EP0448656A1

EP0448656A1 - Elongate container having two compartments, one being an extension of the other.

Info

Publication number: EP0448656A1
Application number: EP90912873A
Authority: EP
Inventors: Gabriel Meyer
Original assignee: Medicorp Holding SA
Current assignee: Becton Dickinson France SA
Priority date: 1989-09-14
Filing date: 1990-09-13
Publication date: 1991-10-02
Anticipated expiration: 2010-09-13
Also published as: JPH0683719B2; US5291991A; DE69004949D1; DK0448656T3; DE69004949T2; ATE97800T1; JPH04501819A; EP0448656B1; ES2047947T3; WO1991004003A1

Abstract

PCT No. PCT/CH90/00219 Sec. 371 Date May 10, 1991 Sec. 102(e) Date May 10, 1991 PCT Filed Sep. 13, 1990 PCT Pub. No. WO91/04003 PCT Pub. Date Apr. 4, 1991.The container (10) comprises a first compartment (11) and a second compartment (12) which are separated by a central cylindrical throat (13). The compartment (11) is extended by a neck (14) which comprises a first region (15) adjacent to the upper open end of the container and a second region (16) located between the first region (15) and the inside of the container. The region (15) has one section which is greater than that of region (16). Both regions (15, 16) are substantially cylindrical. The section of the second region (16) is substantially identical to that of the central cylindrical throat (13). An intermediate sealing plug (17) compressed into the central cylindrical throat (13) allows sealed storage of two different substances in the compartments (11) and (12). A sealing member (23) inserted into region (15) of the neck (14) is displaceable between a first, storage position, in which it acts as a seal, and a second, ready for use position.

Description

EXTENDED CONTAINER HAVING TWO SEPARATE COMPARTMENTS ARRANGED IN THE EXTENSION OF ONE ANOTHER

The present invention relates to an elongated container having two separate compartments arranged in the extension of one another, the first of which contains a liquid and the second either a liquid, a powder or a lyophilisate, these substances being intended to be mixed in the second compartment, this container comprising a central cylindrical throttle in which is disposed an intermediate closure plug arranged to separate the two compartments during storage of the container, as well as an open cylindrical neck of section narrowed with respect to those of said compartments, in which is engaged a movable closure member comprising at least one active part, arranged to be moved between a first so-called storage position, in which it constitutes a sealed shutter, and a second so-called use position.

Containers are already known, in particular for medical use, with two compartments intended to contain respectively a liquid, a powdery substance or a lyophilisate and a liquid solvent, and which are separated during storage by a removable intermediate plug. Such a container is for example described in French patent No. 1.0 -686 which has a tubular bottle which has, in its middle, a throttle in the form of a “V” bead in which is tightened an intermediate closure plug which separates the two compartments. In some versions, the bottle is open at its two ends which are closed, after filling the compartments, by means of closure plugs and, in other versions, the bottle is only open at one of its ends. The bottle has a substantially cylindrical shape over its entire length, apart from the central annular bead which retains the intermediate closure cap.

This type of bottle has many drawbacks due to its construction. The annular bead has an internal diameter which is slightly different from that of the two cylindrical chambers arranged on either side of this bead, this in order to allow guiding and positioning of the intermediate closure plug. But this construction generates a defect. When the cap is pushed back to allow the components to be mixed, if it goes wrong, it can become blocked between the walls of the lower chamber, preventing the flow of the liquid and finally the mixing of the components. This can happen because the diameter of the vial is less than the measurement of the diagonal of the intermediate stopper.

The intermediate closure plug is only weakly retained by the bead. The seal between the two compartments is questionable. In addition, a pressure inadvertently exerted on the end plug generates a displacement of the intermediate plug and a risk of accidental transfer of the liquid from one to the other compartment.

One can also wonder how the end plug can be put in place without the intermediate plug moving if the compartment disposed between these two plugs is filled with liquid. There will necessarily be an overpressure in the bottle, which creates a double risk: that of causing the opening of the bottle and that of causing the displacement of the intermediate stopper.

Finally, the inviolability of the system cannot be guaranteed by the embodiment illustrated by this patent. The end caps are of the ordinary type and can be opened and then replaced without the end user being able to notice it.

