EP0403626A1

EP0403626A1 - Storage and transfer bottle designed for storing two components of a medicamental substance.

Info

Publication number: EP0403626A1
Application number: EP90900743A
Authority: EP
Inventors: Gabriel Meyer
Original assignee: Medicorp Holding SA
Current assignee: Becton Dickinson France SA
Priority date: 1988-12-27
Filing date: 1989-12-27
Publication date: 1990-12-27
Anticipated expiration: 2009-12-27
Also published as: ES2044548T3; JPH03504569A; EP0403626B1; WO1990007319A1; JPH0669475B2; US5533994A; DE68909402T2; DE68909402D1; CA2006582A1; ATE94749T1

Abstract

The bottle (10) includes a narrowed neck (12) closed by a sealing body (29) provided with a radial channel (31) mounted on a capsule (32) sitting on said neck (12). The capsule (32) includes a connecting piece (34) protected by a cap (39). The bottle (10) is of the type with two compartments separated by an intermediate mobile stopper (18). The connecting piece (34) is conical and enables a Luer-lock type connection to be made with another bottle or with an apparatus for using the medicamental substance obtained after mixing the substances contained in the two compartments.

Description

STORAGE AND TRANSFER BOTTLE DESIGNED TO STORE TWO COMPONENTS OF A MEDICINAL SUBSTANCE

The present invention relates to a double-compartment storage and transfer bottle, designed to store two components of a drug substance, namely a solid substance and a solvent, and to transfer this substance directly or after having mixed it with another substance, in a device for use, this bottle comprising an open narrowed neck and a closure device engaged in this neck.

Medicinal substances, whether directly usable or whether they constitute the components of a mixture, are usually stored in containers which can either be flame-sealed glass ampoules or vials sealed with a stopper. shutter.

A bottle of this type is for example described by US Patent No. 3,674,028 and comprises a body provided with a narrowed neck and a central constriction which defines two compartments respectively containing a lyophilisate and a solvent intended to be mixed. The neck is closed by a special plug allowing the evacuation of the vapors during the lyophilization of the substance deposited in the lower compartment. After lyophilization, the plug is pushed back into the central zone of the body comprising the constriction and thus separates the two compartments in a leaktight manner. A shutter is placed at the end of the neck to close the upper compartment after filling it. This obturator comprises a central zone of lesser thickness, intended to be pierced by a needle for the purpose of withdrawing the mixture to be injected from a patient. These vials as well as the ampoules which contain a liquid medicinal substance intended for injection pose a significant problem when transferring their content into a device for use which is usually a syringe. In fact, the caregiver must, in all cases, use a needle to transfer the liquid from the ampoule. However, the needle used to effect this transfer is contaminated on its outer walls by the drug solution. This external contamination of the needle is responsible for pain, bruising or other tissue damage which should not in principle be in contact with the drug substance. In addition, the transfer does not prevent bacterial and particulate contamination. Due to hygienic rules, the transfer needle is not to be reused and replaced with a new sterile needle, and this for each transfer operation.

However, there is no guarantee that the caregiver respects this rule. There is therefore a real danger for the patient, especially when the transfer needle is also used for the injection. It is therefore inevitable that the tissues come into contact with the drug substance and the contaminants, bacteria and particles transported by the needle.

The problem is substantially identical when the substance is contained in a bottle, but in this case are added the known drawbacks of puncturing plugs.

Among the systems which are currently commercially available, there is a device called a "Transfer set" which includes a double needle or a double trocar, and which is used to directly connect a vial closed by an elastomer stopper with a pocket or an infusion bottle. The bottle may contain a liquid or dry drug substance. The transfer device is however supplied independently of the bottle to which it is supposed to connect, and presented in sterile packaging. Therefore, nothing prevents its reuse on another bottle after a first use, even if the rules of hospital hygiene prohibit such reuse.

The relatively high cost of this system accentuates the tendency to reuse.

The only way to prevent both handling errors during the installation of a transfer device and its reuse, is to provide a bottle equipped with a non-removable transfer device.

For a transfer system to meet all the security requirements, it is essential that it be tamper-proof, inactivable during storage, secured to the bottle, resistant to radial stress, sterile and guaranteeing the sterility of the interior space. of the bottle and of all the channels, internal cavities and orifices making it possible to communicate this space with another space delimited by another container which may contain another component intended to be mixed with the substance contained in the bottle.

