EP2645982B1 - Device for packaging, storing, and extemporaneously preparing a plurality of active principles - Google Patents

Description

The present invention relates to devices for packaging, preservation and extemporaneous preparation of several active principles, especially at very low dosages and in particular fragile, labile or unstable active ingredients, with a view more particularly to their local or systemic, intravenous administration, intramuscular, subcutaneous or oral mucosa.

The document WO2009138644 discloses a device for performing a mixture between an active ingredient, preserved in hermetic and sterile conditions in the interior space of a movable head of said device, movable head provided with a breaking means, for breaking a waterproof membrane closing a underlying waterproof tank compartment, containing a liquid solvent of the active ingredient by reference, also sterile solvent. The break-in of the membrane by the breaking means of the movable head allows instantaneous extemporaneous dissolution of the active ingredient deposited in said moving head, during the meeting between active ingredient and liquid dissolution. This device makes it possible, without any externalization of the contents and in an always tight and sterile atmosphere, to carry out the bringing into contact between the active principle and the solvent, in order to obtain the instantaneous dissolution of the active principle. More particularly, this device allows extemporaneous dissolution under sterile conditions, very low dosages of active principle, typically from less than 1 mg to a few tens of milligrams only, minute dosages that the human hand can not handle without generating loss or alteration or contamination of their dry or liquid elements.

The document WO2009016309 similarly describes a means for dissolving the active principle that can be administered by the oral mucosa, in the form of a high-alcohol aqueous solution of ethanol, contained in a sealed reservoir sealed with a perforable membrane. This dissolution is obtained after extemporaneous mixing internal to said device, between active ingredient and solvent. The device also allows therapeutic administration of the small volume solution (typically less than 5 ml), by its precise deposition in contact with an oral mucosal area, by means of a cannula forming the upper part of said device.

However, in these devices, the active ingredient is simply deposited during packaging in enclosures constituting each of the two devices, in this case in the documents WO2009138644 and WO2009016309 , the walls of the movable head and also the floor consisting of the perforable membrane, which can support said active ingredient, while sealingly sealing the solvent reservoir. However, it appears that a certain number of conditions for optimizing the protection of the active principle are not completely satisfactory in each of these two devices, since this active ingredient remains in close contact with the constituent materials of these same enclosures and supports, which do not generally fulfill the best conditions and qualities currently required of preservation materials for active pharmaceutical ingredients. In fact, even deposited for example in the form of lyoc in contact with an inert sealing membrane, there can be a loss of quality of the active ingredient, by simple contact between the active ingredient and ambient air and / or active ingredient and wall polymeric internal container. Thus the best conditions of stability of the active ingredient are not guaranteed, since there may be migration of certain components, in particular polymeric, from the walls of the container to the pharmaceutical active ingredient, very often labile deposited therein. To this end, the Health Authorities still require that long monitoring studies are carried out on the possible exchanges, degradations and pollution, by migrations of residues from the walls of the container to the active ingredient or by alteration of the active ingredient at their only contact. . The documents FR2564433 , EP1023229 , US2002030056 and US6644471 describe other devices of the prior art.

The object of the present invention is to overcome the aforementioned drawbacks of the existing devices, and in particular those of the documents WO2009138644 and WO2009016309 by facilitating their industrialization and their processes for conditioning substances, while providing them with additional skills, in particular the facilitated exploitation of complex preparations with components and / or multiple solvents.

The present invention aims in particular to improve by simplifying the terms and costs of industrial manufacturing of these devices, to better ensure protection, conservation and intrinsic quality in the long term - for at least three years of delay expiry - of several active ingredients introduced in these same devices, active ingredients often extremely fragile and very expensive (sometimes several thousand euros per dose).

The present invention also aims to provide a simple technical solution that will, without complicating or increasing the manufacturing of devices considered, to prevent any risk of contamination and / or chemical degradation of active ingredients over time, for example in the context a possible content / container interaction, and thus prevent the requirements of studies and controls stemming from the Regulations.

The present invention proposes in particular to entrust the separating membrane, located between the dry compartment and the fluid compartment, with dual competence: while remaining a perforable intercompartmental waterproofing membrane, it now has a capacity of a container of multiple active ingredients, both assembled within it but also perfectly separated from each other.

