WO2008116908A1

WO2008116908A1 - Syringe system with piston-barrel construction for improved sterilisation process

Info

Publication number: WO2008116908A1
Application number: PCT/EP2008/053646
Authority: WO
Inventors: Bernd Jesussek
Original assignee: Ferring International Center S.A.
Priority date: 2007-03-28
Filing date: 2008-03-27
Publication date: 2008-10-02
Also published as: DE102007015010A1

Abstract

System for containing and/or preparing an injectable product comprising a liquid and a pharmaceutical product comprising: a cylindrical holder having an inner wall, a proximal end and a distal end; and a piston which is positioned m the cylindrical holder and which is able to slide between an extreme distal position and an extreme proximal position, wherein the piston is provided with two annular low-friction sealing members which are in axial direction separated from each other for maintaining coaxiality independent of an axial position and movement of the piston relative to the cylindrical holder.

Description

SYRINGE SYSTEM WITH PISTON-BARREL CONSTRUCTION FOR IMPROVED

STERILISATION PROCESS

Introduction

The invention is related to a system for containing and/or preparing an injectable product comprising a liquid and a pharmaceutical composition. The system is further related to use of such a system.

Background of the invention

Many pharmaceutical compositions are to be administered via an injection. However, the shelf life of certain pharmaceutical compositions is much longer when these compositions are kept in a low humidity or humidity-free environment. Many of such pharmaceutical compositions are therefore kept in a dry frozen condition. When such pharmaceutical compositions are to be administered via an injection, these compositions need to be mixed with a suitable liquid to end up as an injectable product. It is often preferred that this mixing of the pharmaceutical composition and the liquid takes place just before administering the injectable product. As many of such pharmaceutical compositions are to be administered on a daily basis, systems have been developed for safely mixing the liquid and the pharmaceutical composition, by the person using the pharmaceutical composition, or by someone who is helping that person.

US 3,931,815 describes a system comprising a holder having a closed end by means of a film or other penetrable closure, and a double-ended needle fixed to an adapter. One end of the double-ended needle is insertable into the holder by suitably placing the adapter onto the holder. A piston is intimately fitted into the holder.

Such a system can be used for preparing an injectable product when the adapter is placed such that one end of the double-ended needle is inserted into the holder and the other end of the double-ended needle pierces through a penetrable closure of a vial in which, for instance, a liquid is held- The liquid can be suctioned into the holder when the piston is moved in a withdrawing direction and a negative pressure is created within the holder. When the vial emptied from the fluid is replaced by a vial which holds for instance a dry frozen pharmaceutical composition and the piston is moved in the opposite direction, the liquid is injected into the vial and mixed with the pharmaceutical composition. When the piston is again moved in a withdrawing direction, and thus again a negative pressure is created in the holder, the injectable product is suctioned into the holder. It is then possible that the adapter with the double-ended needle is removed from the holder and that the holder further acts as a cartridge in which the injectable product is stored temporarily for administration into a person. The holder can then be used as part of a syringe or the holder can as a cartridge be inserted into a dedicated injection pen, which is well-known in the art for accurate dosaging and comfortable injection of a pharmaceutical composition into a body.

For accurate dosaging during both preparation and administration via injection, it is important that the relevant movement of the piston in the holder is accurately predictable and reproducible.

In addressing these requirements, use has been made of pistons which are elongated in axial directions. These axially elongated pistons are capable of maintaining accurately the coaxiality of the piston and the holder also when the piston is moved in the withdrawing or opposite direction. This allows for accurate and reproducibly determining the volume in the holder. The surface of the piston facing the inner space of the holder, will due to the maintained coaxiality of the piston and the holder, have a constant orientation within the holder, independent of the axial position of the piston in the holder. The volume of the inner space of the holder therefore almost exclusively depends on the axial position of the piston in the holder.

To reduce the friction between the piston and the inner wall of the holder, it is common that the piston is provided with annular low^friction sealing members which are in axial direction separated from each other. With such a piston there is little slack, if at all, in a movement of a piston in a direction other than the axial direction, so that such a system does in that respect contribute to accurate dosaging and preparation of an injectable product.