The present invention proposes to overcome the above drawbacks by providing a storage bottle which can be connected to all kinds of receptacles or containers on the market, without any noticeable increase in the cost of manufacture and without technical complications. For this purpose, the bottle according to the invention is characterized in that the closure device is designed to be moved between a first position, called storage, in which it constitutes a sealed shutter, and a second position, called use, in which it constitutes an open valve to allow the evacuation of said medicinal substance, and in that this device is integral with a device for connecting the vial with a container containing another component of the medicinal substance and / or with the device of use.

According to a preferred embodiment, the closure device may comprise a flexible elastomeric closure member comprising a central cavity and a radial channel opening into the central cavity, and it is mounted on a capsule fitted to the neck of the bottle and axially movable between said storage position and said use position.

Preferably, the capsule is provided with a conical connection end piece and with a stiffening element engaged inside a cavity of the closure member.

The connection end piece can be a "Luer" type end piece or a "Luer Lock" type end piece.

According to the variants, the connection end piece is a male conical end piece or a female conical end piece.

According to an advantageous embodiment, the two compartments are separated by an intermediate plug movable between a storage position in which it constitutes a watertight partition between the two compartments and a position for preparation for the use in which the two compartments are interconnected to allow the solvent to dissolve the solid component.

Preferably, the position for preparing the use of the movable intermediate plug is a transient position lying between the storage position and the position of use of the closure device.

According to a particularly advantageous embodiment, the bottle comprises at least one filter mounted in the connection device or the closure device, in a compulsory passage zone for the drug substance or the mixture of this substance with another substance, before its use. Preferably this filter is a membrane filter.

The closure device can be linked to the bottle by a tamper-evident label, when said device is in its first so-called storage position.

The connection device may advantageously include a needle, arranged to perforate a closure plug of an empty or pre-filled container.

According to another preferred embodiment, the closure member consists of at least two parts, a head and an annular seal. Preferably, the head and the seal of this closure member are made of different materials.

The invention will be better understood with reference to the description of exemplary embodiments and the attached drawing in which: FIGS ^. 1 to 5 illustrate the filling phases of a bottle with two compartments according to the invention,

FIG. 6 represents the phase of fitting the shutter member,

7 shows the installation phase of one embodiment of device ^r and complete obturation of the transfer device,

FIG. 8 represents the phase of putting in place a tamper-evident label,

FIGS. 9 and 10 show another embodiment of the closure device,

FIG. 11 illustrates a transfer device intended to be coupled to a traditional syringe,

FIG. 12 represents the coupling of the bottle to a flexible bag provided with a nozzle closed by a plug to be drilled,

FIG. 13 represents the connection of the transfer device with a three-way tap,

FIG. 14 represents the bottle of the invention connected to a flexible bottle with a single compartment,

FIG. 15 represents a transfer device consisting of a nozzle intended to be placed in the mouth by the patient,

FIG. 16 represents the bottle of the invention connected to a micropump, FIG. 17 illustrates a conical connection end piece of the so-called Luer-Lock type,

FIG. 18 illustrates a connection device of the infusion type,

FIG. 19 corresponds to a particular use of the bottle according to the invention, in combination with a nebulization device without propellant gas for inhalations, and

FIG. 20 represents a perspective view of a particular embodiment of the movable intermediate stopper separating the two compartments of the bottle.

With reference to FIG. 1, a bottle 10 provided with a closed bottom 11 and an open neck 12, of section narrowed relative to that of the body of the bottle, has a central narrowing 13 which separates a first lower compartment 14 of a second upper compartment 15. In a first phase, illustrated by this figure, the lower compartment 14 is partially filled by means of an aqueous solution 16 which is introduced through a filling tube 17.

The lyophilization phase is represented by FIG. 2. This operation is carried out inside a device essentially comprising an enclosure connected to a vacuum pump and cryogenic means. Before entering this enclosure, the bottle 10 is equipped with a stopper 18, hereinafter called a movable intermediate stopper, which comprises at its lower end a nozzle 19 provided with at least one lateral opening 20 allowing the vapor to water 21 to escape from the bottle. It will be noted that this operation is carried out under sterile conditions since the bottle is sterile at the time of filling, the mobile intermediate stopper is sterile at the time of its placement on the neck of the bottle and the lyophilization enclosure is a sterile enclosure.

The next phase, represented by FIG. 3, consists in driving the movable intermediate plug 18 inside the neck 12 to ensure a tight closure of the bottle. To bring the movable intermediate plug 18 from its freeze-drying position shown in FIG. 2 to a position for sealing the bottle tightly, this plug is pushed in as shown by the arrows A by means of a pusher 22. In practice, this pusher consists of the ceiling of the lowering freeze-drying enclosure. According to other embodiments, the ceiling of the freeze-drying enclosure is fixed and it is the floor supporting the bottles which moves upwards to cause the penetration of the mobile intermediate stopper inside the neck. This procedure allows the aseptic and sealed closure of the bottle under a controlled atmosphere.

