LIQUID DISPENSING DEVICE FROM A STERILE PACKAGING BOTTLE

Abstract

The invention relates to a device for dispensing an aqueous liquid through an interface membrane made partially hydrophilic and partially hydrophobic, made so that when in operation, during each operation of dispensing a metered amount of liquid, the streams of air and liquid flow alternately in a capillary channel (18) downstream from the membrane. Said interface membrane (7) is made of a filtering material which includes biocidal metal cations in the body thereof. Said device comprises a porous insert (8), which is permeable both to liquid and to air, which is arranged upstream from the membrane in the path of the fluids and which is made of a material including sites with negative charges capable of attracting biocidal metal cations from said membrane.

Description

LIQUID DISTRIBUTION DEVICE OUTSIDE OF A STERILE PACKAGING BOTTLE The invention relates to liquid distribution devices which are used in bottling techniques for the packaging of products which must be kept in a sterile state, not only until the bottle is opened, but thereafter as long as the product is consumed until the contents of the bottle are completely exhausted. As a typical example of the needs that the invention aims to satisfy, we will consider the field of multidose bottles, receiving aqueous solutions to be distributed discontinuously, in doses staged over time, which are equipped with air / liquid interface membranes that prevent the passage of microbiological contaminants from the ambient air into the bottle by filtration effect. We also know of such membranes which have the additional characteristic of being doubly selectively permeable, preferentially allowing passage to either air or liquid depending on a pressure differential between their two faces. This permeability alternates between upstream and downstream during the expulsion phase of a dose of liquid from the bottle, and between downstream and upstream during the aspiration phase when air is drawn back into the bottle to compensate for the volume of liquid extracted. The Applicant's existing patents describe how such membranes, referred to as bifunctional (bifunctional from the perspective of liquid or gas flow transport), are used to ensure alternating circulation between liquid and air through a capillary channel for liquid expulsion located downstream of the membrane.Such membranes, acting as an interface between the closed space of a sterile vial containing an aqueous liquid (in particular, an aqueous solution of a pharmacologically active ingredient), are made partly of a hydrophilic material, over a first zone of the total interface area, and partly of a hydrophobic material, over a second zone of the same area. The operation of such a membrane is described in particular in French patent application FR 2872137 (corresponding international application WO 2006000897), for a membrane positioned across a single conduit allowing air and liquid to flow in both directions between the inside and outside of a vial with elastically deformable walls, manipulated to alternate expulsion and aspiration. In such a context, the invention aims to provide a liquid dispensing device with microbiological protection offering high safety with regard to both microbial sterility and chemical toxicity in its application to bottles for packaging sterile liquid products where sterility must be maintained throughout the consumption of the bottle's contents, via successive dispensing operations over time. Enabling significant periods of progressive consumption is a major objective, another being to allow multi-dose packaging for pharmaceutical or parapharmaceutical products used in highly contaminated environments. With these objectives in mind, the invention proposes using a bifunctional hydrophilic-hydrophobic membrane which is further loaded with a biocidal agent through ionic oxidation.Such an agent is provided more specifically by macromolecules carrying positively charged metal ions, such as those offered by a well-known prior art in the form of mineral polymers of the aluminosilicate family, called zeolites, which retain labile metal cations. Among the useful ions, silver ions (Ag+ or Ag++) have proven to be the most advantageous in the industrial context of antibacterial protective membranes implemented according to the present invention. In a liquid dispenser according to the invention, such a membrane is used as a permanent source of biocidal metal ions in combination with a porous mass interposed in the fluid path upstream of the membrane. This mass is designed to retain the biocidal ions that reach it after being extracted from the membrane during the aspiration phase of each liquid dispensing operation, thus constituting a secondary reservoir of active ions while simultaneously acting as a buffer against the transport of these ions, preventing them from reaching the liquid receiving space inside the bottle. In practice, it has been observed that the ions thus stored, when not consumed on site, are readily released and carried back to the membrane during the expulsion phase of a subsequent dispensing operation. Water / air interface membranes loaded with biocidal metallic cations have been known for a long time, as evidenced, for example, by US patent 5,681,468, filed in 1993 and published in 1997. However, it had never been considered that biocidal cations could act other than by attacking bacteria contaminating the expelled liquid when it is downstream of the membrane after passing through it. Nor had it ever been proposed to mount the membrane as described in the invention, in a device combining the membrane with a porous mass for retaining the same active ions as those with which the membrane is loaded, as well as with means for organizing fluid flow through it, ensuring alternating flows at the membrane and in the downstream zone of the device.In the practical implementation of the invention, this porous mass is designed as an insert mounted in the liquid dispensing device, upstream of the membrane, acting as a non-watertight stopper for the communication channel between the inside and outside of the bottle. By virtue of its porosity and arrangement, the insert is advantageously designed to perform the function of the flow-regulating buffers found in ophthalmic drop bottles described in the Applicant's prior patents, by imposing a pressure drop along the path of the liquid being expelled from the bottle. However, for such an insert to perform its role in protecting against sterility pollutants as envisaged according to the present invention, it is specifically made of a polymer material having negatively charged active sites, thus capable of attracting the biocidal metallic cations with which the membrane is initially charged. Preferred materials from this perspective consist of polyolefin-based polymers copolymerized with compounds containing carboxylic acid functional groups. Depending on the relative proportions of the constituents and the conditions under which the copolymerization reactions take place, a significant proportion of free carboxyl