AU770228B2

AU770228B2 - Closure device for a medical container

Info

Publication number: AU770228B2
Application number: AU60437/00A
Authority: AU
Inventors: Arne Eek; Billy Nilsson
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 1999-07-07
Filing date: 2000-07-05
Publication date: 2004-02-19
Anticipated expiration: 2020-07-05
Also published as: ZA200110226B; US20030192791A1; JP2003504120A; EP1198216A1; NO20020035D0; CN1433293A; SE9902610D0; WO2001003641A1; MXPA01013442A; BR0012248A; NZ516099A; AU6043700A; NO20020035L; KR20020028204A; CA2375538A1; IL147152A0

Description

WO 01/03641 PCT/SE00/01445 1 CLOSURE DEVICE FOR A MEDICAL CONTAINER The present invention generally relates to containers, such as vials or ampoules, for holding and transferring injectable solutions to a syringe. More specifically, the present invention relates to a closure device for such containers.

In general, injection solutions are kept in sterile glass vials or ampoules, which are closed offby a suitable seal, such as a rubber stopper or an aluminum foil. Such solutions are injected into a patient by means of a syringe. There are many different forms of syringes that are presently available for use by the medical professions. One particular design difference between various syringes is the manner in which the open end of the syringe is shaped to accommodate a hypodermic needle. The two most popular forms of needle fittings are the friction fit fitting (such as the Luer Slip fitting), and the combination of screw thread and friction engagement fitting (such as the Luer Lock fitting). When a is solution is to be injected in a patient, a broad channeled needle is attached to the fitting at the open end of the syringe. This needle is used to penetrate the seal, so that the solution in the vial can be transferred to the syringe. Following transfer, this broad channeled needle is removed from the syringe and replaced with a narrower channeled needle suitable for injecting the solution into the patient. It will be appreciated that this procedure is costly and complicated since it necessitates the use of a number of separate components. Furthermore, since solution transfer for injection into humans requires scrupulous sterilizing of components, this practice requires separate sterilizing measures to be taken at each step.

These difficulties are at least partly alleviated by the prior art devices known from W097/39720 and WO98/13006, in which a closure member is mounted on a stopper fitted in a neck portion of a container holding a solution. The closure member includes an axial passage, which extends between first and second openings, the second opening being adapted to receive the end of a syringe. A piercing member is arranged in the passage with a piercing tip at the first opening adjacent to the stopper. The piercing member is arranged such that it is displaced to penetrate the stopper when the end of a syringe is received in the second opening. After penetration of the stopper, the solution can be transferred to the syringe through a channel defined in the piercing member, without the need for any broad channeled needle on the syringe itself.

However, in some cases it is necessary to prepare an injectable solution by mixing a first substance, liquid or solid, with a second liquid substance, in given proportions before administering the solution to a patient. Typically, such mixing is a complicated procedure, necessitating the use of a number of separate components.

Thus, this practice involves an increased risk of contamination and therefore requires separate sterilizing measures to be taken at each step. Further, in many cases the substances must be mixed immediately before administration to a patient, at exact proportions, which can be difficult to achieve.

The prior art also includes US-A-5 740 654 which discloses an assembly intended for extemporaneous preparation of solutions and suspensions of a solid active product, the product being enclosed in a container sealed by a stopper fitted in a neck portion thereof. The stopper has an axial channel covered by a thin operculum fixed on the outside face of the stopper. To prepare the solution, a separate connection member is first attached to the neck portion, whereupon a compressible flask holding a liquid product and having a pointed tip portion is opened and screwed into the connection member such that the tip portion of the flask S• penetrates the operculum, thereby establishing fluid communication between the flask and the container. By compressing the flask, the liquid is caused to pass into the container, where it is mixed with the active product. Then, the flask is repeatedly 25 compressed to transfer the solution back to the container, from where it can be transferred by a syringe, as discussed by way of introduction. This known device includes several components, and exhibits an increased risk of contamination. The use of the device involves several separate steps before the solution can be injected •into a patient. Separate sterilizing measures must be taken at each step.

