to a needle or cannula for injection or infusion to a patient. Such arrangements are well-known to those skilled in the art, and are therefore not shown in the drawing.
Figures 6 and 7 show two embodiments of the 5 constriction 8 in the barrel 1 of the injection cartridge of the invention. The figures are cross-sectional views along the lines A-A in figure 5.
In figure 6, it will be seen that the constriction 8 of the barrel 1 of the injection cartridge has an oval 10 cross-section. The front piston 4 is deformed to adapt to this cross-section, but its resilience is not sufficient to adapt completely, and spaces 14 will form between the piston 4 and the interior wall of the barrel 1. These spaces 14 will serve as bypass connections to afford a passage of liquid from the rear chamber 3 into the front chamber 2.
Figure 7 shows an embodiment where the constriction 8 has a cross-section which is essentially shaped like a dumbbell. When the front piston 4 is deformed and strives to adapt to this shape, spaces 15 are formed which allow the passage of liquid from the rear chamber 3 into the front chamber 2.
Other shapes of the cross-section of the constriction 8 are also possible. What is important is that the cross-section should not be circular. A piston which is deformed to adapt to a circular cross-section having a smaller diameter will still seal against the interior wall, and will not give any spaces for a bypass flow of liquid.
The shape and size of the constriction 8 and the shape and resilience of the pistons 4 and 6 should be selected such that the front piston in its initial position close to the rear of the constriction cannot overcome the resistance of said constriction by the action of only the pressure differential during the freeze-drying step. When additional force is applied on the piston, however, it should be able to pass through the constriction while being deformed, and be able to revert to its original shape and resilience after having passed through said constriction.
These parameters may be determined by one skilled in the art by routine experiments, once the basic inventive idea has been understood.
Thus, the constriction 8 and the front piston 4 should be constructed in such a way that the force necessary to push the piston 4 into the bypass zone formed by the constriction 8 (FoPe~) is greater than the force arising from the pressure difference between the two faces of the piston 4 during the freeze-drying process (Fl,,o). This pressure difference reaches a maximum value (0P) of about 1013 millibars (about one atmosphere or 10 N/cm2), which usually occurs in the secondary stage of the freeze-drying process, provided that the rear chamber is closed at the same pressure and temperature as is used in the secondary drying. The necessary force can then be calculated with knowledge of the interior diameter (Di) of the cartridge barrel:
Fopen > Fl,,o = L1P,~,~ x Diz x II/4 However, the value of Fopen should not be too high, as this will make the handling of the injection device inconvenient when the components are to be mixed. In practice, this sets a useful interval for the value of FoPen. An example: If the interior diameter of the barrel is 1.5 cm, the value of Fl,,o will be about 17.7 N. If the maximum necessary force for convenient handling of the device is set to about 25 N, the constriction should provide an intermediate FoPe" value of, lla say, about 20 N. The selection of a suitable size of the constriction in connection with suitable dimensions and materials of the front and rear pistons 4 and 6 is well within the competence of a person skilled in this art.
For the readying of the cartridge by mixing the two WO 94/01150 PCT/SE93/0055$
~.L1~~~1 components into the injectable preparation and the subsequent administering of one or more doses of said preparation, the injection cartridge is usually placed in a holder device; Such holder devices of various w designs are known to those skilled in the art, and need not be described here in greater detail. They usually comprise a piston rod for moving the rear wall forward to establish the liquid bypass connection, and a metering device for the subsequent metering out of_ doses of the injectable preparation for administering to the patient. A number of such devices are intended to be used by a patient for administering injections to .
Many such devices are of a disposable type, himself.
such that an emptied cartridge cannot be taken out from the device without breaking said device, thus making it impossible to use the device more than once. This is an important safety feature.
In NO-A-80 841 is disclosed a tubular ampoule comprising two chambers which are separated by a stopper positioned in a liquid component and which is closed at one end by a movable wall. The separating stopper provides a-complete seal between the two chambers while it is positioned in the constriction, and it may be pushed out into the chamber containing the solid component by applying pressure on the movable wall closing the other end of the ampoule. Once pushed out into the chamber, the stopper lies loose in the chamber and cannot serve as a piston for expelling the mixed preparation from,the ampoule, as it does not seal , against the interior wall of the barrel. The movable wall at the other end of the ampoule is only displaced a short distance sufficient to push out the stopper from the constriction, so that a connection is estab-lished between the two chambers, and there is no question of establishing a temporary bypass connection for a liquid. Also, the opposite end of the ampoule , from the movable wall is closed permanently, and there ", ,1 .L i.~ '~ c~
is no arrangement of a pierceable closure at this end.
Therefore, the disclosure of NO-A-80 841 will not lead a person skilled in the art to the present invention.