sites remain in the resulting polymer, ready to bind with the cations used as biocidal cations that come into contact with the polymer. According to a preferred embodiment of the invention, the specific capacity of the polymer material to retain metal cations can be increased by subjecting the polymer to an irradiation treatment which has the effect of releasing other carboxyl groups. The operating principle of the device according to the invention as a whole will be specified later in this description by referring to the case where it is fitted to a sterile, flexible-walled ophthalmic solution container, elastically deformable by compression of the internal reservoir volume. It should be understood, however, that other means can similarly ensure the pressure variations that, with each dispensing of a dose of liquid, cause first a propulsion phase from the inside to the outside of the container and expulsion of the liquid beyond the capillary channel located downstream of the membrane, then a suction phase drawing outside air into the container, the air being preceded by a reflux of unexpelled liquid. Examples include a container with an axially movable bottom that meets an elastic return mechanism or a container equipped with a pump system.On the other hand, reference will preferably be made to a dropper dispensing device, but it should be understood that the device according to the invention can be adapted to the dispensing of individual doses larger than drops, as well as to an outlet of the capillary channel diffusing the liquid in other forms, for example as a jet or with spatial diffusion. Initially, during the entire storage period prior to first use, the bottle remains hermetically sealed over a blanket of pressurized sterile air covering the liquid receiving space, so that the membrane remains dry. It will only become saturated with liquid in its hydrophilic zone upon the first expulsion of liquid after opening the bottle. The downstream space of the device comprises a capillary channel where liquid and gas flow alternately without ever mixing, so that during operation, when the channel has finished conveying the flow of liquid to be expelled to the outside, a residual amount of unexpelled liquid remains, temporarily occupying the channel. This residual liquid is drawn back through the membrane by the pressure of the airflow drawn in from the outside when the pressure difference between the two faces of the membrane ceases to be in the direction of expulsion. During this aspiration phase, the refluxed liquid passes through the hydrophilic zone of the membrane, while the air entering to compensate for the volume of liquid dispensed passes through the hydrophobic zone. Upstream of the membrane, the space provided in the device according to the invention forms a conduit which, unlike the downstream capillary channel, has a large cross-section. It is within this conduit that the porous insert is placed, supplying negative charges in the reactions that tend to retain the biocidal metallic cations carried by the liquid through chemical bonds of charge with the insert's polymer at the active sites it presents, notably in the form of free carboxyl groups. This insert, also called a plug, is located in the presence of both liquid and air flows, which together come into contact with the polymer constituting it within the cells of the porous material. The contact occurs over a large surface area, corresponding to the specific surface area of ​​the porous material.When the device is in operation, the porous insert retains sufficient biocidal metallic cations to prevent chemical contamination of the liquid in the bottle. Furthermore, it ensures the back-and-forth movement of biocidal cations carried by the liquid's flow and reflux, particularly between the membrane and the porous insert. This phenomenon promotes high biocidal activity within the liquid dispensing device while protecting the stored liquid from microbiological contamination. Indeed, surprisingly, the inventors have demonstrated that the device according to the invention maintains strong biocidal activity throughout its use in discontinuous liquid dispensing. As will be detailed later, it has been shown that the dispensing device according to the invention, when used in a sealed closure on a bottle to create a multi-dose bottle containing, for example, sterile eye drops, exhibits high sterility during the consumption of the eye drops. The contents can thus be consumed over a much longer period than with current bottles, and without any risk of harm to the patient.The incoming airflow, which compensates for the expelled liquid and originates from ambient air laden with microorganisms, is sterilized primarily as it passes through the membrane. This sterilization occurs through the biocidal contact action of biocidal cations within the membrane's hydrophobic pores, and, if necessary, through antibacterial filtration. Furthermore, if needed, because biocidal cations carried by the reflux of residual, unexpelled liquid are retained in the insert at the end of each liquid dispensing cycle, there is always an active biocidal agent available to destroy microorganisms in the air that remains in the insert, mixed with some of the residual liquid. Tests described later confirm that biocidal cations are collected progressively in the porous insert, following a gradient in decreasing quantity from the extreme part closest to the membrane, referred to here as proximal, to the opposite extreme part closest to the liquid reservoir, referred to here as distal, so that the liquid reservoir remains free of biocidal cations. Furthermore, after the initial activation of said device by liquid distribution, said porous insert, which becomes charged with biocidal cations, then forms a source of biocidal cations which can be partially extracted as the liquid flow exiting the inside of the bottle passes through said insert to reach available sites on the membrane. This creates a back-and-forth movement of biocidal cations in the fluid circulation conduit linked to the back-and-forth movement of the liquid, which maintains a relatively stable quantity, during use, of biocidal cations available within the device according to the invention to be active on microorganisms coming into contact with them.In principle, the invention thus appears to consist of making the bifunctional water / air interface membrane on the one hand, the buffer insert installed in the non-sealing cap of the bottle on the other hand, in such a way that in operation, after the bottle is opened for first use in liquid distribution, the membrane and the insert cooperate to create between them a bed of mobile ions which are taken from the insert by the flow of liquid extracted from the bottle at each distribution operation (during the liquid expulsion phase) from those which were brought there by a reflux of undistributed liquid during previous liquid distribution operations (during the air aspiration phase). Overall, it can be assumed that the quantity of biocidal metal ions actually consumed in destroying biological contaminants is very