The French patent application published under No. 2,483,365 describes a vial for medicinal substances in the form of storage in the form of two components isolated in two chambers separated by an intermediate closure plug. The installation of the closure cap is delicate because it cannot be prepositioned in the neck of the vial. On the other hand, this plug has a height substantially equal to that of the central narrowing in which is arranged this plug, so that the latter must not undergo any axial displacement after its installation to avoid a loss of sealing between the two chambers. Consequently, the obturator of the neck of the vial must be put in place by means of special packaging machines, to allow the evacuation of a volume of air substantially equivalent to the volume of the part of the obturator entering the neck, in order to avoid an overpressure liable to move the intermediate closure plug axially. These machines are expensive, cannot reach high speeds and require pressure control means.

To avoid the use of these ancillary equipment, a large volume of gas is left above the liquid in the upper compartment, which makes the delivery phase of the intermediate closure plug difficult and uncertain.

The present invention proposes to overcome all of these drawbacks and to provide a sum of interesting solutions both in terms of filling and in use. The content of the invention fully meets the current requirements of the pharmaceutical industry and the medical community which are:

- the ability to make a complete mixture of products in a closed environment, without contamination of one of the chambers by the product contained in the other,

- safety of use,

- ease of use,

- easy manufacturing and at competitive prices.

For this purpose, the container according to the invention is characterized in that the neck comprises a first zone close to the open end and a second zone formed between said first zone and the interior of the container, in that said second zone has a cross section less than that of the first zone, in that the first zone has a cross section greater than that of said active part of the movable closure member and in that the second zone has a section at most equal to that of this active part. According to a first preferred embodiment of the container, said active part of the movable closure member has a section greater than that of said second zone so that this part is compressed when it is engaged in said zone.

Preferably, the movable closure member comprises at least one bead extending said active part, this bead having a section greater than that of said first region of the neck.

In this embodiment, the height of said active part of the movable closure member can be at least equal to the height of said first zone.

Advantageously, the cross section of the central cylindrical constriction is substantially identical to that of said second region of the neck.

According to this particularly advantageous embodiment, the section of the intermediate closure plug is less than that of said first region of the neck, and at least equal to that of said second region of this neck.

According to another embodiment, the section of the intermediate closure plug can be greater than that of said second region of the neck.

Advantageously, the height of the intermediate closure plug is greater than the height of the central constriction.

Preferably, the movable closure member comprises a rigid structure provided with a connection end piece and a flexible cap provided with an annular skirt comprising at least one lateral opening. According to a second embodiment of a container comprising an axis of circular symmetry, the diameter of the second compartment is greater than the diagonal of the intermediate closure plug.

According to a third preferred embodiment, the container initially has only one opening at the end of its neck.

According to a fourth embodiment, the container initially has a second opening at its end opposite to said neck, this opening being arranged to receive a closure plug after filling of the second compartment.

In the first preferred embodiment, the movable closure member is associated with a rigid connection end piece comprising a central duct and means of communication are provided for ensuring the passage of the solution obtained after mixing the components of said first compartment. in said central duct.

Preferably, said means for placing in communication comprise a lateral passage formed in said flexible skirt of the movable closure member.

In this embodiment, the movable closure member may be integral with a capsule and this capsule may comprise a vent and a hydrophobic filter to ensure the evacuation of the gases under pressure inside the first compartment.

Advantageously, the movable intermediate plug is initially disposed in the central cylindrical constriction so that its height X inside the first compartment corresponds at most to the volume of liquid contained in this compartment and moved when the member mobile shutter is brought into the storage position in said second neck area.

This movable intermediate plug can also be initially placed in the central cylindrical constriction so that its height X inside the first compartment corresponds to a volume less than that of the liquid contained in this compartment and moved when the movable closure member is brought into the storage position in said second neck area.

In this form ^'container, after the pre-positioning the movable sealing member in the first zone of the neck, the volume of liquid corresponding to the height La, representing the difference in level between the surface N of the liquid and the inner end of the neck, is greater than the volume of the part of the intermediate closure plug which is located in said first compartment.