The present invention therefore relates to a device for packaging, preservation and extemporaneous preparation of several active ingredients, comprising a reservoir, comprising at least one compartment intended to contain at least one volume of liquid, said reservoir having a neck defining an opening of the reservoir, a head movable relative to said reservoir between a first storage position in which said head is in a distal position by relative to the body and a second preparation position in which said head is in a position proximal to the body, means for sealing the neck of said tank, and means for breaking said sealing means, said sealing means being formed by a sealed blister containing at least two active ingredients, said blister having at least two compartments separated by longitudinal and / or transverse partitions and / or superimposed, each compartment containing an active ingredient, said blister being fixed on the neck of said reservoir for the sealingly closing, such that after opening said blister by said breaking means, said active ingredients come into contact with the liquid and dissolve therein.

Advantageously, at least one active ingredient is in solid form.

Advantageously, at least one active ingredient is in the form of powder, lyoc, lyophilisate, tablet or gel.

Alternatively, at least one active ingredient is in liquid form.

Advantageously, said blister comprises an outer wall facing outwardly of the reservoir and an inner wall facing towards the inside of the reservoir.

Advantageously, said blister comprises a radially outer peripheral flange fixed on a radial edge of said tank.

Advantageously, said fixing is carried out by hot sealing or high frequency polymerization or mechanical stress-tight crimping processes with flexible joints under a ring formed or retracted or crimped.

Advantageously, said blister is previously manufactured, filled with said active ingredients and sealed, before being sealingly attached to said reservoir.

Advantageously, a seal is interposed between the head and the reservoir to ensure sealing after opening the blister by the breaking means.

Advantageously, said liquid contained in the reservoir is a solvent or a hydro-alcoholic solution.

Advantageously, the volume of said liquid contained in the reservoir is less than 5 ml.

Advantageously, said reservoir comprises a filling opening opposite to said neck of the reservoir, said filling opening being, after filling said reservoir with said liquid, sealingly sealed by a stopper, advantageously secured to a gripping pallet.

According to a first advantageous embodiment, said head comprises a filter and a sampling membrane, an internal component, preferably in the form of a hollow cylinder, being inserted into said head to define said sampling chamber in the volume delimited in said internal component between said filter and said sampling membrane.

Advantageously, the dimensions of said internal component are adjustable to define sampling chambers of varying shapes and volumes.

According to a second advantageous embodiment, said movable head comprises a cannula whose dispensing orifice is closed by an end plug containing solid or liquid active principles, held in said end cap by a separation membrane, said active ingredients being released into said cannula by breaking said separation membrane, advantageously by a complete screwing of said end cap to said dispensing orifice of said cannula.

In a variant, said movable head comprises a cannula whose dispensing orifice is closed by an end plug containing at least one solid or liquid active principle, held in said end cap by a separation membrane, said cannula also containing at least one solid or liquid active principle, said active ingredients being mixed in said cannula by breaking said separation membrane, advantageously by a complete screwing of said end cap onto said dispensing orifice of said cannula.

• la figure 1 est une vue en perspective du dispositif selon un premier mode de réalisation avantageux de l'invention,
• la figure 2 est une vue schématique en coupe du dispositif de la figure 1, avant utilisation,
• les figures 3 et 4 représentent des vues schématiques de deux variantes de l'invention,
• les figures 5 à 7 représentent des vues schématiques de dessus de trois autres variantes de l'invention, et
• la figure 8 est une vue schématique en coupe d'un second mode de réalisation avantageux de l'invention.

These and other features and advantages of the present invention will become more apparent from the detailed description. following, with reference to the accompanying drawings, given as non-limiting examples, and on which,

• the figure 1 is a perspective view of the device according to a first advantageous embodiment of the invention,
• the figure 2 is a schematic sectional view of the device of the figure 1 , before use,
• the Figures 3 and 4 represent schematic views of two variants of the invention,
• the Figures 5 to 7 represent schematic top views of three other variants of the invention, and
• the figure 8 is a schematic sectional view of a second advantageous embodiment of the invention.

In order to make the drawings explicit, the proportion of the scales is not necessarily respected.

With reference to Figures 1 and 2 , an advantageous embodiment of the invention will be described based on the device of the document WO 2009/138644 . It is understood that the present invention also applies to other types of devices, including the type described in the document WO 2009/016309 , which will be more precisely described with reference to the figure 8 .

In the example of Figures 1 and 2 , there is shown a device 10 comprising a reservoir 12 which can be in any material avoiding evaporation through the wall and able to prevent the action of light or air on the contents. Preferably, the material constituting the reservoir 12 does not release unwanted constituent substances in contact with the solvent it contains, in particular an aqueous solvent. This reservoir comprises a neck defining a dispensing opening through which the contents of said reservoir can be dispensed.