The position of the movable intermediate plug as shown in Figure 3 is transient. In fact, this stopper is intended for sealingly separating the lower compartment 14 ^' from the upper compartment 15. The phase which consists in bringing this stopper into its storage position is represented by FIG. 4. The movable intermediate stopper 18 is pushed through the neck, then through the upper compartment 15 into the constriction 13 by a pusher 23 mounted at the end of an axially movable rod 24. This plug 18 is pressed in such a way that the end piece 19 comprising at at least one lateral opening 20 is entirely located inside the lower compartment 14 and that the upper part provides a perfect seal between the two compartments.

During the phase represented by this same figure 4, the upper compartment 15 is degassed by injecting, as shown by the arrows B, a gas 25 through the rod 24 of the pusher 23, this rod being provided with at least one radial opening 26 allowing the gas to invade the upper compartment 15. This gas is a neutral gas having no reaction with the solvent intended to be subsequently introduced into the upper compartment.

Figure 5 shows the filling phase of the upper compartment 15 with a solvent 27 which is poured through a supply tube 28 engaged in the neck 12 of the bottle.

As shown in Figure 6, after this filling phase of the upper compartment, the bottle is equipped with a flexible closure member 29 which is engaged inside the neck 12 and which has an internal cavity 30 and at least one radial duct 31 whose role will be defined later.

FIG. 7 illustrates the complete installation of the closure device which consists of the closure member 29 and of a capsule 32 provided with a stiffening element 33, of substantially cylindrical shape, which engages the inside the cavity 30 of the shutter member 29 and of a connection end piece 34 intended to ensure the connection with a use device (not shown). This connection end piece 34 is conical and, in the example shown in the figure, is a tip of the female Luer type.

The capsule 32 also includes a peripheral flange 35 which is engaged over the rim 36 of the neck 12 of the bottle 10 and which carries internal protuberances 37 and 38 having the object of cooperating with the rim 36 to define, on the one hand the storage position and on the other hand the use position defined above.

A protective cap 39 having a substantially cylindrical shape, is mounted over the capsule. Note that the diameter of the cap 39 is substantially equal to the diameter of the bottle 10 and that the free end of the side walls of the cap 39 is supported on the outer wall of the bottle 10 at the base of the neck 12. This support constitutes a safety to prevent accidental activation of the shutter and transfer device.

FIG. 8 illustrates the final phase of fitting a tamper-evident label 41 which extends above the support area of the free edge of the cap 39 on the outside wall of the bottle 10.

To use the bottle shown in its storage position in FIG. 8, the cap 39 is first removed by tearing off the tamper-evident label 41. The closure member 29 is then pushed inside the neck 12. During this penetration, the radial channel 31 remains closed since its orifice remains in abutment against the interior wall of the neck 12. This penetration also has the effect of generating a pressure which is transmitted, by the intermediate of the liquid contained in the upper compartment 15, at the stopper mobile intermediate 18 which is pushed back inside the lower compartment 14. This plug falls into this compartment which allows communication between the two compartments and causes the liquid to flow into the lower compartment. The solvent dissolves the lyophilisate and forms a ready-to-use liquid drug substance. To activate the transfer device previously connected either to another container, or to any use device known per se, equipped with a conical tip, for example of the Luer type, complementary to the conical tip 34, the capsule towards the inside of the bottle until the protuberance 38 exceeds the rim 36 of the neck 12. In this position, the closure member 29 is pressed enough towards the inside of the bottle for the radial duct to open into the upper compartment. Communication with the user device is ensured through the transfer device.

Figures 9 and 10 show a bottle 10 identical to that of the previous figures and whose neck is closed by a closure member 50. This closure member has a lower part 51 whose outer diameter is slightly greater than the inner diameter of the neck, so as to ensure closure of the bottle, and an upper part 52 whose diameter is narrower. An internal cavity 53 is formed in this shutter member and is closed at its upper end by a wall 54 of relatively small thickness. The upper part 52 of the shutter member 50 is engaged in a central opening of a capsule 55 whose outer rim is mounted on the neck of the bottle. As shown in Figure 10, a protective cap

56 is preferably placed over the capsule 55 and the closure member 50. A tamper-evident label

57 is fixed so as to cover the junction line of the cap and the bottle.