The injection cartridge of the present invention is manufactured from previously known materials, such as glass or plastics, and in a conventional way. As stated above, the dimensions of the constriction and the material and dimensions of the pistons are selected such that a suitable resistance is achieved against the forward movement of the pistons through the constric-tion It must be ensured that the front piston is not inad~rertently displaced during the freeze-drying , process or the heat sterilizing process, but that it may be displaced against the resistance of the con-striction by the application of a reasonably greater force, at the same time as it is temporarily deformed to affc~-d the bypass liquid connection.
The injection cartridge of the present invention may be used for any injectable preparation which is unstable in its ready-mixed state and which must be prepared immediately before use by mixing a solid and a liquid component. It is especially suitable for the prepara-tion and administering of such preparations as solu-tions or dispersion of hormones, such as human growth hormone, and other proteins which are easily degraded ' in an aqueous solution.
Through the present invention, it has been made possible to provide an injection cartridge of the dual-chamber type, which can be subjected to a heat-steri-lizing process and a freeze-drying process while the liquid component is present in the rear chamber of the cartridge, without any risk of inadvertent displacement of the front piston separating the front and the rear chamber. This will considerably decrease the risk of contamination by micro-organisms during the manufacture ' and preparation of the cartridges. Also, the injection cartridges of the invention do not require any impor-WO 94/01150 -~ . PCT/SE93/00558 ~~~J~~~
taut modification of the freeze-drying equipment con-ventionally used. This makes the invention advantageous from an economical point of view.
Furthermore, through the bypass arrangement of the invention, there will be no neea xor a pypass cnanne~
arranged in the wall of the cartridge, so that there will be no external projection from the barrel of the cartridge. This makes the cartridge take up less space in a holder device, which may therefore be made simmer and less bulky, so that it will be easier for a patient to carry around.
In the foregoing specification, the invention has primarily been described with reference to the embodi-ments shown in the drawings. However, a person skilled in the art will realize that other embodiments and modifications are possible within the scope of the annexed claims.
Claims (7)
1. An injection cartridge of the dual-chamber type, comprising a cylindrical cartridge barrel having a front chamber for a solid component and a rear chamber for a liquid component of an injectable preparation, said chambers being sealingly separated from each other by a displaceable front piston of a resilient material, an openable bypass connection for liquid from the rear chamber to the front chamber, and a pierceable closure sealing the front end of the front chamber, characterized in that in the barrel of the cartridge is arranged a constriction such that said cartridge barrel has a non-circular cross-section at said constriction, that before said liquid bypass connection has been opened, said separating front piston is positioned close to the rear of said constriction, such that said constriction exerts a resistance against any forward displacement of said front piston, such that said front piston is prevented from moving forward when there is a vacuum in front of it and essentially atmospheric pressure behind it, and that said front piston during a forward displacement through said constriction while overcoming said resistance is deformed such that said liquid bypass connection is established.
2. An injection cartridge according to claim 1, characterized in that the barrel of the cartridge has an oval cross-section at said constriction.
3. An injection cartridge according to claim 1, characterized in that the barrel of the cartridge has a dumbbell-shaped cross-section at said constriction.
4. An injection cartridge according to any one of claims 1-3, characterized in that the rear chamber, containing the liquid component, is closed at its rear end by a displaceable rear piston which on being urged forward exerts a pressure on the front piston to urge it into and through said constriction while overcoming said resistance.
5. An injection cartridge according to any one of claims 1-4, characterized in that the liquid component in the rear chamber is sterile water or a sterile aqueous solution.
6. A method for manufacturing an injectable preparation of a pharmaceutically active agent suitable for storage in a dual-chamber injection cartridge according to any one of claims 1-5, characterized by the steps of A. filling the rear chamber of said injection cartridge with the liquid component of the injectable preparation;
B. sealing said rear chamber and optionally subjecting said injection cartridge to a heat sterilization;
C. charging a solution of said pharmaceutically active agent in the front chamber of said injection cartridge;
D. subjecting said injection cartridge to a freeze-drying process; and E. sealing said front chamber of said injection cartridge.
B. sealing said rear chamber and optionally subjecting said injection cartridge to a heat sterilization;
C. charging a solution of said pharmaceutically active agent in the front chamber of said injection cartridge;
D. subjecting said injection cartridge to a freeze-drying process; and E. sealing said front chamber of said injection cartridge.