Such a reservoir is advantageously thick monobloc plastic or glass, preferably opacified, pharmaceutical grade, with high mechanical strength, any section, for example square, oval, rectangular, triangular or round.

This device 10 comprises a head 14, secured in a mobile manner at least in translation relative to the reservoir 12.

This head 14 is movable between a first storage position in which said head 14 is distal to the reservoir 12 and a second preparation position in which said head 14 is proximal to the reservoir 12.

The reservoir 12 comprises at least one compartment intended to contain a very small volume of at least one pharmaceutical solvent 22, such as saline for an application in injectable form, or an aqueous-alcoholic solution to allow the administration of the active ingredients dissolving in contact with the oral mucosa.

Preferentially, the volume of solvent in a compartment is a volume of less than 5 ml, very preferably less than 1 ml.

The neck of the reservoir 12 is closed in a sealed manner. According to one aspect of the invention, this sealing of the reservoir neck is carried out by a blister-shaped membrane having an internal volume for receiving substances, hereinafter called blister 100, comprising at least two compartments intended for each contain a dose of at least one active ingredient in solid form, for example in the form of lyophilisate, powder, tablet or specific polymeric gel, or in liquid form. Preferably, the active ingredient is in powder form or freeze-dried.

The dose of active principle in such a blister is preferably a dose less than 50 mg, preferably less than 10 mg, or even less than 5 mg.

The device according to the invention is suitable for variable dosages according to the type of active principles considered, their specific routes of administration and the number of components and different compartments of the device. It is particularly suitable for administering very low dosages of active ingredients, but can be used for larger dosages.

Active ingredient means a substance or combination of substances capable of producing a demonstrated pharmacological activity on sets of tissues or receptors, extra or intracellular, in order to reduce, prevent or correct an acute or chronic or epidemic disease or a particular degeneration.

The blister 100 comprises a radially outer peripheral flange 110 adapted to be sealingly attached to the edge of the neck of the reservoir 12. If the filling of the reservoir 12 is done by said neck, the blister 100 will be fixed after filling. Alternatively, if the filling of the reservoir 12 is done by another filling passage, for example by a filling opening provided in the reservoir, placed in any section of said reservoir, for example its basal portion, the filling can be advantageously after prior fixing of the blister 100 on the neck of the tank. The fixing of said blister 100 for sealing the neck of the reservoir 12 may, for example, be carried out by heat sealing or high frequency polymerization methods, or any other methods customary in these applications, or by the use of other compatible and adapted methods, such as mechanical stress sealing (ring formed or retractile or crimped). The Figures 3 and 4 illustrate two variants of fixing the blister 100 on the reservoir 12, with the cavity of the blister facing respectively inwards ( figure 3 ) or to the outside ( figure 4 ) of the reservoir 12, after fixation. The figure 2 takes up the variant of the figure 3 , but it is understood that this is only an example of non-limiting embodiment. This blister 100 has an outer wall 101 and an inner wall 102. The outer wall 101 is thus turned towards the outside of the reservoir 12 and the inner wall 102 is turned towards the inside of the reservoir 12. These two outer and inner walls 101 , 102 are preferably parallel to one another, and substantially perpendicular to the longitudinal central axis of the reservoir 12.

The structure of the blister may vary, for example according to the number of compartments that one wishes to have. The figure 3 shows a blister with two compartments 105a and 105b separated by a longitudinal partition 120, that is to say a partition which extends in the width direction parallel to the upper and lower walls 101 and 102 of the blister 100. figure 4 has three compartments 105a, 105b and 105c separated by two longitudinal partitions 120 and 130. The figure 6 discloses four compartments 105a, 105b, 105c and 105d separated by three transverse bulkheads 120 ', 130' and 140 ', i.e. partitions extending in the direction of height perpendicular to the upper and lower walls 101 and 102 blister 100. The figure 7 discloses a complex structure with a 120 "star-shaped partition viewed from above, which defines five compartments, four compartments 105a, 105b, 105c and 105d on the outside of the partition 120", and a compartment 105e on the inside Of course, any number of compartments, and partitions of any desirable shape are conceivable, and the examples shown are therefore not limiting.

With the blister of the invention, several active ingredients can thus be assembled without difficulty in this space both shutter and perforable waterproof container, to allow the practice of extemporaneous internal dissolutions.

With this perforable shutter blister located inside the device for extemporaneous preparation, said active ingredients are concentrated at the best contact point for their dissolution and at the same time, protected from any damage or deterioration, whether they come from the walls of the devices or reciprocal between different constituents, since they remain kept strictly separated from each other in said blister, possibly compartmentalized or laminated. In this way, taking into account the sealing competence related to the quality of this blister pack, an effective barrier continuously separates the active ingredients from any possible chemical contamination arising from the persistence of the chemical structures constituting the materials of these devices and this until they are dissolved.