small compared to the quantity displaced with each liquid dispensing operation, which is itself very small compared to the membrane's initial capacity. The quantity consumed depends on the degree of contamination of the ambient air being drawn in; air treatment efficiency will be higher the larger the contact surface area with the charged materials. The quantity displaced depends on the liquid flow rate that carries the active cationic charge, or more precisely, on the mass of liquid displaced with each backflow from the membrane to the insert and with each direct flow expelled back to the membrane. With these considerations in mind, the liquid distribution device according to the invention can be adapted to applications in more or less contaminated environments, even under severe conditions in terms of the overall volume of solution to be distributed, the total duration of use of the bottle, and the frequency of repetition of distribution operations, by playing on the respective shapes and dimensions of the membrane and the porous insert, assuming that the materials constituting each of them remain unchanged. With regard to the membrane itself, the present invention advantageously provides that it is made from a porous, hydrophilic polymer material homogeneously charged with a biocidal agent by ionic oxidation. This material constitutes the entire mass of the membrane and is then, locally, over a portion of the membrane spanning the fluid circulation channel between the inside and outside of the bottle, rendered hydrophobic by a complementary polymerization treatment that preserves its biocidal activity. This allows for a suitable volume to be created for contact between the gaseous phase, consisting of air, and the polymer material charged with ions active by biocidal effect within the porous mass throughout the entire thickness of the membrane.Similarly, the fact that the hydrophilic base material of the membrane is finely homogeneous precludes previous designs of filter membranes made of a fibrous material that retains charged particles between the fibers. According to the invention, it is preferable to start with a molten polymer base comprising fusible granules of a master mixture that itself incorporates mineral macromolecules carrying the active ions through a biocidal effect. While conventionally, bacterial filtration requires a fine porosity, not exceeding 0.2 µm, the presence of a biocidal agent within the membrane allows for satisfactory preservation of sterility with coarser porosities, preferably around 0.3 or 0.4 µm, or more broadly up to 0.5 µm, or even up to 0.6 or 0.8 µm, or even 1 µm, which is advantageous from the point of view of pressure drop and allows the treatment of viscous liquids. In practice, the invention thus provides, according to a preferred embodiment, for a membrane with an average pore diameter suitable for filtering microorganisms with particle sizes larger than 0.3 to 1 µm, in particular between 0.3 and 0.6 micrometers. In total, the porosity of the membrane can thus be adjusted to any value between 0, 1 and 1 micrometer depending on the physicochemical properties of the liquid. The macromolecules supporting the biocidal ions are advantageously, as already indicated, mineral polymers of the aluminosilicate type in which the biocidal ions are integrated, more specifically, in a manner known per se, metallic ions such as silver ions or similar metals in ionic form, which bind to the free sites of the polysiloxane chains by polar covalent bonds. These mineral polymers are preferably crystalline polymers. The concentration of active ions in the membrane is preferably, although not limiting the application conditions of the invention, chosen to be between 100 and 100,000 ppm, taking as an example the case of an aluminosilicate-based mineral polymer carrying silver ions in a membrane with a porosity of approximately 0.2-0.3 micrometers and an effective area of ​​approximately 3 cm². Among the metallic ions useful to the invention, we can consider copper and zinc ions, but it is silver ions that have proven to be the most advantageous in the industrial context of the antimicrobial protection device implemented according to the present invention. As a secondary feature, the invention extends, beyond the liquid distribution device according to the invention, to a sterile packaging bottle applying it, to be used in particular in the context of the sterile packaging of pharmaceutical or parapharmaceutical products. The invention also relates to a particular method of manufacturing the membrane itself. Advantageously, means for organizing fluid circulation complement the distribution device mounted on a packaging bottle. Preferably, said packaging bottle has a wall with reversible elastic deformation to ensure the entry of outside air to compensate for any dose of liquid expelled from the bottle, as well as the reflux back through said device of any residual unexpelled liquid. The membrane is mounted with said porous insert in said liquid distribution device in association with means for organizing the circulation of air and liquid through it, and wherein said membrane is disposed at the base of a dropper tip comprising the capillary channel for expulsion of drops, facing a base of said tip in which means are provided for...respective guidance of the air drawn in from the outside and of any undistributed liquid residue intended to flow back through the membrane from the downstream space to the upstream space, said means tending to direct the airflow towards the hydrophobic part of the membrane preferably located in the center of said membrane and to distribute the liquid over its hydrophilic part. Description of a method for embedding a bottle The invention will now be described more fully in terms of preferred features and their advantages, following non-limiting examples, by referring to a device for dispensing a sterile liquid according to the invention in its application to preserving sterility in a dropper bottle as illustrated in Figures 1 to 4, in which: Figure 1 shows, in longitudinal section and exploded view, the different elements of a deformable wall bottle from which a liquid is expelled in successive doses through a microbiological protection distribution device according to the invention; the longitudinal section of Figure 2 shows more particularly the distribution device, once its own elements have been assembled to constitute a liquid distribution head and external air inlet inserted into the neck of the bottle; Figure 3 illustrates the configuration of the base of the nozzle on its surface opposite the nacelle of the device illustrated in Figures 1 or 2; Figure 4 illustrates, in partially exploded view, the return flow of fluids in the circulation conduit of the distribution device according to the invention shown in figures 1 or 2. In its general constitution and as represented in all its elements in Figure 1, the bottle equipped with a dispensing head appears to conform to the usual design of sterile packaging bottles. The bottle comprises a reservoir 2 receiving the aqueous liquid to be dispensed