*oe The above discussion of background art is included to explain the context of the present invention. It is not to be taken as an admission that any of the documents or other material referred to was published, known or part of the common general knowledge in Australia at the priority date of any one of the claims of this specification.

The present invention is directed towards alleviating at least some of the problems described above.

In a first aspect, the present invention provides a closure device for attachment on a neck portion of a container holding a first substance, said closure device comprising a first end portion and a second end portion, a first opening being defined in the first end portion, a second opening being defined in the second end portion, and a passage extending within said closure device for fluid communication between the first and second openings, comprising a sealing means which closes off the first opening and confines a second substance in the passage and a penetration means which is operable to penetrate the sealing means such that fluid communication is established between the passage and the container.

Since the passage is formed such that a substance can be confined therein, two different substances can be separately enclosed in one and the same packaging and be *mixed with each other immediately prior to injection. With the inventive closure device attached to the container, a medical practitioner can access the contents of the container 0000

S.

-and introduce, and preferably engage, the end of a syringe in the second opening of the e o o 25 closure device. Since both substances enter the syringe from the passage in the closure device, they will be mixed automatically, in the syringe and/or in a chamber defined in the passage connecting the first and second openings. Thus, the inventive closure device o.o both minimizes the need for sterilization and obviates the need for two different needles.

Further, the inventive closure device comprises a minimum of parts and is of costoes *30 effective construction.

The container might contain a unit dose of the first substance. If another unit dose of the second substance is confined in the passage of the closure device, the invention provides the further advantage that the first and second substances will be automatically mixed in known and precise proportions.

Preferably, the closure device is of unitary or one-piece construction. In one embodiment, the closure device is formed to replace commonly used seals, such as rubber stoppers or aluminum foils, fitted to the neck portion of the container. In another embodiment, the closure device holding the second substance is mounted onto an existing conventional seal, such as a rubber stopper or a foil, on the container holding the first substance. One advantage of the latter variant is that the sealed container, with respect to the liquid substance confined therein, can be of conventional design. This should facilitate and shorten the procedure of obtaining an approval for the closure device, and a container having such a closure device, from the competent authorities.

With the closure device mounted on a conventional rubber stopper, the penetration means preferably comprises a hollow needle for facilitated penetration of the stopper.

Preferably, a non resealable cap is provided at the second portion to seal the •*.msecond opening. This allows the medical practitioner to access the contents of the container by simply removing the cap to expose the second opening.

Preferably, the second end portion comprises a Luer fitting near the second 25 opening, the fitting being adapted for direct fluid tight engagement with the open end of a syringe.

*o o• .•In a preferred embodiment of the invention, the penetration means is provided in the passage such that, when the end of a syringe is inserted into the second opening, the penetration means is displaced towards the first opening to penetrate the sealing means that closes off the first opening of the device. Thus, the *oo penetration means is enclosed in a sterile and confined space, minimizing the need for additional sterilization steps during use of the inventive closure device. In one simple construction for penetration of a thin foil closing off the first opening, the penetration means has a cutting element in the shape of an arc extending over more than 1800 and less than 360'. Such a cutting element will provide a clean non-closed cut in the foil and minimize the risk of cut-away foil portions falling into the container. Preferably, the cutting element is connected to a stem which extends to the second opening for engagement with the end of the syringe, the periphery of the stem being provided with one or more longitudinal grooves to define a flow path in the passage of the closure device.

In yet another preferred embodiment of the invention, the closure device as such is displaceable towards the container to establish fluid communication between the passage holding the second substance and the container holding the first substance. The penetration means has a first end with a cutting element adapted to rupture the sealing means, a second end sealingly fitted to the first opening, and an internal channel in fluid communication with the first and second ends thereof.

Thus, when mounted on the neck portion of the container, the closure device can be displaced towards the container such that the cutting element ruptures the sealing means, thereby establishing fluid communication between the passage and the container and allowing for confined mixing of the first and second substances.

Preferably, the sealing means is attached to the first end of the penetration means to close off the internal channel, and indirectly the first opening. The invention provides for a device of simple construction, without moving parts, that can be attached to the neck portion of the container, for example by a releasable snap fit engagement.