The deposits of active principle (s) can thus be carried out within said blister, in all known forms (powder, lyoc, granule, grain, semi-solid gel, etc ...).

Very low dose powders can for example be very precisely deposited without losses in these same blisters, by robotic systems designed for this purpose.

It should be noted that said blister could even include in its available internal spaces, a compartment of liquid. In the case of a blister pack having dry and liquid compartments, the packaging / filling of the blister can take place in two successive stages, for example first that of the dry compartment (powder, lyoc ...) sealed in a first operation, then the liquid compartment, filled and sealed during a second step.

In the embodiment of Figures 1 and 2 , the head 14 comprises in its upper part at least one sampling chamber 32 provided with a filter or filter membrane 40, which makes it possible to prevent any particulate contamination of the active ingredient dissolved during the sampling, by ensuring mechanical filtration of the solution before this sampling. If necessary, the device may also include several sampling chambers.

The sampling chamber 32 is preferably of a suitable size. Its length is advantageously greater than or equal to that of a sampling needle, typically between about 8 and 40 mm, so that at the end of the stroke a needle can never damage the filter 40 and also that the end of the sampling needle introduced, remains more constantly located in the very heart of the liquid to be taken.

The filter 40 preferably has a mesh size of between 5 and 500 microns.

The device 10 Figures 1 and 2 also comprises rupture means 18 of the blister 100 so that the active ingredients come into contact with the solvent 22 and dissolve therein.

According to a preferred embodiment, the breaking means 18 are means for cutting the walls 101 and 102 of the blister 100, for example perforating means.

The reservoir 12 and the head 14 are equipped with displacement means 30, 34 for translational movement of said head 14 from the distal position to the proximal position. In the preferred embodiment, the translational displacement means comprise, for example, a set of screws 30 or a bayonet device allowing the rotation to be maintained, preferably entirely traversed over a quarter of a rotation only, and carried by the reservoir 12. more particularly by the neck of this reservoir, and a thread 34 of conjugate profile of the screw thread of the container carried by the head 14 so as to cooperate by screwing.

The container is also provided with safety locking means so as to prevent any involuntary displacement, in translation, of the head 14 relative to the reservoir 12. The locking means advantageously comprise a removable ring 36 interposed between the head 14 in position distal and the reservoir 12. This ring 36 may have a C-shaped profile or be a continuous tear-off continuous band, which is mounted elastically on the thread 30 carried by the reservoir 12, prohibiting the translational movement of the head 14 by compared to this reservoir 12.

In another aspect, the head 14 is provided with a flexible sampling membrane 38 and waterproof, protective and perforable to allow sampling. This sampling membrane 38 is intended to be perforated for removal of the contents of the device 10 by sterile syringe and needle. Preferably, this sampling membrane 38, which may be in sterile medical latex gum or in polymer, is fixed on the head and protected by a protective cap 42 held, for example via a fastener 45 by screwing or clipping or crimping, on the head 14. This cap 42 may comprise a central axial opening closed by a removable safety tab 44, protecting the sterility of said sampling membrane 38.

When the practitioner wishes to administer the drug composition, it suffices to remove the ring 36 by simply pulling and screwing the head 14. There then occurs a displacement in translation of said head which causes the breaking means 18 to open the walls 101 and 102 from blister which ensured the tight closure of the reservoir 12 and the separation between the solvent 22 and the active ingredients, allowing the active ingredients to dissolve in the solvent. For better dissolution, it is best to shake the solution for a few seconds. The removal of the safety tab 44 makes it possible to access the sampling membrane 38 through the axial central opening of the cap 42. As a variant, the cap 42 can also be removable from the head 14, for example unscrewable. The user only has to punch the sampling membrane 38 with a sterile mini syringe and a needle to collect the contents of the device. The device being held vertically, the sampling membrane 38 downwards, the user can then inject through the membrane 38, a volume of air preferably at least greater than twice the volume of drug solution he wishes take, in order to create a positive internal air pressure in the upper part of the device during the extraction of the liquid and thus, facilitate the passage of the therapeutic solution through the filter 40. It retrieves by suction in the syringe withdrawal the desired volume of the solution contained in the device 10 and deposits this volume at the expected location, for example in the anterior chamber of the eye in the case of the prevention of post-phacocystectomy infections.