To activate the bottle and push the movable intermediate stopper 18 back into the lower compartment, it suffices, in the example illustrated in FIG. 9, to push the capsule on the neck and, in the example in FIG. 10 handling after first removing the cap and label.

The bottle of FIG. 11 is original by the construction of the capsule 60 which covers the neck 12 of the bottle 10. This capsule 60 is provided with a connection device constituted by a connection end piece 61 which defines an interior cavity 62 aux conical walls. This interior cavity is dimensioned so as to be able to receive a needle-holder tip 63 of a conventional syringe 64. The activation of the bottle is carried out in an identical manner to that which has been described with reference to FIGS. 7 and 8. The solution contained inside the bottle, after mixing the lyophilisate and the solvent, can be transferred to the inside the syringe 64 by simple aspiration by means of the piston 65 of this syringe.

The bottle of FIG. 12 comprises a capsule 70 which is extended by a tubular element 71 making it possible to protect a needle 72 secured to a needle holder element 73 mounted on a conical tip 74 secured to the capsule 70. The needle 72 is intended to perforate a sealing plug 75 which ensures the tight closure of a flexible bag 76 which may contain a medicinal solution, a physiological liquid or water distilled etc., to which the caregiver must mix the solution obtained after activation of the bottle 10. The transfer can be carried out alternately in both directions, that is to say from the bag to the bottle and from the bottle to the bag until the total amount of liquid in the bottle is transferred to the bag.

The closure member 76 may, in a conventional manner, comprise a radial channel for the flow of the liquid. However, in the embodiment shown, it consists of two parts, a head 77 made of a material compatible with the substances contained in the bottle, and a seal 78 which can be made of any elastomeric material since it is not constantly in contact with the solvent contained in the upper chamber of the bottle 10.

FIG. 13 illustrates a form of use of the bottle 10 in which there is a connection of this bottle with a three-way valve 80. This connection is made by means of a connection device 81 of the Luer-Lock type, that is to say by means of a conical connection with locking. This connection is made on a connection endpiece 82 which is integral with the capsule 83 mounted on the neck 12 of the bottle.

In the embodiment of FIG. 14, the three-way valve has been replaced by a flexible bottle 90. It will be noted that the means for connecting this bottle to the end of the capsule are identical to those described with reference to Figure 13 and therefore bear the same reference numbers.

In the example illustrated in FIG. 15, the capsule 100 is extended by a tubular element 101 which is intended for oral absorption of the solution contained inside the bottle 10.

FIG. 16 illustrates a connection of the bottle 10 to a pump 110, for example to a peristaltic micropump, via a flexible conduit 111 which is connected by means of a connection member 112 of the Luer-Lock type to a tip 113 extending the capsule 114 mounted on the neck 12 of the bottle 10.

FIG. 17 illustrates a transfer device which is constituted by a tip 120 extending the capsule 121, this tip being capped by a shutter element 122 based on the Luer-Lock principle. A cap 123 covers this assembly and a tamper-evident label 124 covers the junction zone between the free end of the cap and the body of the bottle 10.

FIG. 18 illustrates a bottle 10 fitted with a capsule 130 which is extended by a tubular element 131 intended to protect a needle 132 mounted on a needle holder 133 which is engaged on the conical end piece 134 secured to the bottom of the capsule 130 .

It will be noted that all of these bottles can be fitted with a filter which is, in this case, mounted inside the capsule. In the example of FIG. 18, this filter 135 is welded by ultrasound or glued to the bottom of the capsule across the radial channel through which the solution contained in the bottle must necessarily flow.

It will also be noted that the neck of the bottle 10 is closed by a shutter member 136 made in two parts, the part 137 which constitutes the head of the shutter member and a seal 138 which constitutes its base. The advantage of this construction is that the two parts can be made of different materials. The head 137 can be made of a material compatible with the drug substance, while the seal 138, which is in contact with this substance only for a very short period of time, can be made of a material which would not withstand the contact with this substance during a storage period which can be relatively long.