In a second aspect, the present invention provides a container having attached thereto the separate closure device defined above.

*00V

V.

In a third aspect, the present invention provides a method of preparing a solution by mixing two substances by means of the container defined above, comprising the steps of inserting the end of a syringe into the second opening, operating the penetration means to penetrate the sealing means, and operating the syringe to transfer the first and second substances to the syringe.

Throughout the description and claims of this specification, the word "comprise" and variations of that word, such as "comprising" and "comprises" are not intended to exclude other additives, steps or integers.

The invention will now be described in more detail with reference to preferred embodiments of the invention shown in the accompanying drawings.

Fig. 1 a is a cross-sectional view of a closure device according to the first aspect of the invention, and Figs l b-1 d is a perspective view, an elevated side view, and a bottom plan view, respectively, of the penetration means of Fig. la.

Fig. 2 is a cross-sectional view of a variant of the closure device of Figs la- Id.

Figs 3a-3b is a perspective view and a cross-sectional view, respectively, of a closure device according to the second aspect of the invention.

Referring to Figs la-ld, and in particular Fig la, there is shown a first embodiment of the inventive closure device according to the first aspect. The closure 0* •device is attached to a neck portion 1 of a container 2, thereby enclosing an 0 injectable solution therein. The container 2, or at least the neck portion 1 thereof, is i generally made of a non-collapsible material, such as glass. The closure device of the first embodiment has a body 3 comprising an engaging portion 4, which is adapted to 30 mate with and engage the inner .eee WO 01/03641 PCT/SE00/01445 6 periphery of the neck portion 1. The engaging portion 4 is joined with a shell portion 5. A spigot 6 extends from the shell portion 5 to a distal end 7. A flat grip 8 is connected to the distal end 7 via a weakened portion 9, which has a smaller wall thickness than the distal end 7. A passage 10 is formed within the body 3 and extends from a proximate opening 11 defined in an end surface 12 of the engaging portion 4 to a distal opening 13 defined in the distal end 7, where the passage 10 is closed off by the grip 8. The spigot 6 defines a fitting for engagement with the open end of a syringe (not shown), in this case a Luer Slip fitting, in which the interior of the spigot 6 is adapted to mate with and frictionally engage the outer periphery of the end of the syringe, thereby allowing for a temporary fluid tight engagement therewith.

A foil 30, preferably of aluminum or aluminum laminate, is attached to the body 3 of the closure device to close off the passage 10 at the end surface 12 of the body 3. The closed passage 10 holds a liquid substance, to be mixed with the injection solution in the container 2, as will be explained below. The passage 10 consists of a smaller-diameter conduit 31, which is defined in the spigot 6, and a larger-diameter chamber 32, which is defined in the engaging portion 4 and in the shell portion 5. The chamber 32 opens in the end surface 12 and defines the opening 11 therein.

A pusher 33, which is shown in more detail in Figs lb-ld, is slidingly arranged in the passage 10. The pusher 33 is preferably of one-piece construction of a material that is compatible with the fluids in the container and the passage, respectively. The pusher 33 comprises an elongate shaft 34 and a plate 35 at a first end thereof. Elongate recesses 37 extend between the ends of the shaft 34. The outer periphery of the plate 35 is shaped to be snugly received in the chamber 32. The plate 35 is provided with through holes 39 connecting the opposite sides of the plate. On the side facing away from the shaft 34, the plate 35 carries an arcuate cutting edge 40 extending essentially in parallel to the perimeter of the plate 35. For reasons given below, it is preferred that the cutting edge 40 forms an arc extending over more than 1800 and less than 3600. The cutting edge 40 comprises an axial projection 41 facilitating penetration of the foil WO 01/03641 PCT/SE00/01445 7 As indicated in Fig. la, the pusher 33 is arranged with the cutting edge 40 adjacent to the foil 30 sealing the opening 11. The shaft 34 extends through the chamber 32 and into the conduit 31, such that the second end of the shaft 34 is arranged close to the opening 13.