in a sterile state, surmounted by a dispensing device mounted airtight in the neck of the bottle 10. However, it differs from this design by characteristics specific to the invention, which are distributed among its essential constituent elements for dispensing under microbiological protection according to the invention, along the circulation channel of the aqueous liquid to be dispensed and the air entering to compensate for the expelled liquid, namely, primarily in the upstream part of this channel, the porous insert 8 in the form of a pad occupying the internal space in the nacelle 4, and at the interface of these upstream and downstream parts, the membrane 7.It also differs in their relative assembly related to the circulation of fluids and the resulting effects on biocidal activity in the conduit. According to the invention, the selectively permeable membrane comprising the distribution device is used to separate the liquid and air flows passing through it, as a microbiological protection membrane by filtration, and, through its material containing mineral macromolecules carrying biocidal cations, to destroy bacteria or similar microorganisms carried in the fluids passing through it. In the example chosen to best illustrate the invention, the membrane is based on an organic polymer, more specifically in this case, on a polyester resin modified by a polyamide or polyethersulfone resin, into which the mineral macromolecules carrying the biocidal cations have been incorporated in bulk, more particularly here a zeolite with a cationic charge of silver.It is hydrophilic in nature and is rendered hydrophobic over only a portion of its length across the conduit in the distribution device. For example, local exposure to ultraviolet radiation is used, which modifies the polymer structure in situ through radical cross-linking reactions between its constituents, while preserving the properties of the biocidal cations of the zeolites. The membrane illustrated in Figure 4 thus exhibits a hydrophilic zone 22, which allows aqueous liquid to pass preferentially through it in the presence of air, and a hydrophobic zone 23, which allows air to pass preferentially through it in the presence of water or aqueous liquid. The ionic charge with biocidal effect is present in both the hydrophobic and hydrophilic zones. During operation, during successive operations of distributing doses of liquid out of the bottle, staged over time, the structure of the membrane, in connection with the organization of the circulation of fluids through it, tends to favor a destructive action of microorganisms which is exerted on the air flow within the hydrophobic material itself, by contact between the air and the ion-charged polymer on the surface of the pores, whereas on the contrary, in the hydrophilic part of the membrane, the biocidal ions are not consumed but carried away and transported further by the liquid passing through the membrane. Inside the fluid circulation conduit, upstream of the membrane 7 on the side of the closed internal space of the bottle, there is a porous insert 8 which has the main role, according to the invention, of retaining the biocidal cations brought to it by each reflux of aqueous liquid consisting of the unexpelled residue of the dose of liquid previously withdrawn from the bottle, and of allowing the biocidal cations which it has taken up to return to the membrane when a new dose of liquid is then expelled from the bottle. In typical ophthalmic applications, the porous insert has a length of 9 mm along the vial axis and a diameter of 9.6 mm. More generally, and as a guideline, the insert can have a length between 5 and 15 mm. The insert's dimensions are adapted to the size of its receptacle. Its distance from the membrane considered on its upstream face is of the same order of magnitude. Its porosity corresponds to an airflow of 3,000 ml / min, as measured using the capacitive "water flow" method, which consists of measuring the time it takes to fill a given volume with a stopwatch. Its volumetric density, in this example, is approximately 0.50 g / cm³. More generally, the insert, which comprises a large number of open cells, has a porosity that preferably corresponds to an airflow between 1,000 and 4,000 ml / min, measured using the capacitive "water flow" method. Its density is preferably between 0.20 and 0.80 g / cm³. Acidity tests of the porous insert The porous insert for an ophthalmic fluid bottle, as described here, is made from an extruded polyethylene-based polymer filament that undergoes compaction. The polymer initially contains carboxylic groups because methylene has been copolymerized with carboxylic acid compounds, such as higher homologs (C4-C10 hydrocarbon chains) of carboxylic acids, in a proportion of up to 25%. At this stage, it already contains carboxyl sites left free by the polymerization reactions. This explains the test results reported later, which relate the effect on cations to the acidity measured in the insert. The proportion of free carboxyl sites can be increased by exposing the product to radiation capable of breaking down polymer molecules. Beta or gamma rays are suitable for this purpose. As an example, the compacted insert is subjected, in the presence of air, to irradiation by gamma rays (Cobalt 60 source, 25 kGy). The radicals formed in the polymer material during irradiation react with the air to form, in particular, anionic carboxyl groups. The carboxyl site content before and after irradiation is studied by acidity measurements performed according to the principle of acidity or alkalinity determination in European Pharmacopoeia 8.6 for polyolefins. These measurements are carried out by comparison with purified water, with water heated with non-irradiated inserts, and with water heated with irradiated inserts. The results are presented in Table 1 below. Table 1: The decrease in pH and the increase in equivalent volume (Vh) at the color indicator's turning point indicate the creation of a large number of acidic sites in the irradiated inserts, hence a significant increase compared to the case of copolymer inserts with monomers with carboxylic functional groups not yet irradiated. The residual liquid that reaches the internal liquid receiving reservoir of the bottle arrives sterile and free of biocidal cations. This is proven by the tests below. Safety tests for the sterile stored liquid Tests were carried out to determine the quantity of silver ions found in the closed space, upstream of the membrane, of a first bottle containing solution A and a second bottle containing solution B, solutions described below, namely in the insert cut lengthwise into three slices of equal thickness forming the proximal part of the insert, the central part of the insert and the distal part of the insert, as well as in the reserve solution, at different times of use of the bottles which correspond to a volume of solution extracted from the bottle by intermittent expulsions of drops. In these tests, two solutions in aqueous medium known as eye drops are tested: a physiological solution A containing sodium chloride as the active