Holders are often provided with a penetrable closure at the end through which fluids are entering and leaving the holder. Such a penetrable closure may for instance be a well-known and commercially available shrinkage cap. An advantage is that when no needle is inserted via that penetrable closure into the inner space of the holder, the inner space of the holder is always closed off. If a needle penetrates such a closure, then also after removal of that needle, the holder will be closed off as the film used in the penetrable closure re-seals the hole made by the needle. This allows for the use of the holder as a cartridge in which for instance an injectable product can be temporarily stored. In particular when the holder is at one end provided with such a penetrable closure and on the other end provided with an axially elongated piston and/or a piston having two annular low-friction sealing members which are in axial direction separated from each other, the inner space of the holder can be considered as a closed system. For the practical use in terms of accurate dosaging and preparing an injectable product, such a tight fitting of the piston in the holder is highly advantageous. However, such a system provides a problem for the sterilization procedure of the inner space of the holder after assembly and prior to packaging of the system.

It is an object of the invention to provide a system for containing and/or preparing an injectable product comprising a liquid and a pharmaceutical composition wherein the system allows for accurate dosaging and accurate preparation of the injectable product, but also for a method of sterilizing the inner space of the holder in an economically viable way.

Summary of the invention

Provided is a system for containing and/or preparing an injectable product comprising a liquid and a pharmaceutical composition. The system comprises: a cylindrical holder having an inner wall, a proximal end and a distal end; and a piston which is positioned in the cylinder and which is able to slide between an extreme distal position and an extreme proximal position. The piston is further provided with two annular low-friction sealing members which are in axial direction separated from each other for maintaining coaxiality independent of an axial position and movement of the piston relative to the cylindrical holder. The system is further provided with a fluid communication which extends, at least when the piston is in its extreme proximal position, from a position proximal of the piston to a position which is between the two annular low-friction sealing members. Within the context of the specification, a proximal direction is a direction into which the piston moves for enhancing in the cylindrical holder the volume of an inner space for holding in the holder a liquid. The distal direction is in the context of the specification a direction into which the piston moves for reducing in the holder the volume of the inner space in which a liquid can be held in the holder. The expressions proxiraally and proximal position as well as distally and distal position are used in accordance with the use of the words proximal and distal as used for qualifying directions.

Whilst maintaining the coaxiality and as such the contribution to accurate dosaging and accurate preparation of an injectable product, the system also allows for a sterilization procedure similar if not equal to a sterilization procedure applied to a system having one annular low-friction sealing member less than the system according to the invention. Surprisingly, the fluid communication brings the time used for the full sterilization cycle down to economically very acceptable times. The short exposure times to the sterilization gas as well as aeration times at the end of the cycle in order to bring the levels of sterilization gases down to acceptable standards are very advantageous for the production and commercialization of a system according to the invention.

In an embodiment, the fluid communication comprises at least one channel. Such a channel may be formed in the piston and/or in the inner wall of rhe cylindrical holder. The channel may for instance be a groove or a tunnel.

In an embodiment, the system is provided with a backstopper for providing adjacent to the proximal end of the cylindrical holder an abutment member, so that upon moving the piston proximally, the piston arrives whilst abutting the backstopper in its extreme proximal position and is thus prevented from exiting the cylindrical holder. A system according to this embodiment allows the cylindrical holder to be used as a cartridge for storing the injectable product. Such a cartridge can for instance be inserted into a dedicated injection pen, which in itself is well-known in the art.

In an embodiment, the backstopper is configured to allow for assembly of the system by insertion of the piston into the cylindrical holder at the proximal end such that the piston is permanently received between the backstopper and the distal end. This embodiment allows for an easy way of assembling at least a parr of the system and removes the need for having extra parts for forming the backstopper.