On penetration, the arcuate cutting edge 40 will form a correspondingly arcuate cut in the foil 30. This cut will define a tongue that can be automatically folded into the container 2 without coming loose, thereby minimizing the risk of cut-away foil portions falling into the container 2.

1o To access the contents of the container 2, the user grasps the flat grip 8 and tears it off at the weakened portion 9, thereby exposing the distal opening 13 at the distal end 7.

Then, the end of a syringe (not shown) is introduced in the distal opening 13 to abuttingly engage with the pusher 33. As the end of the syringe is brought into fluid tight engagement with the Luer fitting formed in the spigot 6, the cutting edge 40 of the pusher 33 will be automatically driven through the foil 30 to establish fluid communication between the syringe and the container 2 via the passage 10. Thus, when the user operates the syringe to transfer the solution from the container 2 to the syringe, the solution will flow via the through holes 39 into the chamber 32, where it at least partly mixes with the liquid substance contained therein, before leaving the chamber 32 through channels defined by the recesses 37 and the walls of the conduit 31. Thus, the first embodiment allows two different substances to be separately enclosed in one and the same packaging and mixed with each other immediately prior to injection. Since both substances enter the syringe through the opening 13, they will be mixed automatically, in the syringe and/or in the chamber 32. Following such transfer and mixing, a hypodermic needle can be attached to the end of the syringe for injecting the solution into a patient. Alternatively, the end of the syringe can be brought to direct engagement with an intravenous cannula or the like.

The body 3 of the closure device in the embodiment shown in Fig. la is formed in one piece, preferably by injection moulding, of a plastic material, preferably a nonrigid material such as polyethylene or polypropylene. In assembly, the pusher 33 is first inserted WO 01/03641 PCT/SE00/01445 8 into the body 3 through the opening 11 in the body 3. Then, a liquid substance is filled into the passage 10 through the opening 1 1. Finally, the foil 30 is attached to the body 3 to provide a unitary closure device which can be attached to a filled container 2 in a subsequent step. With containers 2 that conventionally are sealed with rubber stoppers, only minor modification of the sealing equipment is required to replace the rubber stopper with the closure device. Further, standard filling equipment can be used.

In this and the following embodiments, the container can be filled with a solution of any drug which is suitable for injection but is particularly advantageous for use with sterilizable anaesthetic or anaesthetization agents, such as propofol or other drugs which are used under conditions where the demands for easy handling and sterility is high. The inventive closure device is most suited for use with substances that, for example in order not to exhibit reduced potency, should be mixed immediately prior to injection into a patient.

One example of an injection solution is propofol, which is commonly used both as anaesthetic and as sedative drug. Injection of propofol is frequently associated with pain on intravenous administration. The pain can be reduced by addition of a pH-lowering substance, such as HCI, or a local anaesthetic, such as lidocaine or ropivacaine. Thus, by enclosing propofol in the container 2, and a pH-lowering substance or a local anaesthetic in the closure device attached thereto, these substances can be administered together.

A second embodiment of a closure device according to the first aspect of the invention is shown in Fig. 2, albeit only in an operative position. As compared with Fig. 1, like elements have been given like reference numerals and a detailed description of such elements will not be repeated.

Similar to the first embodiment, the closure device of the second embodiment has a body 3 comprising an engaging portion 4, a shell portion 5, and a spigot 6, the interrelationship of which is described above with reference to Fig. 1. A stopper WO 01/03641 PCT/SE00/01445 9 preferably of resilient material such as rubber, is fitted in the neck portion 1 of the container 2 to confine a substance therein. Preferably, although not shown in Fig. 2, a recess is formed in the top surface of the stopper 20 to facilitate penetration thereof. A sealing means in the form of athin foil 30 is attached to the body 3 of the closure device to close off the proximal opening 11 and thus the passage 10. The distal opening 13 is sealed off by a suitable non-resealable cap (not shown), such as a foil or a grip of the type shown in Fig. la. Like the first embodiment, a pusher 33' is arranged in the passage 10 of the closure device of the second embodiment. One end portion 35' of the pusher 33' has the shape of a broad channeled needle, i.e. a hollow needle with a central channel 39'. The 1o sharp tip 40' on one end of the needle 35' is arranged adjacent to the stopper 20. The opposite end of the needle 35' is attached to a shaft 34' (not shown in detail) of similar construction as the shaft 34 in the first embodiment (see Figs lb and Ic). Thereby, there is provided a fluid path for the injection solution from the container 2 to the distal opening 13, via the chamber 32. In the operative position shown in Fig. 2, the end of a syringe S is has been engaged in the distal opening 13, thereby driving the needle 35' through the foil and the stopper 20 to establish fluid communication between the syringe S and the container 2, via the chamber 32.