ingredient in aqueous medium, usually used as eye drops in the treatment of dry eye, and an ophthalmic solution B containing timolol maleate as the active ingredient in aqueous medium, usually used as eye drops in the treatment of glaucoma. The results are presented in Table 2 for solution A and in Table 3 for solution B below. Table 2: Quantity of silver ions in the upstream part of the fluid circulation duct for solution A First Time Usage period: 15 days, 30 days, 90 days per bottle Volume of 4 drops: 1.67 ml, 3.35 ml, 10 ml (approximately 300 drops of solution A extract (0.15 ml)). In part proximal 4.18 0.88 1.03 0.94 the insert (ppm) In part central 1.75 0.56 0.44 0.61 the insert (ppm) In the distal part 0.81 0.26 0.31 0.22 of the insert (ppm) In the tank < 0.001 ppm < 0.001 ppm < 0.001 ppm < 0.001 ppm (ppm) Table 3: Quantity of silver ions in the upstream part of the fluid circulation duct for solution B The results in Tables 2 and 3 show on the one hand that silver ions are indeed retained in the insert and on the other hand that the quantity of silver ions retained in the insert decreases from the proximal part to the distal part of the insert, while in the liquid reservoir the quantity of silver ions is below the detection threshold (0.001 ppm). The liquid reserve is therefore well protected from chemical contamination by biocidal cations. The amount of silver cations retained in the insert is significant during the first use, but it tends to decrease with prolonged use of the bottle, without, however, dropping abruptly. This indicates that an exchange of biocidal ions occurs upstream of the membrane between the membrane, as the primary source of cations, and the insert, as a retention zone for biocidal cations carried by the reflux of liquid. The insert then becomes a secondary source of biocidal cations available for use during liquid withdrawals to the membrane. Forced contamination tests Tests relating to the antimicrobial efficacy of the device by so-called forced and time antimicrobial efficacy tests are carried out on the one hand with a device D 1 with an irradiated insert as described with reference to the figures, on the other hand with a device D2 constituted like the device D 1 except that the insert is not irradiated, in comparison with a device D3 whose insert is made of polyethylene irradiated like the device D 1, but whose antimicrobial membrane is made of the same basic polymer material as that of the device of the invention but free from any biocidal agent. The forced biological contamination test involves simulating the use of the vial by expelling drops of liquid followed by inoculation with a given large quantity of contaminating germs. The quantity of germs found in a subsequently expelled drop of solution is then determined. The test results presented below in Tables 4 and 5 were determined following the protocol below. After activating a vial containing a sterile solution by expelling four drops of this solution, a large quantity of contaminating germs, in this case 10⁵ (one hundred thousand) germs, is inoculated into the orifice of the vial tip. The quantity of germs present in a drop of liquid expelled 6 hours (time T6) after this initial inoculation is then determined.The following day, 24 hours after the bottle was put into use, a drop of solution is withdrawn from the bottle, followed by inoculation of 10⁵ bacteria into the bottle's tip. This procedure is performed three times during the day: once in the morning, once at midday, and once in the evening, to simulate the usual use of eye drops. A drop of solution is withdrawn 24 hours (time T24) after the last inoculation, and the number of bacteria present in this drop is determined. On the other hand, forced contamination tests are carried out on similar bottles by first extracting drops of solution in a volume corresponding to three months of use of a given solution, then the forced contamination protocol is applied as above by inoculating 105 germs into the orifice of the tip and analyzing a drop of solution 6 hours later (at time T6) and the following day is continued by the manipulation of extraction of a drop followed by an inoculation, three times in the day, and the quantity of germs present in a drop extracted 24 hours after this last inoculation is determined (time T24). The vials are tested with physiological solution A and ophthalmic solution B, which have been previously described for the examples in Tables 2 and 3. In these tests, two strains of contaminating aerobic bacteria were used: a P strain of Pseudomonas aeruginosa and an E strain of Escherichia coli. The results are presented in Tables 4 and 5 below: TABLE 4: Forced contamination tests with physiological solution A Device D1 Device D2 Device D3: No Duration Irradiated Insert Non-irradiated Insert of Ag cations in the membrane) of the vial Time T6 T24 T6 T24 T6 T24 analysis Strain 8 2 1,000 10 10,000 100,000 Immediate P Strain <1 <1 1,000 10 10,000 100,000 A 3 months P (10 ml extracts) Strain 100 <1 10,000 100 100,000 100,000 Immediate E Strain 10 <1 10,000 100 100,000 100,000 A 3 months E (10 ml extracts) TABLE 5: Forced contamination tests with ophthalmic solution B The results in Tables 4 and 5 show the high efficiency of the distribution device according to the invention in maintaining the sterility of a liquid, kept sterile in reserve, during long use by doses staggered over time. The results reported here are significant because, outside the normal conditions of use for eye drop bottles, they demonstrate that the microbiological quality of the liquid delivered through the device of the invention remains acceptable even when exceptionally high levels of contamination have been artificially induced. It follows that the same device of the invention can be used in applications involving much more severe contamination risks, for example, for products intended for application to wounds, burns, or atopic skin in cosmetics, etc. The packaging of such products in multi-dose bottles thus becomes possible thanks to the invention. Furthermore, it is clear that such results could not have been expected with previously known systems. Tests with a viscous liquid The forced contamination tests are carried out here to suit a viscous solution, thanks to the use of a membrane with an average pore diameter significantly greater than 0.2 μιτι, chosen here as an example at 0.8 μιη, well above the porosity of 0.2 μιη usually accepted for good bacterial filtration efficiency. A device according to the invention, equipped with a membrane having a mean pore diameter of 0.22 μm, is tested in use with a viscous solution V in comparison with a device according to the invention equipped with a membrane having a mean pore diameter of 0.22 μm in use with a low-viscosity solution T. The two solutions are based on hyaluronic acid in different quantities, dissolved in buffered water at a pH of approximately 7. For a total volume of 100 ml of aqueous solution, the viscous solution V contains 0.30 g of hyaluronic acid and has a viscosity of 60 mPa·s, while the low-viscosity solution T contains only 0.15 g of hyaluronic