The present invention will be better understood with reference to the description of various embodiments and the accompanying drawing in which:

fig. 1 to 7 illustrate the different filling phases of a container according to the invention, open at its two ends and intended to receive a liquid in one of the two compartments and a powder in the other compartment,

fig. 8 to 15 illustrate the different filling phases of a container according to the invention closed at one of its ends and intended to receive a lyophilisate in one of the two compartments and a solvent in the other compartment,

fig. 16 and 17 are detailed views which show what are the dimensional relationships existing between certain parts of the container and the closure members,

fig. 18 and 19 illustrate the activation phases of the container according to the invention,

fig. 20 and 21 / illustrate forms of particular use of the container according to the invention, and fig. 22 and 23 show particularly advantageous embodiments of the container according to the invention.

With reference to fig. 1, the container 10 comprises a first compartment 11 and a second compartment 12 which are separated by a central cylindrical throttle 13. The compartment 11 is extended by a neck 14. which comprises a first zone 15 close to the upper open end of the container and a second zone 16 between the first zone 15 and the interior of the container. Zone 15 has a section which is greater than that of zone 16. The two zones 15 and 16 are substantially cylindrical. The section of the second zone 16 is substantially equal to that of the central cylindrical throttle 13.

During the first phase of producing the container, or more precisely filling the latter, an intermediate closure plug 17 is prepositioned in said first zone 15 of the neck 1. The section of this intermediate closure plug 17 is less than that of said first zone 15 but equal, or even slightly greater, than that of the second zone 16. This prepositioning, which is made possible by the existence of said first zone at enlarged section, is extremely important for various reasons which will become evident in the remainder of this description. A first advantage which results from this is that it makes the installation of the intermediate closure plug 17 particularly easy.

Fig. 2 illustrates the phase which consists in positioning the intermediate closure plug 17 in the central cylindrical throttle 13. This is done by means of a pusher 18 linked to a mechanism 19 (shown diagrammatically) by means of a rod 20. This pusher pushes the intermediate closure plug through the neck 14 to bring it into the position shown in the figure. Note that the height of the intermediate plug is greater than that of the central cylindrical throttle for reasons which will be explained later.

The next phase, which consists of filling the compartment 11 with a liquid 21, generally a solvent, is shown in FIG. 3. The liquid is supplied by means of a cannula 22 which penetrates into the neck 14 of the container 10. The seal between the two compartments is ensured by the intermediate closure plug 17 which is compressed in the central cylindrical constriction, in a manner sufficient to guarantee a tight closure of the compartment 12.

Fig. 4 illustrates the start of the phase of setting up a movable closure member 23 in the first zone 15 of the neck 14. In fact, this member is prepositioned in said first zone 15 which has, as mentioned previously, a section greater than that of zone 16 of this pass. The movable closure member 23 has a cross section which is smaller than that of the zone 15 so that this prepositioning allows the gas 24 which overcomes the liquid 21 to escape and thus avoids inducing an overpressure inside of compartment 11. This is particularly important because, during this phase of prepositioning of the movable obturation member 23, the intermediate obturation plug 17, which is not subjected to any stress, does not move axially in the central cylindrical throttle 13.

Fig. 5 illustrates an additional step in the production of the container, which consists in putting in place the sealed closure member 23 as well as a connection end piece 25 whose capsule-shaped rim 26 is engaged over the neck 14 and in particular on the bead 27 which equips the end of this neck. A protective cap 28 covers the connection end piece 25 and covers this end of the container. Note that the movable closure member 23 has been pushed back at least into the second zone 16 of the neck. Since the section of this movable closure member, at least in its lower part, is greater than the section of said second zone 16, said closure member is compressed and ensures a sealed closure of the compartment 11. The movement of this member generates an overpressure inside the compartment 11, which has the effect of axially displacing the intermediate closure plug 17. Since the height of this closure plug intermediate is greater than that of the central cylindrical throttle, ^' this displacement does not in any way modify the sealing conditions between the two compartments 11 and 12.

For security reasons, to prevent the movable closure member 23 from being pushed too deep inside the neck, the latter has at its upper part one or more beads 29 which both provide a retaining function and an aseptic barrier and which, when the device is used, serve as leaktight seals which prevent accidental passage of the solvent 21.