The skilled person realizes that there are many alternative structures achieving this function. In one example (not shown), the pusher 33' is a long broad channeled needle which extends into the conduit 31 and has lateral perforations communicating the interior channel 39' with the chamber 32. The needle might be connected to an annular gasket which is slidingly arranged in the conduit 31 to seal a space defined between the needle and the walls of the conduit 31. The gasket can guide the needle in the conduit 31 and provide a surface for engagement with the end of the syringe S. As a further alternative, there could instead be provided two separate fluid paths in the closure device; one fluid path for the injection liquid from the container to the distal opening 13, and another fluid path for the liquid substance from the chamber 32 to the distal opening 13, the mixing being performed in the syringe.

WO 01/03641 PCT/SE00/01445 It is also conceivable to fixedly attach the stopper 20 to the body 3, for example by means of glue or the like, thereby closing off the proximate opening 11 and forming a unit that can be directly fitted in the neck portion 1 of the container 2. In this case, the foil can be omitted.

In operation and manufacture, the second embodiment is essentially identical to the first embodiment, and a description thereof will not be repeated. In essence, the second embodiment confers similar advantages as the first embodiment.

An embodiment of a second aspect of the inventive closure device will now be described with reference to Figs 3a-3b. As compared with Figs 1 and 2, like elements have been given like reference numerals, and a detailed description of such elements will not be repeated.

Similar to the above embodiments, the closure device in Figs 3a-3b has a body 3 comprising an engaging portion 4, a shell portion 5, and a spigot 6, the interrelationship of which is described above with reference to Fig. 1. Like the embodiments of Figs 1 and 2, the passage 10 consists of a smaller-diameter conduit 31, which is defined in the spigot 6, and a larger-diameter chamber 32, which is defined in the shell portion 5. The chamber 32 2o opens in the end surface 12 and defines the proximal opening 11 therein. A hollow needle with an internal channel 39' is sealingly fitted in the opening 11 and extends to a sharp tip 40'. A sheath 30' of resilient material, such as rubber, is slipped over the needle, thereby forming a bonnet sealing the open tip 40' of the needle 35'. Thus, the sheath indirectly closes off the opening 11 and confines a liquid substance in the passage 10. The distal opening 13 is sealed offby a foil 8. The engaging portion 4 of the closure device comprises two parallel extensions 4' for snap-fit engagement with the neck portion of a container, which holds an injection solution and is closed off by a conventional seal, such as a stopper or a foil. Thus, the closure device of Figs 3a-b is designed for releasable attachment on the container with the sharp tip 40' being arranged adjacent to the seal.

WO 01/03641 PCT/SE00/01445 11 The body 3 of the closure device shown in Figs 3a-3b is a two-piece construction, preferably formed by injection moulding of a plastic material, preferably a nonrigid material such as polyethylene or polypropylene. More specifically, the body 3 is formed by joining a lid part, including the spigot 6 and a peripheral flange at one end thereof, to a sleeve part, including the shell portion 5 and the engaging portion 4. The lid part is engaged with the sleeve part at the open end thereof, thereby forming a non-releasable peripheral snap-fit joint 60. The two-piece construction reduces manufacturing costs in that the lid part can be produced with narrow tolerances, as required by the Luer fitting, whereas the sleeve part can be produced with wider tolerances. Evidently, the snap-fit joint 60 could be incorporated in any one of the embodiments of the invention.