acid and has a viscosity of 3 mPa·s. Forced contamination tests were performed following the same protocol as described previously and with the same two strains of contaminating germs, for immediate use of the vial and for a simulated 3-month use. The results are presented in Table 6 below. These tests prove a high efficiency of the distribution device according to the invention by biocidal effect over time to maintain the sterility of the liquid in the bottle despite a significantly lower antibacterial efficiency by filtration. TABLE 6: Contamination tests with solutions T and V The above tests were carried out using a bottle equipped with a liquid dispensing head in which, according to the invention, the initial ionic charge concentration in the membrane, of silver cations, is on the order of a few thousand ppm. These are, of course, examples, which can be adapted by modifying the numerical data according to the conditions encountered in practice in each application of the invention. Continuation of the description of the figures According to a particular embodiment of the invention, the capillary channel is formed within a tip made of a material loaded with a biocidal agent, here also provided by a zeolite carrier for the ions. The capillary channel 1 8 is thus formed within a tip of dense polymer material, impermeable to liquid and air, loaded with silver biocidal cations that can migrate from the bulk to the surface. For example, the tip can be made of polyethylene loaded with a biocidal agent, in particular zeolites carrying silver cations. A distribution head whose nozzle is thus loaded with biocide agent while the material constituting the nacelle is devoid of it, is sufficiently described in the Applicant's earlier patent application WO2010 / 01 3131 that it is unnecessary to describe the details further here. To complete the description of the liquid dispensing device in its application to a bottle, with reference to Figures 3 and 4, it should be noted that upstream of the membrane, in the wide part of the fluid circulation channel formed by the annular shape of the nacelle 4, the free surface of the membrane is unobstructed. However, support fins 16, 17 are formed on the nacelle, on the inner side, to limit the stresses that may be exerted during operation on the periphery of the membrane, where it is bonded to a peripheral ring of the base of the nozzle equipped with the capillary channel for liquid expulsion, but these fins allow the membrane to bulge away from the base 3 of the nozzle. In relation to the external face of the membrane seen in its hydrophilic nature, the base 3 of the tip 5 forms a support surface for the membrane in the phases of liquid expulsion, which joins the wall of the capillary channel 18 at the level of its flared mouth 28.Around this opening, the free surface of the nozzle is hollowed with radial grooves offering a wide passage cross-section for the liquid near the membrane on the outside of the bottle. These radially arranged grooves 31 have the role of collecting the liquid exiting the bottle by guiding it towards the opening of the capillary channel 18 after it has passed through the membrane in its hydrophilic zone, but their role is also, on the remaining unexpelled liquid which is re-aspirated towards the bottle in the air inlet phase to compensate for the expelled liquid, to facilitate that under the pressure of the air it is directed towards the hydrophilic zone 22, by clearing the central hydrophobic zone 23 for the air which then arrives on it. The surface of the base 3 also has corrugations which tend to finely divide any air circulation vein originating at the exit of the capillary channel mouthpiece, which tends to reduce the speed at which it then passes through the membrane, even though the latter is pushed away from the transverse surface of the mouthpiece base. In the preferred embodiment of a nozzle thus made according to the invention, particularly in the case of a dropper nozzle, the corrugations dividing any circulating air stream are present in the form of relatively narrow and shallow grooves 32, thus having a small cross-section, each of which is annular in shape and distributed concentrically around each other around the central capillary channel of the nozzle. These grooves 32 are cut into the surface of the nozzle base, in the areas of the base protected by the liquid flow guide grooves 31, where the surface of the nozzle base is primarily used to support the diaphragm when it is pushed by the internal pressure of the compressed bottle to expel liquid. It is understood that, during operation, the specific configuration of the nozzle surface facing the membrane plays a role in organizing fluid flow, not only by promoting an alternation between liquid and gas flow in the nozzle's central channel, but also by guiding the fluids on their return path, as shown by the arrows in Figure 4. Arrows f1 illustrate that the residual, unexpelled liquid, drawn back first, is diverted from a direct axial path and directed towards the hydrophilic part of the membrane 22. This prevents it from being projected onto the central part of the membrane, where it would tend to wet the hydrophobic membrane material in that area. The airflow drawn towards the bottle thus has free access to the hydrophobic material of the membrane in its central part 23, as illustrated by arrows f2. Returning now to Figure 1, supplemented by Figure 2, we observe other details of the realization of the liquid distribution head out of a sterile packaging bottle which, although classic in themselves of bottles manufactured industrially by the Applicant, are nonetheless means participating in the implementation of the present invention by the quality of the preservation of sterility in the bottle. In this sense, we will note the presence of the external peripheral ribs 15 of the nacelle 4, which ensure a seal against bacteria with the neck of the bottle 10 at the level of the porous insert 8. We will also note the configuration of the cap 6 which is such that, when it is screwed (at 12) onto the neck of the bottle, it closes the external mouth of the channel 18. Its role, among others, is to ensure a pressure drop downstream of the membrane which prevents it from being wetted by the liquid contained in the bottle as long as the tamper-evident ring 26 has not been broken for first use (first expulsion of a drop of liquid). Along the same lines, noteworthy is the shape of the nacelle 8 at its upstream end, inside the bottle. Its usefulness will be most apparent in devices designed for dispensing eye drops with surfactant or viscous physicochemical properties. In such cases, the illustrated means will be advantageously used in combination with more specific embodiments of the invention, namely those incorporating a membrane with relatively coarse porosity, resulting in lower protection through filtration of microorganisms while providing high protection through biocidal effect. These means consist of the configuration forming arches 13 around a central disc 11 and positioned in the bottle 2 beyond its neck 10. They have been