In an embodiment, the cylinder and/or or the piston is made from a thermoplastic material such as, for instance, polypropylene. Such a material Is virtually incompressible, also reducing the possibility of "slack" in the movement of the piston relative to the cylindrical holder. Furthermore, when the piston is in its extreme distal position, i.e. a distal surface of the piston is in contact with a proximally facing surface at a distal end of the inner space of the cylindrical holder, its position is stable. So that a so- called "dead volume" distal from the piston is little and constant, avoiding phenomena such as "drip leaking".

In an embodiment, the piston on its proximally facing end Is provided with a drivable contact surface for receiving driving contact with a driving member. The contact surface is flat. This allows for a good and stable match of the contact surface with a driving member of, for instance, an injection pen, as such also contributing to a reduction in possible slack of the driving mechanism, in its turn further contributing to accurate and reproducible dosaging. SYRINGE SYSTEM WITH PISTON-BARREL CONSTRUCTION FOR IMPROVED

STERILISATION PROCESS

These and other features, as well as their advantages, are further described with reference to a drawing which shows by way of example in:

Fig. 1 an exploded view an embodiment of a system according to the invention;

Fig. 2: the embodiment of Fig, 1 in assembled condition;

Fig. 3: in a semi-exploded view, an embodiment of a system according to the invention;

Fig. 4 in a cross sectional view the embodiment shown in Fig. 3 as in use;

Fig. 5: in a cross sectional view, with an insert showing in more detail a part of that view, an embodiment of a system according to the invention;

Fig. 6: in a semi-cross sectional view, a part of an embodiment of a system according to the invention;

Fig. 7; a view of the embodiment shown in Fig. 6 as seen when looking in the distal direction;

Fig. 8: a perspective partly opened view of a proximal end of a part of an embodiment of a system according to the invention; and

Fig. 9: in perspective a partly opened view of a part of an embodiment of a system according to the invention. Detailed description of the figures

In the drawings, like parts are provided with like references .

Fig. 1 shows a cylindrical holder 1 having a proximal end 2 and a distal end 3. In this example, the cylindrical holder has the shape of a cylinder. Piston 4 is positionable in the cylinder 1 and then able to slide between an extreme distal position and an extreme proximal position. Piston 4 is in general provided with two annular low-friction sealing members which are in axial direction separated from each other. In the embodiment shown in Fig. 1, each of the two annular low-friction sealing members comprises a rubber Coring 5. The piston 4 shown in Fig. 1 is provided with annular recesses 6, each for receiving an 0-ring 5. In Figs. 3, 4 and 5 is in more detail shown where the piston 4 is provided with the two annular low-friction sealing members. In particular from Fig. 5 it is clear that the axial separation of the two annular low-friction sealing members contributes to maintaining coaxiality independent of the axial position and movement of the piston 4 relative to the cylinder 1. Due to the two annular sealing members and the space between these members, the piston is restrained from wobbling around the axis of the cylinder. Fig. 1 also shows a piston rod 7 which can via a so-called bayonet connection be attached to piston 4 and can as such also easily be disconnected from the piston 4. The cylinder 1 is at the distal end provided with a neck 8. In this embodiment, the neck is an integral part of the cylinder 1. Ax. the distal end, the cylinder 1 may be provided with a penetrable closure 9 which can for instance be a well-known and widely available shrinkage cap. Fig. 2 shows the system of Fig. 1 in an assembled condition.

Fig. 3 shows in addition to components shown in Figs. 1 and 2 a transfer device 10 for transfer of a fluid from and/or to the cylinder 1, The device has a proximal socket 11 for receiving the distal end 3 of the cylinder 1 and a distal socket 12 for receiving an openable part of a container, in this example a vial 13, containing a liquid and/or a pharmaceutical composition. Vial 13 is also provided with a penetrable closure 14, in this case also a so-called shrinkage cap. Fig. 4 shows in a cross sectional view how the proximal socket 11 of the transfer device 10 may receive the distal end 3 of the cylinder 1 and how the distal socket 12 of the transfer device 10 may receive the openable part

15 of the vial 13.