FIG. 19 illustrates a particular use of a bottle as described. This bottle 10 is housed inside a box 140 which contains a vaporization or nebulization device which comprises an ultrasonic generator (not shown) intended to spray in the form of very fine droplets the drug substance initially contained in the bottle . This substance is sucked through a conduit 141 by a micropump 142 and then discharged towards a mouthpiece 143. First, the bottle 10 must be activated, that is to say that the movable intermediate plug 18 must be pushed back into the compartment furthest from the neck of the bottle and the flexible closure member 29 must be partially pushed back into the other compartment to clear the radial channel and allow the liquid to flow. This activation takes place outside the housing and the bottle is mounted inside this housing after being activated. The bottle 10 is carried by a support 144 integral with the housing and which comprises a cylindrical cavity intended to receive a stopper 145 provided with an axial duct for the passage of a needle 146 allowing the passage of air inside the bottle and guaranteeing the functioning of the micropump which draws the liquid from the bottle, the withdrawn volume being replaced by an equivalent volume of air. An elastic membrane 147 is disposed above the plug 145. It ensures the sealed closure of the flow circuit of the liquid, below the zone of connection to the conduit 141. The needle 146 is carried by a nozzle 148 which is provided with a sterilizing filter 149. The support 144 is mounted on a door 150 pivoting about an axis 151 and allowing to set up a bottle after activation and after having emptied an empty bottle. The spraying of the liquid is controlled by a pusher 152.

Figure 20 shows a perspective view of a particular embodiment of the movable intermediate plug. It consists of an upper part 160 of cylindrical shape and a lower part 161 having a substantially elliptical section, the largest dimension being equal to the diameter of the cylindrical part 160. During lyophilization, the stopper is put in place. on the bottle so that the lower part 161 is partially engaged in the neck, which allows the evacuation of gases and vapors contained in the bottle. As soon as the upper part 160 is engaged in the neck, the bottle is sealed.

The bottle described above fully meets the constraints imposed on the conservation and use of medicinal substances. It is inviolable. It has a blocking system which makes it inactivable during storage. It includes a transfer device secured to the actual bottle which is stable and does not fear pressure or radial stress. It guarantees the sterility of the contents and of the interior space including the volumes of the transfer device which are placed in communication with the interior space of the bottle at the time of use. In addition, at the time of use, the locking due to the tamper-evident label and the storage security system is eliminated with a single gesture. The activation of the bottle and its transfer device is carried out in a simple manner, without effort, and without piercing a closure plug. Activation is irreversible and there is no way to allow return to the storage position. This activation can be done without external equipment, next to the patient. The transfer takes place in a vacuum, without contact with the outside. The coupling of the bottle and another container is carried out by means of standard members whose characteristics are perfectly known.

Claims

1. Double compartment storage and transfer vial, designed to store two components of a drug substance, namely a solid substance and a solvent, and to transfer this substance directly, or after mixing, to another substance , in a device for use, this bottle comprising an open narrowed neck and a closure device engaged in this neck, characterized in that this closure device is designed to be moved between a first position, called storage, in which it constitutes a sealed shutter and a second position, known as of use, in which it constitutes an open valve to allow the evacuation of said medicinal substance, and in that this device is integral with a device for connecting the bottle with a container containing another component of the drug substance and / or with the device for use.

2. Bottle according to claim 1, characterized in that the closure device comprises a flexible elastomeric closure member comprising a central cavity and a radial channel opening into the central cavity, and in that it is mounted on a capsule adjusted on the neck of the bottle and movable axially between said storage position and said position of use.

3. Bottle according to claim 2, characterized in that the capsule is provided with a conical connection end piece and with a stiffening element engaged inside a cavity of the closure member.

4. Bottle according to claim 3, characterized in that the connection end piece is an end piece of the "Luer" type.

5. Bottle according to ^' claim 3, characterized in that the connecting end piece is an end piece of the "Luer Lock" type.

6. Bottle according to claim 3, characterized in that the connection end piece is a male conical end piece.

7. Bottle according to claim 3, characterized in that the connecting end piece is a female conical end piece.

8. Bottle according to claim 1, characterized in that the two compartments are separated by an intermediate stopper movable between a storage position in which it constitutes a watertight partition between the two compartments and a position for preparation for use, in which the two compartments are interconnected to allow the solvent to dissolve the solid component.

9. Bottle according to claim 8, characterized in that the position for preparing the use of the movable intermediate plug is a transient position lying between the storage position and the position of use of the closure device.

10. Bottle according to claim 1, characterized in that it comprises at least one filter mounted in the connection device or the closure device, in a compulsory passage zone for the drug substance or the mixture of this substance with a other substance, before use.

11. Bottle according to claim 10, characterized in that the filter is a membrane filter.

12. Bottle according to claim 1, characterized in that the closure device is linked to the bottle by a tamper-evident label, when said device is in its first so-called storage position.

13. Bottle according to claim 1, characterized in that the connection device comprises a needle, arranged to perforate a closure cap of an empty or pre-filled container.

14. Bottle according to claim 1, characterized in that the closure member consists of at least two parts, a head and an annular seal.

15. Bottle according to claim 14, characterized in that the head and the seal of the closure member are made of different materials.