fully described in patent application WO 2011 / 095877.They contribute to an organization of fluid circulation favorable to the needs of the present invention in the case of the same liquids. The test results reported above demonstrate an improvement in microbiological safety over time and under significant contamination conditions, an improvement that could not be expected from the simple use of a membrane loaded with biocidal cations. Nor could such an improvement be expected from a membrane that is also partially hydrophilic and partially hydrophobic, since such a membrane alone could not ensure the alternating flow of liquid and air from the bottle to the outside and vice versa. In the case of the invention, this alternating circulation is ensured by the fact that the partially hydrophilic and partially hydrophobic membrane interfacing between the inside and outside of the bottle is combined with a capillary channel for liquid expulsion and air intake located downstream of the membrane. It is also further ensured by other means which contribute in a known manner to controlling the alternation of flows under pressure effects, and thereby to the regularity and reproducibility of the masses and volumes conveyed.Finally, while applying the membrane loaded with biocidal ions into a conventional bottle of the Applicant is already inventive due to the role it plays in transporting the active charge to the reflux of liquid created with each distribution of a dose of liquid, the fact remains that the demonstrated results would not be achieved without the addition of an insert made porous to act as a non-watertight closure cap for the bottle, and where appropriate, a flow regulator by its porous nature as is conventional, but which in addition is made of a polymer material having anionic sites in its mass having the attracting effect of metallic cations that carboxylic sites are known to have in particular. Differences in ion transfer behavior can be explained by considering that the membrane is a finely porous piece with a relatively large cross-section across the fluid circulation channel and a small thickness, whereas the insert has a relatively coarse porosity and is thick, and therefore relatively long along the fluid circulation circuit. Also, unlike the capillary channel on the downstream side, this insert occupies a relatively large cross-section of the bottle neck, like the membrane. Furthermore, while in the membrane the individual cells of the material are filled with only either liquid or air, in the insert both fluids are present simultaneously within the cells. Therefore, atmospheric oxygen can influence the transfer of ionic charges within the cells. The biocidal activity in destroying aerobic bacteria thus operates differently than in the membrane cells. Moreover, air and liquid come into contact with a large surface area of ​​active material, corresponding to the specific surface area of ​​the insert. The use of cationic charges in bacterial destruction is therefore all the more effective. Clearly, a similar effect cannot occur in the circuit downstream of the membrane, since the tip material there is dense and impermeable to both liquid and air. Consequently, even if this material is based on an ionic polymer initially carrying silver ions, these ions must migrate to the surface to be active on the fluids. The contact surface with the fluids at the tip is long but has a small perimeter around the capillary channel cross-section. Furthermore, it is alternately exposed to either air or water, including during the reflux of any remaining aqueous solution. The differentiation of phenomena involving ionic charge transfer between the bifunctional interface membrane and the porous insert sealing the bottle is all the more pronounced when the organization of fluid flow through them is better controlled to ensure that the membrane remains dry in its hydrophobic zone and that the liquid refluxes through its hydrophilic zone. While the bottle is in storage, before its first use consuming liquid, the membrane remains dry regardless of the bottle's position, thanks to overpressure maintained downstream by the airtight closure of the capillary channel; this overpressure also exists upstream, thus keeping the membrane isolated from any contact with the porous insert.In any case, it is a fact that between the two porous bodies—the membrane and the porous insert—a bed of mobile ions is created during operation. These ions are drawn from the insert by the flow of liquid extracted from the bottle with each dispensing operation, originating from biocidal ions that were brought there by a reflux of undispensed liquid during previous dispensing operations. In practice, the biocidal ions thus remain confined to moving from one porous body to the other. Downstream of the membrane, the expelled liquid is not altered.Without claiming to fully understand the phenomena occurring at the molecular and ionic charge level, one can consider a mechanism involving the availability of directly accessible active sites for contact with fluids on the surface of the polymer material. This is due to the large specific surface area and void volume at the insert, as well as the thinness of the membrane. The membrane constitutes a primary source, having been loaded with biocidal agent during manufacturing to provide ample ions to meet the needs of each application throughout the bottle's lifespan until its initial liquid content is depleted. The insert, for its part, plays a crucial role in manufacturing as a source of active sites with a charge complementary to that of the biocidal ions.Once the bottle has been opened for the first dispensing operation, the insert sealing the bottle becomes functional, both to protect the sterile interior and to act as a source of secondary biocide. This secondary biocide retains the ions introduced at the end of the dispensing operation (air aspiration phase) until they are collected during a subsequent dispensing operation. Those ions collected by the liquid flow from the bottle are carried to the membrane and retained there, with the exception of those consumed by airborne bacteria. The high quality of sterility preservation observed during forced contamination tests goes well beyond the specific needs of eye drop bottles and other ophthalmic liquids, which are routinely stored under membranes that filter out external microorganisms. However, it demonstrates that the technique of the invention remains valuable as an alternative to conventional methods even in this case, while more generally it will be useful in many applications that do not require or permit a high degree of bacterial filtration at the membrane level.It is also easy to understand that the implementation of the invention can be realized in embodiments suitable for large liquid capacities and long service lives in discontinuous use and / or very diverse doses and forms of diffusion for the liquid expelled from the channel with alternating fluid circulation, by simple dimensional adaptations of the essential constituent elements of the device according to the invention.