The transfer device 10 is provided with a tubular element 16 which is at both ends provided with a hollow needle 17, 18, In the embodiment shown in Fig. 4, the tubular element 16 and the hollow needles 17, 18, are all part of one hollow needle, i.e. the needles 17, 18 provided on the ends and the tubular element 16 are integrally connected to each other. The hollow needle 17 extends into the proximal socket of the transfer device and then penetrates through the penetrable closure 9 at the distal end 3 of the cylinder 1. Likewise, the hollow needle 18 extends into the distal socket 12 of the transfer device 10 and then penetrates the openable part, i.e. the penetrable closure 14 of the vial 13. As shown in Fig. 4, with the piston 4 in irs extreme distal position in the cylinder 1 it is possible to pull piston rod 7 proximal Iy , and suctioning liquid 19 via tubular element

16 into the inner space 20 of the cylinder 1. This process is preferably carried out when the system shown in Fig. 4 is turned upside down .

Fig. 5 shows a cross section of a cylinder 1 and a piston 4 in its extreme distal position and a piston 4 in its extreme proximal position. In reality only one piston 4 will be present in the cylinder 1. Piston 4 in the distal position shows that the distal surface 21 of the piston 4 and the proximaiiy facing surface 22 at the distal end 3 of the cylinder 1, match accurately and as such reduce a volume in which residual liquid may remain even after an attempt to fully empty this cylinder 1 by minimizing the volume of the inner space 20. This accurate matching of the distal surface 21 and the proximally facing surface 22 further contributes to the accuracy of the final dosage to be injected .

It is conceivable that the distance in axial direction between the two annular low-friction sealing members is larger than shown in the figures. However, the stiffer the piston 4 itself is, and the more narrowly the piston 4 fits into the cylinder 1, the closer the axial distance between the two annular low-friction sealing members can be without compromising the coaxiality of the piston and the cylinder at any axial position and/or during movement of the piston 4 relative to the cylinder i.

It is shown that the system according to the invention is provided with a backstopper 23, in this example for providing adjacent to the proximal end 2 of the cylinder 1 an abutment member. Upon moving the piston proximally, for instance from the extreme distal position to the extreme proximal position, the piston 4 arrives, whilst abutting the backstopper 23, in its extreme proximal position. As a consequence thereof the piston 4 is prevented from exiting the cylinder 1. In other words, the backstopper 23 allows the cylinder to be used as a cartridge without the risk that the piston will exit the cylinder proximally. The backstopper 23 may be an integral part of an inner wall 24 of the cylinder 1. The backstopper 23 may comprise a narrowed part of the cylinder 1. As shown in the insert, which is an enlargement of a part of the system shown in Fig. 5 at position C, it is seen that the backstopper 23 is configured to allow for assembly of the system by insertion of the piston 4 into the cylinder 1 at the proximal end 2 such that the piston 4 is permanently received between the backstopper 23 and the distal end 3. The backstopper 23 is asymmetrical, having a proximal gently rising surface and a distal more steeply rising surface. The proximal surface allows for easy insertion of the piston into the cylinder passing the backstopper. The steeply rising surface prevents proximal return of the piston along the backstopper. The backstopping function is further enhanced by a narrowed diameter of the piston 4 providing an annular shoulder 24 on the piston 4. Interaction between the shoulder 24 and the backstopper 23 on proximally moving the piston 4 enhances the backstopping function.

Cylinder 1, piston 4 and piston rod 7 are preferably provided of a plastic, which allows for a low friction and accurate dimensions of the various parts of the system, further allowing for well-matching surfaces. This further improves the accuracy of the dosaging of the system when injecting an injectable product and when preparing an injectable liquid using the system. Preferably, such plastic is a hard incompressible thermoplastic such as for instance polypropylene.

The piston 4 is on its proximally facing end provided with a drivable contact surface 28 for receiving driving contact with a driving member. The contact surface 28 is flat. The contact surface is preferably transverse to a direction into which the piston is able to slide. This further reduces a possibility to have "slack" in the driving of the piston, in its turn contributing further to accurate dosaging.