In assembly, the sheath 30' is slipped on the needle 35', whereupon a liquid substance is filled into the passage 10 through the spigot 6. Then, the foil 8 is attached to seal the distal opening 7, thereby providing a unitary closure device that can be attached to a filled container in a subsequent step.

To access the contents of the container, the user pushes the closure device towards the container to drive the tip 40' of the needle 35' through the seal of the container. In the process, the extensions 4' align the needle 35' perpendicularly to the seal for controlled penetration of the seal. While penetrating the seal, the tip 40' simultaneously penetrates the sheath 30' to establish fluid communication between the passage 10 and the container.

Then, the user grasps the grip portion 8' and removes the foil 8 to expose the distal opening 13. Thereafter, the end of a syringe (not shown) is introduced in the distal opening 13 and brought into fluid tight engagement with the Luer fitting formed in the spigot 6.

When the user then operates the syringe to transfer the solution from the container to the syringe, the solution will flow into the chamber 32, where it at least partly mixes with the liquid substance contained therein, before leaving the chamber 32 through the conduit 31.

It is to be understood that various alterations, modifications and/or additions may be introduced into constructions and parts previously described without departing from the WO 01/03641 PCT/SEOO/01445 spirit or ambit of the invention as defined in the following claims. In one conceivable alternative, the closure device is formed integrally with the container.

Claims

1. A closure device for attachment on a neck portion of a container holding a first substance, said closure device comprising a first end portion and a second end portion, a first opening being defined in the first end portion, a second opening being defined in the second end portion, and a passage extending within said closure device for fluid communication between the first and second openings, comprising a sealing means which closes off the first opening and confines a second substance in the passage, and a penetration means which is operable to penetrate the sealing means such that fluid communication is established between the passage and the container.

2. A closure device according to claim 1, wherein the second opening is defined in the second end portion to receive the end of a syringe for fluid communication between the passage and the syringe.

3. A closure device according to claim 1 or 2, wherein the first end portion is adapted to engage directly or indirectly with the neck portion. S. 20 4. A closure device according to any one of claims 1-3, wherein the S.penetration means is provided in the passage such that, when the end of the syringe is received in the second opening, the penetration means is displaced towards the first •gee oooe opening to penetrate the sealing means.

5. A closure device according to claim 4, wherein the penetration means S is slidingly arranged in the passage and has a first end with a cutting element adapted to rupture the sealing means and a second end adapted to directly or indirectly cooperate with the end of the syringe. *30 6. A closure device according to claim 5, wherein the cutting element is arranged adjacent to the sealing means. 14

7. A closure device according to any one of the preceding claims, wherein said sealing means comprises a breakable foil, preferably of aluminum material or an aluminum laminate, which is arranged to close off the first opening.

8. A closure device according to any one of the preceding claims, which is adapted to be directly mounted in an opening defined by the neck portion of the container.

9. A closure device according to any one of claims 5 to 8, wherein the cutting element is connected to one side of a holder member and projects from said one side essentially in the shape of an arc, said arc extending over more than 1800 and preferably less than 3600. A closure device according to claim 9, wherein a part of said arc forms a leading portion for initial penetration of the sealing means.

11. A closure device according to claim 9 or 10, wherein the holder member is snugly received in the passage and is provided with at least one through hole.

12. A closure device according to any one of the preceding claims, which is adapted for arrangement on a stopper, preferably of rubber material, fitted in the neck portion of the container, wherein an internal channel extends in the penetration means from the first end thereof, the penetration means being arranged such that fluid communication is established between the container and the passage through the channel after penetration of the sealing means and the stopper.

13. A closure device according to any one of the preceding claims, wherein the passage comprises a conduit extending from the second opening, and a chamber communicating with the conduit and the first opening, and wherein the penetration means is guided in the conduit and extends into the chamber, which is wider than the conduit (31) and contains said second substance.

14. A closure device according to any one of the preceding claims, wherein the penetration means comprises a stem which is connected to the cutting element and extends into the conduit, the outer periphery of the stem being provided with at least one longitudinal groove defining at least one channel between the stem and a wall portion of the conduit.