Claims

DEMANDS 1. A device for distributing an aqueous liquid, in doses staged over time, from a closed upstream space receiving the liquid to an open downstream space via a capillary channel opening to ambient air, through an interface membrane made partly of hydrophilic and partly of hydrophobic nature, such that in During operation, during each dispensing of a dose of liquid, the air and liquid flows circulate alternatively in the capillary channel and that a reflux occurs of a residual unexpelled liquid, characterized in that said interface membrane (7) is made of a filter material comprising biocidal metallic cations by mass, and in that said device comprises a porous insert (8), permeable to both liquid and air, which is disposed upstream of the membrane in the path of the fluids and which is made of a material having negatively charged sites capable of attracting biocidal metallic cations from said membrane.

2. Device according to claim 1, characterized in that said biocidal metallic cations comprise silver cations.

3. Device according to any one of the preceding claims, characterized in that said biocidal metallic cations of the membrane are supported by mineral macromolecules of the zeolite type integrated into the mass of the base material of the membrane.

4. A device according to any one of the preceding claims, characterized in that said negatively charged sites capable of attracting biocidal metal cations are carboxyl anionic groups.

5. A device according to any one of claims 1 to 4, characterized in that said porous insert has a density of between 0.2 and 0.8 g.cm3.

6. Device according to any one of the preceding claims, characterized in that said insert is based on a polyolefin polymer, preferably selected from polyethylene, polypropylene, and ethylene or polypropylene copolymers with up to 25% higher homologues of carboxylic acids or esters.

7. Device according to any one of claims 1 to 6, characterized in that said insert is made of a compacted fibrous material.

8. Device according to any one of the preceding claims, characterized in that said negative charge sites capable of attracting biocidal metallic cations result from irradiation of the porous insert by beta or gamma rays in the presence of oxygen.

9. Device according to any one of the preceding claims, characterized in that the material constituting said membrane has an average pore diameter between 0.1 and 1 micrometer.

10. Device according to claim 9, characterized in that the material constituting said membrane has an average pore diameter of between 0.4 and 0.8 micrometers.

11. Device according to one of the preceding claims, characterized in that said capillary channel is formed within a material incorporating biocidal metallic cations, in particular carried by mineral macromolecules.

12. Sterile packaging bottle for an aqueous liquid to be distributed in doses staged over time, by expulsion of a dose of liquid from the bottle and entry of outside air in compensation, characterized in that it is equipped with a distribution device for said liquid constituted according to one of claims 1 to 11, of which said insert (8) is mounted in a non-tight closure of the inside of the bottle, said closed space then being the inside of the bottle.

13. Bottle according to claim 12, having a wall with elastically reversible deformation to ensure the entry of outside air to compensate for any dose of liquid expelled from the bottle as well as the return through said device of any residual unexpelled liquid, said membrane being mounted with said porous insert (8) in said liquid distribution device in association with means for organizing the circulation of air and liquid fluids through it, and in which said membrane is disposed at the base of a dropper tip within which is provided the capillary channel (18) for expulsion of drops, facing a base of said tip in which are provided means for guiding respectively the air drawn in from the outside and any residual undistributed liquid intended to flow back towards the downstream part of the fluid circulation conduit,which tend to direct the airflow towards the hydrophobic part of the membrane, preferably located in the center of said membrane, and to distribute the liquid over its hydrophilic part.

14. Bottle according to claim 12 or 13, in which said insert is determined to participate in the organization of the circulation of fluids by constituting a flow regulator.

15. A method for manufacturing a membrane loaded with biocidal cations for a sterile aqueous liquid distribution device as defined in any one of claims 1 to 11 or for a bottle according to any one of claims 12 to 14, wherein in a first step said membrane is made of a porous material of hydrophilic polymer material which is loaded with said biocidal cations throughout its mass, and then said polymer material is locally in the entire thickness of the membrane over a part of its extent, made hydrophobic by a complementary polymerization treatment preserving the biocidal activity of said biocidal cations.

16. A process according to claim 15, characterized in that the membrane is produced by shaping said material by melting said hydrophilic polymer material with fusible granules of a master mixture incorporating mineral macromolecules carrying biocidal cations, said shaped material being made uniformly porous in its mass.

17. A process according to any one of claims 15 or 16, characterized in that said polymer material initially of a hydrophilic nature is made locally hydrophobic by a radical crosslinking reaction between its constituents which is initiated by local irradiation of the membrane under ultraviolet radiation.