It is possible that the system is employed in a method for preparing an injectable product comprising a liquid and a pharmaceutical (dry frozen) composition and for storing such an injectable product in a cartridge. In such a method the transfer device 10 is placed between the cylinder 1 and a vial 13 as shown in Fig. 4. A liquid 19 will be suctioned into the inner space 20 of the cylinder 1 by moving the piston 4 proximally in the cylinder 1, by pulling piston rod 7 proximaily . When a sufficient amount of liquid has been suctioned into the inner space 20 of the cylinder i, vial 13 will be removed out of the distal socket 12 of the transfer device 10 and the transfer device will be connected to another vial with a pharmaceutical composition (dry frozen) . By moving the piston rod 1, and thus the piston 4 distally in the cylinder 1, the liquid will be injected into the vial with the pharmaceutical composition. By shaking the vial now containing the liquid and the pharmaceutical composition, the mixing of the liquid and the pharmaceutical composition will be accelerated. The mixture of liquid and pharmaceutical composition can now be suctioned into the cylinder 1 by moving the piston proximally (using via piston rod 7) . The transfer device 10 can subsequently be removed from the vial and the cylinder 1. The penetrable closure will automatically close the cylinder 1 and the piston rod 7 can be detached from the piston 4 which will be in a position to allow for sufficient inner space 20 for holding the prepared injectable product in that inner space 20 of cylinder 1. The cylinder 1 has now become a cartridge which can be placed in a dedicated injection pen. The system can easily be made to meet the requirements of ISO 11608-3 cartridges. Those cartridges can be used with ISO 11608-1 compatible pen systems, and used with ISO 11608-2 needles.

As explained above, the system is optimized for accurate dosaging of the injectable product when administering via injection, but also for accurately preparing the composition of the injectable product, i.e. the ratio of liquid to pharmaceutical compositions.

After assembling and before packaging the cylinder 1 with the piston 4 in its extreme proximal position and the cylinder at the distal ends closed off by the penetrable closure 9, the inner space 20 of the cylinder 1 needs to be sterilized. To ensure that the sterilization gases can actually enter the inner space 20 within a reasonable period of time, the system is provided with a fluid communication which extends, at least when the piston is its extreme proximal position, from a position proximal of the piston 4 to a position which is between the two annular low-friction sealing members, in this case between the two O-rings 5.

Fig. 6 shows an embodiment with such a fluid communication. In the embodiment shown in Figs. 6, 7 and 8 is the fluid communication provided by channels 26 which each extend in an axial direction from the proximal end of the cylinder to a position which is between the two annular low-friction sealing members 5 when the piston 4 is its extreme proximal position. In this example, each of the channels 26 is formed in the inner wall 25, The channel is a groove in the inner wall 25. Although much more complicated, it is not inconceivable that the channel is formed by a tunnel {not shown) in the inner wail 25. Such a tunnel would have an open end proximal of the piston 4 when the piston 4 is in its extreme proximal position. Another open end of the tunnel would be at a position wnich is between the two annular low-friction sealing members when the piston 4 is its extreme proximal position.

Fig. 8 displays the backstopper 23 as an integral part of the inner wail 25. Although interrupted by the grooves 26, the backstopper is substantially annularly shaped.

Fig. 9 shows an alternative embodiment of a system having a fluid communication which extends, from a position proximal of the piston 4 to a position which is between the two annular low-friction sealing members. In this embodiment, the fluid communication is formed by a channel 27 as present in the piston 4. The channel 27 is again displayed as a groove, but can as outlined above for the channel provided in the inner wall 25 of the cylinder 1, also be a tunnel (not shown) .

It will be understood that the embodiment shown in Fig. 9, having the fluid communication provided in the piston 4, ensures that the fluid communication can always be present, independent of the axial position of the piston 4 in the cylinder 1. The embodiment shown in Figs. 6, 7 and 8 is such that the fluid communication is only present when the piston is its extreme proximal position, such as for instance provided for by abutting the backstopper 23. The embodiment shown in Figs. 6, 7 and 8 is more easily manufactured and has as further advantage that the sealing of the two sealing members against the inner wall 25 is more effective once the piston is situated more distally from the extreme proximal position.