The sterile needle carried by a suitable syringe allows the immediate administration of the reconstituted solution, whatever the route of administration, intra-ophthalmic, intravenous, intramuscular, subcutaneous, intra-articular, intra-cavitary.

Thus, the active ingredient is dissolved in the solvent just before its administration, which prevents any premature degradation.

A required dose of active ingredient is administered in a precise and controlled manner.

As has just been described, the dimensions of the device have been maximized to better reveal the details of constitution but it must be taken into account that it may be a container of 0.01 ml to 5 ml, extremely small device and difficult to handle.

A gripping pallet 46, advantageously disposed in the lower part of the reservoir 12, can also be provided. This gripping pallet 46 allows a good gripping bidigitale gripper, despite the small size of the container to allow the user to maneuver the head 14 in rotation. This pallet 46 can also form an extension of a sealing plug of a filling opening which would be provided in the base of the tank 12. The pallet 46 also provides an advantage of handling after rotation of the head relative to the reservoir and after removal of the safety tab 44, namely that of allowing easy removal of the content with a device adapted to this manipulation.

In addition, the head 14 may comprise on its outer peripheral surface facilitated gripping means 50, such as support fins.

• lors de la perforation dudit blister, les principes actifs sont dissous extemporanément et simultanément à la rencontre avec la solution liquide délivrée par cette rupture; ils se trouvent de ce fait idéalement assemblés pour leur meilleure dissolution en un seul temps, puisque mis au contact du liquide exprimé lors de la rupture à ce même point de l'ensemble blister,
• le blister, lorsque compartimenté, présente l'avantage de pouvoir contenir plusieurs principes actifs qui ne seraient jamais compatibles entre eux dans le temps s'ils devaient demeurer en contiguïté et surtout, de les protéger de manière parfaitement étanche et séparée,
• l'invention répond de la manière la plus appropriée aux recommandations des Autorités de Santé, soucieuses de prévenir des échanges prolongés et migrations par contact entre principe(s) actif(s) et les parois du contenant; en effet, grâce à l'invention, la solution thérapeutique étant mise en forme au seul instant de son usage médical, elle ne sera pas en contact plus de quelques secondes avec les matériaux pariétaux du contenant avant d'en être extraite, pour administration, soit un délai dépourvu de conséquences vraiment mesurables,
• sur le plan pharmaceutique, le blister garantit une protection optimale des principes actifs considérés, puisqu'à travers l'usage très répandu depuis des décennies de ces structures composites, par exemple de type métalloplastique, se trouve employé un moyen extrêmement répandu dans les industries pharmaceutiques et leurs sous-traitants, moyen longuement évalué comme parfaitement adapté à la plupart des principes actifs pharmaceutiques et à leurs particularités spécifiques, pour leur meilleure conservation dans le temps, ce sous des formulations diversifiées,
• l'invention simplifie considérablement le procédé de fabrication industrielle, puisqu'elle permet de réaliser une double opération par le même moyen, à savoir obturer le réservoir de solvant et en même temps, rassembler et protéger les principes actifs dans les meilleures conditions de stabilité requises sur plusieurs années, tout en les plaçant dans les meilleures dispositions possibles pour leur mise en solution, à savoir au contact proximal du liquide solvant,
• l'invention permet aussi, de manière extrêmement avantageuse et économique par rapport aux techniques antérieures, de mettre en oeuvre des programmes de fabrication distincts dans le temps, à savoir le conditionnement du blister obturateur étanche contenant les principes actifs, le remplissage du réservoir de solvant, et l'obturation du réservoir par ce même blister, sans aucune contrainte de simultanéité pour des opérations également exigeantes, toujours réalisées en atmosphère et conditions stériles.

The advantages of using a blister pack are numerous:

• during the perforation of said blister, the active ingredients are dissolved extemporaneously and simultaneously with the encounter with the liquid solution delivered by this rupture; they are thus ideally assembled for their best dissolution in a single time, since put in contact with the liquid expressed during the rupture at the same point of the blister assembly,
• blister, when compartmentalized, has the advantage of being able to contain several active ingredients that would never be compatible with each other in time if they were to remain in contiguity and above all, to protect them perfectly sealed and separated,
• the invention responds in the most appropriate manner to the recommendations of the Health Authorities, anxious to prevent prolonged exchanges and migrations by contact between active principle (s) and the walls of the container; indeed, thanks to the invention, the therapeutic solution being shaped at the only moment of its medical use, it will not be in contact for more than a few seconds with the parietal materials of the container before being extracted, for administration, a delay without really measurable consequences,
• Pharmaceutical blister guarantees optimal protection of the active ingredients considered, since through the widespread use for decades of these composite structures, for example of metalloplastic type, is used an extremely widespread means in the pharmaceutical industry and their subcontractors, medium long evaluated as perfectly adapted to most pharmaceutical active ingredients and to their specific peculiarities, for their better conservation in time, this under diversified formulations,
• the invention considerably simplifies the industrial manufacturing process, since it makes it possible to perform a double operation by the same means, namely to close off the solvent reservoir and at the same time to collect and protect the active ingredients in the best stability conditions required over several years, while placing them in the best possible arrangements for their dissolution, ie at the proximal contact of the solvent liquid,
• the invention also makes it possible, in an extremely advantageous and economical manner with respect to prior techniques, to implement manufacturing programs that are distinct over time, namely the packaging of the sealed blister pack containing the active ingredients, the filling of the solvent reservoir , and the closure of the reservoir by the same blister, without any constraint of simultaneity for equally demanding operations, always performed in an atmosphere and sterile conditions.

The invention therefore greatly simplifies the packaging of the active ingredients concerned, especially if it is very low dosages and guarantees their pharmaceutical quality maintained over time.

The manufacture and filling of these blisters of very small dimensions, comprising one or more separate compartments or one or more superimposed filling layers, each (e) concealing low dosages of active ingredients, can be achieved by conventional automatic filling machines / sealing for pharmaceutical packaging of microdoses, for example of the type "Xcelodose" proposed by Capsugel Inc., or the microsose devices with unit delivery of the type Quantos Dosing of Mettler Toledo.

• 1°/ maintenir le filtre ou membrane filtrante 40 de la tête mobile 14, par exemple en coinçant ledit filtre entre le bord inférieur du cylindre (dans la position de la figure 2) et un épaulement interne approprié de la tête mobile 14,
• 2°/ maintenir la membrane protectrice 38 de la tête mobile 14, par exemple en coinçant ladite membrane entre le bord supérieur du cylindre (dans la position de la figure 2) et le capuchon de protection 42 ; ceci permet aussi de mieux assurer, du fait de la contrainte exercée, l'étanchéité de la tête au niveau de cette membrane protectrice 38,
• 3°/ simplifier l'assemblage du filtre 40 et de la membrane protectrice 38,
• 4°/ possibilité d'utiliser le volume interne dudit cylindre comme contenant d'un principe actif supplémentaire, qui y serait déposé sous quelque forme appropriée ; on comprend ici que le corps dudit cylindre 200 peut être constitué d'un matériau parfaitement inerte et par là-même, dépourvu de toute rémanence chimique, par exemple verre ou métal, de sorte que le principe actif qui s'y trouverait déposé au contact n'en ressentira pas d'altérations,
• 5°/ créer une chambre de prélèvement 32 de volume et de hauteur modulables, volume défini par la cavité interne disponible dudit cylindre, avec une capacité déterminée spécifiquement pour chaque application à des principes actifs particuliers ; avec ce cylindre modulable, l'invention permet d'obtenir une colonne liquidienne interne à ladite chambre de prélèvement, de telle façon que se trouvant établie sur une hauteur adaptée, ladite colonne liquidienne demeure toujours suffisamment étroite en largeur ou en section pour que l'extrémité de l'aiguille aspirante qui a été introduite à travers la membrane stérile perforable 38, reste en présence d'une quantité suffisante de liquide à aspirer, de sorte que lors d'un prélèvement conventionnel en position verticale, l'aiguille de prélèvement va demeurer plus constamment au contact de la solution qu'elle prélève sans aspirer de l'air.

In another aspect, the device of Figures 1 and 2 , adapted to the extemporaneous preparation of injectable sterile solutions, comprises an internal component 200 which can be placed in contact with the walls of the sampling chamber 32, which will therefore be modified in size, and particularly in section, in height and in volume. This internal component 200, preferably made in the form of a hollow cylinder, can be introduced into said sampling chamber 32 to provide several functions:

• 1 ° / maintain the filter or filter membrane 40 of the movable head 14, for example by wedging said filter between the lower edge of the cylinder (in the position of the figure 2 ) and an appropriate internal shoulder of the movable head 14,
• 2 ° / maintain the protective membrane 38 of the movable head 14, for example by wedging said membrane between the upper edge of the cylinder (in the position of the figure 2 ) and the protective cap 42; this also makes it possible to better ensure, due to the stress exerted, the tightness of the head at the level of this protective membrane 38,
• 3 ° / simplify the assembly of the filter 40 and the protective membrane 38,
• 4 ° / possibility of using the internal volume of said cylinder as containing an additional active ingredient, which would be deposited therein in any suitable form; it is understood here that the body of said cylinder 200 may be made of a perfectly inert material and thereby free from any chemical remanence, for example glass or metal, so that the active ingredient that would be deposited therein in contact will not feel any alterations,
• 5 ° / create a sampling chamber 32 of variable volume and height, volume defined by the available internal cavity of said cylinder, with a capacity determined specifically for each application to particular active ingredients; with this modular cylinder, the invention makes it possible to obtain a liquid column internal to said sampling chamber, such that, being located on a suitable height, said fluid column always remains sufficiently narrow in width or in section so that the end of the aspirating needle which has been introduced through the pierceable sterile membrane 38, remains in the presence of a sufficient quantity of liquid to be sucked, so that during a conventional sampling in a vertical position, the sampling needle goes stay more constantly in contact with the solution it takes without sucking air.

It should be noted that the use of this cylinder is advantageously combined with the use of the blister described above, but that the cylinder could also be implemented independently of said blister. In particular, such a cylinder can be used very advantageously in a device as described in document WO 2009/138644 .

It should be noted that the use of the blister 100 has been explained above with reference to the Figures 1 and 2 for a device of the type described in the document WO2009138644 . Of course, this blister could also be used on other types of devices, for example of the type described in the document WO2009016309 as schematically illustrated on the figure 8 . In this second embodiment, there is described a device for the oral mucosal administration of active ingredients in aqueous-alcoholic solution. Similar building blocks have the same numerical reference. The device 10 comprises a reservoir 12, typically made of plastic or glass, containing a small volume of a hydro-alcoholic solution 23. The reservoir is sealed by a blister structure 100 containing several active ingredients. The structure and function of the blister 100 may be identical or similar to those described above with reference to the first embodiment, and shown on the Figures 3 to 7 . This blister provides an exclusive service by allowing the extemporaneous mixing of labile active principles with an aqueous-alcoholic solution to allow instantaneous therapeutic systemic administration, by this oral mucosal route. The neck of the tank 12 may comprise a screw thread 30 on which can for example screw a thread 34 in a movable head 14. A safety band 36 is advantageously provided to prevent any unwanted movement of the head 14 relative to the reservoir 12. This moving head 14 comprises a cannula 141 defining a tube with air intake 142. The dispensing orifice of the cannula 141 may be closed by an end plug 143. This end cap 143 may also contain at least two active ingredients, they are in solid or liquid form, retained in said end cap by a suitable separating membrane. These active principles are likely to be released into the free space of the cannula 141 by breaking said separation membrane, which can be achieved for example by a complete screwing of said end cap 143 on the dispensing orifice of Alternatively, the stopper may comprise at least one active ingredient and said cannula 141 may also contain at least one active ingredient. In this case, the active ingredients can also be mixed in the cannula, in particular by complete screwing of said end cap. In the example of the figure 8 , the liquid filling of the reservoir 12 is performed not by the neck of the reservoir closed by the blister 100, but by a filling opening 121 provided at the base of said reservoir, and therefore opposite to said neck. In this particular case, said tank is closed by a leakproof cap 400, which can be secured to the gripping pallet 46, sealing cap which is advantageously permanently sealed after the same filling. It is readily understood that this implementation provides a decisive technical advantage, namely that of allowing the complete assembly of the device and the installation of the blister shutter tank in conditions of cleanliness and drought. The tank can thus be filled in the very last phase, in an automated way, as soon as it is necessary, while the entire device is already ready. The modalities and the organization of the manufacturing and assembly sequences thus become extremely flexible, the tank being able to be filled as soon as necessary on already complete products, reducing the constraint of the manufacturing delays.

According to yet another advantageous aspect, both for the first embodiment of the Figures 1 and 2 for injectable solutions than for the second embodiment of the figure 8 for oral mucosal administration of active ingredients in aqueous-alcoholic solution, a seal 300 may be disposed inside the portion of the head 14 which receives the thread 34, to ensure the sealing of the device after perforation, when the screwing of the head 14 abuts on the upper edge of the tank neck 12. The compression of the seal 300 between the two sections of the head 14 and the tank 12 ensures the achievement of a complete and sufficient sealing given the short time of use of the product when it was set up.

Preferably, in a device of the first embodiment of the Figures 1 and 2 , namely a device of the type described in the document WO2009138644 for injectable solutions, the device will preferably contain an amount of active ingredient and a liquid dissolution volume slightly higher than the useful therapeutic dosages, so as not to risk a product defect, that it is linked to a loss by internal residual confinement device or handling error during sampling.