7. A method according to claim 6, characterized in that said front and rear chambers are separated by a displaceable front piston which is prevented from being displaced during the freeze-drying step.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9202108A SE9202108D0 (en) | 1992-07-07 | 1992-07-07 | DUAL-CHAMBER INJECTION CARTRIDGE |
| SE9202108-8 | 1992-07-07 | ||
| PCT/SE1993/000558 WO1994001150A1 (en) | 1992-07-07 | 1993-06-23 | Dual-chamber injection cartridge |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2116031A1 CA2116031A1 (en) | 1994-01-20 |
| CA2116031C true CA2116031C (en) | 2005-02-22 |
Family
ID=20386737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002116031A Expired - Lifetime CA2116031C (en) | 1992-07-07 | 1993-06-23 | Dual-chamber injection cartridge |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US5472422A (en) |
| EP (1) | EP0606429B1 (en) |
| JP (1) | JP3431629B2 (en) |
| KR (1) | KR100276374B1 (en) |
| AT (1) | ATE185079T1 (en) |
| AU (1) | AU664641B2 (en) |
| BR (1) | BR9305573A (en) |
| CA (1) | CA2116031C (en) |
| DE (1) | DE69326601T2 (en) |
| DK (1) | DK0606429T3 (en) |
| EE (1) | EE02996B1 (en) |
| ES (1) | ES2139664T3 (en) |
| FI (1) | FI112034B (en) |
| GR (1) | GR3032229T3 (en) |
| NO (1) | NO309967B1 (en) |
| NZ (1) | NZ253819A (en) |
| SE (1) | SE9202108D0 (en) |
| WO (1) | WO1994001150A1 (en) |
| ZA (1) | ZA934879B (en) |
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-
1992
- 1992-07-07 SE SE9202108A patent/SE9202108D0/en unknown
-
1993
- 1993-06-23 NZ NZ253819A patent/NZ253819A/en not_active IP Right Cessation
- 1993-06-23 EP EP93915068A patent/EP0606429B1/en not_active Expired - Lifetime
- 1993-06-23 WO PCT/SE1993/000558 patent/WO1994001150A1/en active IP Right Grant
- 1993-06-23 AU AU45189/93A patent/AU664641B2/en not_active Ceased
- 1993-06-23 BR BR9305573A patent/BR9305573A/en not_active IP Right Cessation
- 1993-06-23 JP JP50321694A patent/JP3431629B2/en not_active Expired - Fee Related
- 1993-06-23 US US08/196,194 patent/US5472422A/en not_active Expired - Lifetime
- 1993-06-23 CA CA002116031A patent/CA2116031C/en not_active Expired - Lifetime
- 1993-06-23 ES ES93915068T patent/ES2139664T3/en not_active Expired - Lifetime
- 1993-06-23 KR KR1019940700743A patent/KR100276374B1/en not_active IP Right Cessation
- 1993-06-23 AT AT93915068T patent/ATE185079T1/en active
- 1993-06-23 DK DK93915068T patent/DK0606429T3/en active
- 1993-06-23 DE DE69326601T patent/DE69326601T2/en not_active Expired - Lifetime
- 1993-07-07 ZA ZA934879A patent/ZA934879B/en unknown
-
1994
- 1994-03-04 FI FI941041A patent/FI112034B/en not_active IP Right Cessation
- 1994-03-04 NO NO940769A patent/NO309967B1/en not_active IP Right Cessation
- 1994-11-15 EE EE9400138A patent/EE02996B1/en not_active IP Right Cessation
-
1999
- 1999-12-22 GR GR990403316T patent/GR3032229T3/en unknown
Also Published As
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|---|---|
| DE69326601T2 (en) | 2000-05-11 |
| JP3431629B2 (en) | 2003-07-28 |
| CA2116031A1 (en) | 1994-01-20 |
| ATE185079T1 (en) | 1999-10-15 |
| US5472422A (en) | 1995-12-05 |
| EP0606429B1 (en) | 1999-09-29 |
| EP0606429A1 (en) | 1994-07-20 |
| DK0606429T3 (en) | 2000-04-10 |
| FI941041A0 (en) | 1994-03-04 |
| FI112034B (en) | 2003-10-31 |
| BR9305573A (en) | 1996-01-02 |
| FI941041A (en) | 1994-03-04 |
| NO940769D0 (en) | 1994-03-04 |
| KR100276374B1 (en) | 2000-12-15 |
| NO940769L (en) | 1994-05-02 |
| AU664641B2 (en) | 1995-11-23 |
| NO309967B1 (en) | 2001-04-30 |
| JPH06510469A (en) | 1994-11-24 |
| EE02996B1 (en) | 1997-06-16 |
| NZ253819A (en) | 1996-07-26 |
| GR3032229T3 (en) | 2000-04-27 |
| ES2139664T3 (en) | 2000-02-16 |
| SE9202108D0 (en) | 1992-07-07 |
| WO1994001150A1 (en) | 1994-01-20 |
| AU4518993A (en) | 1994-01-31 |
| ZA934879B (en) | 1994-04-12 |
| DE69326601D1 (en) | 1999-11-04 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130626 |
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| MKEC | Expiry (correction) |
Effective date: 20131009 |