The invention is by no means limited to the embodiments described and referred to above. Many variations are possible. It is, for instance, possible that the fluid communication is provided by both a channel 26 in the piston 4 and a channel 26 in the inner wall 25 of the cylinder i. Although the low-friction sealing members comprise preferably 0-rings, for instance O-rings made of silicon rubber, it is also possible than the low-friction sealing members are integrally connected with the piston. Further, although the embodiments discussed show two annular low- friction sealing surfaces, it is possible that the piston is provided with more annular low-friction sealing surfaces. The cylindrical holder is preferably a cylinder. However, it is not impossible to have a cylindrical holder having for instance an elliptical cross section or another suitable cross section.

In an embodiment where the fluid communication comprises a tunnel, it is possible that the tunnel can be closed after the sterilization process, so that sealing between the piston and the inner wall of the cylinder becomes optimal.

Although the backstopper is by way of example shown as an integral part of the cylinder, it is possible that the backstopper is a separately insertable and fixable part which can be positioned in the cylindrical holder after insertion of the piston.

As to use of the system, the system is in principle usable as a syringe for any purpose.

All such variations are understood to fall within the framework of the invention as defined by the dependent claims .

Claims

Cl aims

1. System for containing and/or preparing an injectable product comprising a liquid and a pharmaceutical product comprising: a cylindrical holder having an inner wall, a proximal end and a distal end; and a piston which is positioned in the cylindrical holder and which is able to slide between an extreme distal position and an extreme proximal position, wherein the piston is provided with two annular low-friction sealing members which are in axial direction separated from each other for maintaining coaxiality independent of an axial position and movement of the piston relative to the cylindrical holder, the system further being provided with a fluid communication which extends, at least when the piston is in its extreme proximal position, from a position proximal of the oiston to a position which is between the two annular low-friction sealing members .

2. System according to claim 1, wherein the fluid communication comprises at least one channel.

3. System according to claim 2, wherein the channel is formed in the piston.

4. System according to claims 2 or 3, wherein the channel is formed in the inner wall of the cylindrical holder.

5. System according to any one of the previous claims 2, 3 or 4, wherein the channel is formed by a groove.

6. System according to any one of the previous claims 2-4, wherein the channel is formed by a tunnel.

7. System according to any of the previous claims, wherein the system is provided with a backstopper for providing adjacent to rhe proximal end of the cylindrical holder an abutment member so that, upon moving the piston proximally, the piston arrives whilst abutting the backstopper in its extreme proximal position and is as such prevented from exiting the cylindrical holder.

8. System according to claim 7, wherein the backstopper is an integral part of the inner wall,

9. System according to any one of the claims 7 or 8, wherein the backstopper is configured to allow for assembly of the system by insertion of the piston into the cylindrical holder at the proximal end such that the piston is permanently received between the backstopper and the distal end.

10. System according to anyone of the previous claims, wherein the cylindrical holder and the piston are made from a thermoplastic material.

11. System according to claim 10, wherein the thermoplastic material is polypropylene.

12. System according to anyone of the previous claims, wherein each of the two annular low friction sealing members comprises a rubber 0-ring.

13. System according to anyone of the previous claims, wherein the system further comprises a transfer device for transfer of fluid from and/or to the cylinder, the device having a proximal socket for receiving the distal end of the cylindrical holder and a distal socket for receiving an openable part of a container containing a liquid and/or a pharmaceutical product.

14. System according to claim 13, wherein the transfer device is provided with a tubular element which is on both ends provided with a hollow needle .

15. System according to anyone of the previous claims, wherexn the piston is on its proximally facing end provided with a drivable contact surface for receiving driving contact with a driving member, the contact surface being flat.

16. Use of a system according to anyone of the previous claims for preparing and storing an injectable product.