Various modifications are possible for a person skilled in the art without departing from the scope of the present invention as defined by the appended claims. In particular, the various features and functionalities of the device described in the various embodiments and variants may be combined with each other in any suitable manner.

Claims (16)

1. A device (10) for packaging, conserving, and extemporaneously preparing a plurality of active principles, said device comprising:

   • a reservoir (12) having at least one compartment for containing at least one volume of liquid, said reservoir (12) including a neck that defines a dispenser opening of the reservoir (12);

   • a head (14) that is movable relative to said reservoir between a first position for conservation, in which said head (14) is in its distal position relative to the reservoir (12), and a second position for preparation, in which said head (14) is in its proximal position relative to the reservoir (12);

   • leaktight closure means (100) for closing the neck of said reservoir (12); and

   • rupture means (18) for rupturing said leaktight closure means (100);

   the device being characterized in that said leaktight closure means (100) are formed by a leaktight blister that contains at least two active principles, said blister (100) having at least two compartments (105a, 105b, 105c, ...) that are separated by longitudinal and/or transverse and/or superposed partitions (120; 120'; 120"; 130; 130'; 140', ...), each compartment containing an active principle, said blister being fastened on the neck of said reservoir (12) so as to close it in leaktight manner, such that after opening said blister (100) by said rupture means (18), said active principles enter into contact with the liquid and dissolve therein.
2. A device according to claim 1, wherein at least one active principle is in solid form.
3. A device according to claim 2, wherein at least one active principle is in the form of a powder, an ODT, a lyophilisate, a tablet, or a gel.
4. A device according to any preceding claim, wherein at least one active principle is in liquid form.
5. A device according to any preceding claim, wherein said blister (100) includes an outer wall (101) that faces towards the outside of the reservoir (12), and an inner wall (102) that faces towards the inside of the reservoir (12).
6. A device according to claim 5, wherein said blister (100) includes a radially-outer peripheral flange (110) that is fastened on a radial edge of said reservoir (12).
7. A device according to claim 6, wherein said fastening is achieved by heat-sealing or high-frequency polymerization methods, or by leaktight crimping by mechanical stress with flexible gaskets under a formed or heat-shrink or crimped ring.
8. A device according to any preceding claim, wherein said blister (100) is manufactured beforehand, filled with said active principles and sealed, before being fastened in leaktight manner on said reservoir (12).
9. A device according to any preceding claim, wherein a sealing gasket (300) is interposed between the head (14) and the reservoir (12) so as to guarantee sealing after the blister (100) has been opened by the rupture means (18) .
10. A device according to any preceding claim, wherein said liquid contained in the reservoir (12) is a solvent (22) or a hydro-alcoholic solution (23).
11. A device according to any preceding claim, wherein the volume of said liquid contained in the reservoir (12) is less than 5 mL.
12. A device according to any preceding claim, wherein said reservoir (12) includes a filling opening (121) that is remote from said neck of the reservoir, said filling opening (121) being sealed in leaktight manner by a stopper (400) after filling said reservoir with said liquid, said stopper advantageously being secured to a grip tab (46).
13. A device according to any preceding claim, wherein said head (14) includes a filter (40) and a dose-taking membrane (38), an internal component (200), preferably in the shape of a hollow cylinder, being inserted into said head (14) so as to define a dose-taking chamber (32) in the volume defined in said internal component (200) between said filter (40) and said dose-taking membrane (38).
14. A device according to claim 13, wherein the dimensions of said internal component (200) can be varied, so as to define dose-taking chambers of shapes and volumes that vary.
15. A device according to any one of claims 1 to 12, wherein said movable head (14) includes a cannula (141) having a dispenser orifice that is closed by an end stopper (143) that contains solid or liquid active principles that are held in said end stopper (143) by a separator membrane, said active principles being released into said cannula (141) by rupturing said separator membrane, advantageously by tightening said end stopper (143) fully onto said dispenser orifice of said cannula (141).
16. A device according to any one of claims 1 to 12, wherein said movable head (14) includes a cannula (141) having a dispenser orifice that is closed by an end stopper (143) that contains at least one solid or liquid active principle that is held in said end stopper (143) by a separator membrane, said cannula (141) also containing at least one solid or liquid active principle, said active principles being mixed in said cannula (141) by rupturing said separator membrane, advantageously by tightening said end stopper (143) fully onto said dispenser orifice of said cannula (141).

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