15. A closure device according to any one of claims 1-3, wherein the penetration means has a first end with a cutting element adapted to rupture the sealing means, a second end sealingly fitted to the first opening, and an internal channel in fluid communication with the first and second ends thereof, wherein said closure device, when mounted on the neck portion of the container, allows for displacement towards the container such that the cutting element ruptures the sealing means, thereby providing the fluid communication between the passage and the container.

16. A closure device according to claim 15, wherein the sealing means, 20 preferably in the form of a resilient bonnet, is attached to first end of the penetration means to close off the internal channel and thus the first opening.

17. A closure device according to claim 15 or 16, wherein the penetration means comprises a hollow needle which is attached to and projects from the first opening.

18. A closure device according to any one of claims 15-17, wherein the first end portion has at least two parallel extensions adapted to engage with the neck portion and to allow for said displacement while aligning the penetration means with the container. 16

19. A closure device according to any one of claims 15-18, which is adapted for arrangement on a stopper, preferably of rubber material, fitted in the neck portion of the container.

20. A closure device according to any one of the preceding claims, wherein the passage is defined in a body comprising a sleeve element and a lid element comprising the second opening, the lid element being attached to an open end of the sleeve element to define the passage.

21. A closure device according to any one of the preceding claims, wherein the second end portion at the second opening comprises a Luer fitting, such as a Luer Slip fitting or a Luer Lock fitting.

22. A closure device according to any one of the preceding claims, which is of unitary construction and adapted to be attached to the neck portion of the container.

23. A closure device according to any one of the preceding claims, wherein a non-resealable cap is provided at the second end portion to seal the second 20 opening.

24. A closure device according to claim 23, wherein the cap is attached to oo the second end portion along a weakened section thereof.

25. A closure device according to claim 23, wherein the cap is a foil V. attached to the second opening.

26. A closure device according to any one of the preceding claims, wherein said second substance is a pH-lowering substance. o. o30o

27. A closure device according any one of the preceding claims, wherein said second substance is HCI.

28. A closure device according to any one of claims 1 25, wherein said second substance is a local anaesthetic.

29. A closure device according to any one of claims 1 25 and 28, wherein said second substance is lidocaine or ropivacaine.

30. A closure device according to any one of the preceding claims, wherein said first substance in the container is a pharmaceutically active drug.

31. A closure device according to any one of the preceding claims, wherein said first substance in the container is propofol.

32. A container having attached thereto a separate closure device as claimed in any one of claims 1-31.

33. A method of preparing a solution by mixing two substances by means of a container according to claim 32, comprising the steps of inserting the end of a syringe into the second opening, operating the penetration means to penetrate the sealing means, and operating the syringe to transfer the first and second substances to the syringe.

34. A method according to claim 33, wherein the transfer step comprises transferring the first substance to the passage to mix with the second substance confined therein. A closure device for attachment on a neck portion ofa container 0 *30 holding a first substance, said closure device comprising a first end portion and a second end portion, a first opening being defined in the first end portion, a second second end portion, a first opening being defined in the first end portion, a second 18 opening being defined in the second end portion and a passage extending within said closure device for fluid communication between the first and second openings, comprising a sealing means which closes off the first opening and confines a second substance in the passage, and a penetration means which is operable to penetrate the sealing means such that fluid communication is established between the passage and the container, substantially as hereinbefore described with reference to any one of the accompanying drawings.

36. A container having attached thereto a separate closure device as claimed in any one of claims 1-31, substantially as hereinbefore described with reference to any one of the accompanying drawings.

37. A method of preparing a solution by mixing two substances by means of a container according to claim 32, comprising the steps of inserting the end of a syringe into the second opening, operating the penetration means to penetrate the sealing means, and operating the syringe to transfer the first and second substances to the syringe, substantially as hereinbefore described with reference to any one of the accompanying drawings. DATED: 27 November, 2003 SPHIILLIPS ORMONDE FITZPATRICK Attorneys for ASTRAZENECA AB C *0*g t C *o C• Qo*** *o