After inverting the container, the compartment 11 of which is filled and sealed, the compartment 12 is prefilled by means of a powder 30 which is supplied by means of an appropriate device 31 and which is intended to be mixed with the solvent. before using the mixture thus obtained. This phase is illustrated in fig. 6. The device 31 is engaged in the lower opening 32 of the container 10. Since the compartment 11 is filled and closed in leaktight manner at its two ends, no contamination by powder 30 can take place.

The next phase is illustrated in fig. 7 which represents the container ready for use or ready to be stored. A closure cap 33 has been put in place to close off the end 32 of the compartment 12. A capsule 34 has been crimped over said end 32 to ensure a definitive closure of this end of the container. Two tamper-evident labels 35 and 36 respectively have been put in place to prevent unauthorized opening of the container.

Fig. 8 represents the first phase of filling a container 10 ′ which differs from the container 10 in that it is closed to one of its extremities. As before, it has a first compartment 11 'and a second compartment 12' separated by a central cylindrical throttle 13 '. The upper compartment 11 'is extended by a neck 14' which comprises, as previously, a first zone 15 'and a second zone 16' having the same characteristics as the corresponding zones 15 and 16 of the preceding figures. The first zone consists in filling the lower compartment 12 'with a solution 40 which is poured out through a tube 41 which penetrates inside the container.

The next phase consists in prepositioning an intermediate closure plug 17 'in the first zone 15' of the neck 14 '• This intermediate closure plug 17' has a lower zone 42 provided with notches or clearances 43 whose role will be explained below, and an upper zone 44 which is substantially identical to the intermediate closure plug 17.

Fig. 10 illustrates the freeze-drying phase during which gases 45 can escape from the container 10 ′ despite the fact that the intermediate closure plug 17 ′ is prepositioned in the neck 14 ′ • This can be done thanks to the fact that the section of the lower part 42 of this intermediate closure plug is less than the section of said first zone 15 'of the neck 14' and thanks to the existence of the clearances 43.

At the end of freeze-drying, the intermediate closure plug 17 ′ is pressed into the neck 14 ′ by means of a plate 46 (shown diagrammatically) in the enclosure of the freeze-dryer and under inert gas. This phase is illustrated in fig. 11.

Fig. 12 illustrates the final positioning of the intermediate plug 17 'in the central cylindrical throttle 13' by means of a pusher 18 identical to that which has been illustrated in FIG. 2. The intermediate closure plug 17 'is pressed into the central cylindrical constriction 13' in a manner sufficient for its upper part 44 to be engaged in this constriction, the lower part 42 being located beyond this constriction inside the lower chamber 12 ′ containing the lyophilisate 47.

Fig. 13 illustrates the phase of filling the compartment 11 ′ by means of a liquid 21 which is mainly a solvent, intended to be mixed with the lyophilisate 47. This filling is done through a cannula 22 identical to that represented in FIG. 3.

The container 10 is then closed by means of a movable closure member 23 which is identical to that which is shown in FIG. 4. This shutter member is first of all prepositioned in the first zone 15 ′ of widened section of the neck 14 ′, as shown in FIG. 14, then pressed as previously during a phase which is represented by FIG. 15. This phase is identical in all respects to that which has been described with reference to FIG. 5. The establishment of the movable closure member 23 causes an overpressure inside the chamber 11 '. This overpressure is reflected on the intermediate closure plug 17 'which engages further forward in the central cylindrical throttle 13'. As before, its length is determined in such a way that this recess maintains the seal between the two compartments 11 'and 12'.

With reference to fig. 16 and 17, the movable closure member 23 has, in its lower part, a diameter B which is less than the diameter A of the first area 15 of the neck 14. Let Li be the height of the second narrowed area 16 of the neck 14 and L2 the distance which separates the level N of the liquid in the upper compartment 11 from the base of the narrowed area 16. Let X be the height of the part of the intermediate closure plug 17 which exceeds in height the central cylindrical constriction 13 when the movable closure member 23 is prepositioned in the first zone 15 without being pushed into the second zone 16. Let L3 be the total height of the neck 14 and let Lo be the total height of the central cylindrical throttle 13. At the time of filling , the volume of the liquid introduced into compartment 11 is calculated in such a way that before the closure of this compartment, the intermediate closure plug protrudes in height the central cylindrical throttle of the value X. The movable closure member 23 must be positioned in such a way that La is greater than or equal to X. The volume of gas which surmounts the level N of the liquid can be minimal and could theoretically be zero since it plays no role in the hydraulic operation of the system during the activation of the container. In other words, La could increase to reach the value Lx. In practice, a certain quantity of gas is allowed to remain which allows the tolerances of the glass to be absorbed and the compartment 11 to be filled without causing the solvent to overflow. The volume of liquid corresponding to the height La is greater than that corresponding to the value X.

Fig. 18 illustrates the closing phase of the container, that is to say the positioning of the movable closure member 23 in the neck 14. At the time of closure, the movable closure member 23 moves of a value and generates an equivalent displacement of the intermediate closure plug 17, assuming that the sections of these two components are identical. If the sections are different, the volume displaced by the movable closure member 23 is equivalent to that displaced by the intermediate closure plug 17. Theoretically, W can be equal to X. If one neglects the losses due to the friction of the intermediate closure plug against the walls of the central throttle, this plug moves with a stroke equivalent to W or with a stroke corresponding to a displaced volume W. Level N is brought to level N '. Since the volume equivalent to La is greater than or equal to the volume corresponding to X or W, the new level N 'of liquid in the compartment 11 does not exceed the neck 14. In practice, for safety reasons and because of the presence of a gas which surpasses level N 'and of the existence of friction forces of the intermediate closure plug on the walls of the central cylindrical throttle, there will remain a residual value X' which corresponds to a certain displacement of the intermediate closure plug 17 in the compartment 11. The activation of the container is illustrated in fig. 19. Y represents the height of the central cylindrical throttle increased by the residual value X ′ of the displacement of the intermediate plug 17 in the upper compartment 11. Z represents the activation stroke of the movable closure member 23. So that the intermediate closure plug 17 drops into the compartment 12, the stroke Z must be greater than Y. For safety reasons, the level N 'defined above must be located in the zone corresponding to the stroke Z of the movable closure member, which guarantees the hydraulic operation of the system, that is to say the setting in communication between the two compartments.

In the examples of use represented by FIGS. 20 and 21, the container 10 is closed, at the level of the neck, by a movable closure member secured to a connection end piece 25 to which an injection syringe 50 is coupled. In the case of fig. 20, the movable closure member 23 is constituted by a flexible skirt 51 mounted on a cylindrical extension 52 of the connecting piece 25. The flexible skirt 51 has a lateral opening 53 which allows the injectable drug solution, which has after the two components initially contained in the two compartments 11 ′ and 12 ′ have been mixed, to flow through the central duct of the tubular extension of the connection end piece, then through the central duct of this end piece, up to in the syringe 50. The two central conduits mentioned above are advantageously separated by a filter 54 which retains any solid particles present in the mixture.

In the case of fig. 21, the movable closure member 23 does not have a lateral opening. To allow the flow of the mixture, this movable closure member is mounted on a support integral with the connection endpiece 25, which has lateral openings 55. A hydrophobic filter 56 can also be interposed on the discharge path of the mixture, and a vent 57 for evacuating gases is provided in the capsule carrying the connection end piece 25. Some substances have the particularity of generating quantities carbon dioxide when mixing the two components. This is the case, for example, with fourth generation cephalosporins, of which 1 g of powder mixed with 4 to 5 ml of water can produce up to 50 ml of COa. In the absence of said hydrophobic filter and the corresponding vent, the piston of the syringe 50 would be ejected under the effect of the gas pressure. In this case, the movable closure member 23 must be pushed back entirely inside the first compartment. The seal in the neck is ensured by an O-ring 59.

The embodiment illustrated in FIGS. 22 and 23 comprises a movable closure member 70 constituted by an elastomer plug whose flexibility is given by the existence of a central cavity 71. As in the examples illustrated previously, this plug can be prepositioned in the first zone 15 of enlarged section of the neck 14, before being placed in a sealed manner in the second zone 16 of narrowed section and crimped by means of a safety cap 72.

The container shown has many advantages over the prior art. In particular, the embodiment which is open at both ends makes it possible to carry out a final sterilization after filling by autoclaving of the solvent at 120 ° C. This removes bactericidal preservatives from the solvent.

Claims

1. Elongated container having two separate compartments arranged in the extension of one another, the first of which contains a liquid and the second either a liquid, a powder or a lyophilisate, these substances being intended to be mixed in the second compartment, this container comprising a central cylindrical throttle in which is disposed an intermediate closure plug arranged to separate the two compartments during storage of the container, as well as an open cylindrical neck of section narrowed relative to those of said compartments, which is engaged a movable shutter member comprising at least one active part, arranged to be moved between a first so-called storage position, in which it constitutes a sealed shutter, and a second so-called use position, characterized in that the neck has a first zone close to the open end and a second zone formed between the adite first zone and the interior of the container, in that said second zone has a cross section smaller than that of the first zone, in that the first zone has a cross section greater than that of said active part of the organ mobile shutter and in that the second zone has a section at most equal to that of this active part.

2. Container according to claim 1, characterized in that said active part of the movable closure member has a section greater than that of said second zone, so that this part is compressed when it is engaged in said zone.

3. Container according to claim 1, characterized in that the movable closure member comprises at least one bead (29) extending said active part, this bead having a section greater than that of said first zone (15, 15 ') neck (14, 14 ').

4. Container according to claim 3, characterized in that the height of said active part of the movable closure member is at less equal to the height of said first zone (15, 15 ') of the neck (14, 14' ⁾ -

5. Container according to claim 1, characterized in that the cross section of the central cylindrical constriction is substantially identical to that of said second region of the neck.

6. Container according to claim 1, characterized in that the section of the intermediate closure plug (17, 17 ') is less than that of said first region of the neck (15, 15'), and at least equal to that of said second zone of this pass (16, 16 ').

7. Container according to claim 6, characterized in that the section of the intermediate closure plug (17, 17 ') is greater than that of said second region of the neck (16, 16').

8. Container according to claim 6, characterized in that the height of the intermediate closure plug (17, 17 ') is greater than the height of the central throttle (13, 13').

9. Container according to claim 1, characterized in that the movable closure member comprises a rigid structure provided with a connection end piece and a flexible cap provided with an annular skirt comprising at least one lateral opening.

10. Container according to claim 1 comprising an axis of circular symmetry, characterized in that the diameter of the second compartment (12, 12 ') is greater than the diagonal of the intermediate closure plug (17, 17').

11. Container according to claim 1, characterized in that it initially comprises only one opening at the end of its neck (14).

12. Container according to claim 1, characterized in that it initially comprises a second opening at its opposite end at said neck, this opening being arranged to receive a closure plug (33) after filling the second compartment (12).

13. Container according to claim 1, characterized in that the movable closure member (83) is associated with a rigid connection end piece (25) comprising a central duct and in that communication means are provided for ensuring the passage of the solution obtained after mixing the components of said first compartment in said central duct.

14. Container according to claim 13, characterized in that said means for establishing communication comprise a lateral passage (53) formed in said flexible skirt (51) of the movable closure member (23)

15. Container according to claim 1, characterized in that the movable closure member (23) is integral with a capsule (58) and in that this capsule comprises a vent (57) and a hydrophobic filter (56) to evacuate the overpressure gases inside the first compartment (11).

16. Container according to claim 5 characterized in that the movable intermediate plug (17) is initially disposed in the central cylindrical throttle (13, 13 ') so that its height X inside the first compartment (11, 11 ') corresponds at most to the volume of liquid contained in this compartment and displaced when the movable closure member (23) is brought into the storage position in said second zone (16, 16') of the neck (14, 14 ' ⁾ .

17. Container according to claim 5 characterized in that the movable intermediate plug (17) is initially disposed in the central cylindrical throttle (13, 13 ') so that its height X inside the first compartment (11, 11 ") corresponds to a volume less than that of the liquid contained in this compartment and displaced when the movable closure member (23) is brought into the storage position in said second zone (16, 16 ') of the neck (14, 14').

18. Container according to claim 5, characterized in that after the prepositioning of the movable closure member (23) in the first zone (15, ^' 15') of the neck (14, 14 '), the volume of liquid corresponding to the height La, which represents the difference in level between the surface N of the liquid and the inner end of the neck, is greater than the volume of the part of the intermediate closure plug (17) which is located in said first compartment ( 11, 11 ' ⁾ .