Device for dispensing liquid 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.

Claims

1. A device capable of dispensing an aqueous liquid, by doses spaced out over time, comprising a closed upstream space accommodating a liquid, an open downstream space via a capillary channel opening to ambient air, a partially hydrophilic and partially hydrophobic interface membrane, whereby, in operation, during each time a dose of liquid is dispensed, the flows of air and of liquid circulate alternately in the capillary channel and a back flow of non-expelled remaining liquid takes place, said interface membrane (7) being a filtration material the mass of which comprises biocidal metal cations, said device further comprising a porous insert (8), permeable both to liquid and to air, which is arranged upstream of the membrane on the path of the fluids and which is made of a material containing negatively charged sites capable of attracting biocidal metal cations originating from said membrane, and wherein the porous insert progressively collects the biocidal metal cations originating from said membrane present in the back flow of non-expelled remaining liquid, such that liquid accommodated in the closed upstream space remains free of biocidal cations, so that to-and-fro movements of biocidal cations are established, conveyed by flow of liquid outward and back flow of liquid in return direction between the membrane and the porous insert, providing biocidal activity in the device for dispensing liquid, thus protecting the liquid accommodated in the closed upstream space from microbiological contamination.

2. The device according to claim 1, wherein said biocidal metal cations comprise silver cations.

3. The device according to claim 1, wherein said biocidal metal cations of the membrane are supported by mineral macromolecules incorporated in the mass of the base material of the membrane.

4. The device according to claim 1, wherein said negatively charged sites capable of attracting biocidal metal cations are anionic carboxyl groups.

5. The device according to claim 1, wherein said porous insert has a volumetric mass density of 0.2 to 0.8 g.cm.sup.3.

6. The device according to claim 1, wherein said insert is based on a polyolefin polymer.

7. The device according to claim 1, wherein said insert is constituted by a compacted fibrous material.

8. The device according to claim 1, wherein said negatively charged sites capable of attracting biocidal metal cations result from irradiation of the porous insert with rays of the beta or gamma type in the presence of oxygen.

9. The device according to claim 1, wherein the material constituting said membrane has a pore diameter of 0.1 to 1 μm.

10. The device according to claim 1, wherein the material constituting said membrane has an average pore diameter of 0.4 to 0.8 μm.

11. The device according to claim 1, wherein said capillary channel is formed within a material incorporating biocidal metal cations.

12. A sterile packaging bottle capable of dispensing an aqueous liquid in doses spaced out over time, by expulsion of a dose of liquid out of the bottle and entry of outside air in compensation, said sterile packaging bottle comprising a device dispensing said liquid according to claim 1, said insert (8) of which is mounted as a non-sealing closure of the inside of the bottle, said closed space then being inside the bottle.

13. The bottle according to claim 12, having a wall that can be reversibly elastically deformed, in order to ensure the entry of outside air compensating for any dose of liquid expelled from the bottle as well as the back flow through said device of any non-expelled remaining liquid, said membrane being mounted with said porous insert (8) in said device for dispensing liquid in combination with means of organization of the circulation of the air and liquid fluids through it, and in which said membrane is arranged at the base of a dropper tip within which is arranged the capillary channel (18) for the expulsion of the drops, opposite a base of said tip in which are arranged respective means for guiding the air aspired from the outside and any remaining liquid that has not been dispensed and is required to flow back to the downstream portion of the duct for the circulation of the fluids, which tend to direct the airflow to the hydrophobic part of the membrane and to distribute the liquid over its hydrophilic part.

14. The bottle according to claim 12, in which said insert participates in the organization of the circulation of the fluids by constituting a flow regulator.

15. The device according to claim 6, wherein the polyolefin polymer is polyethylene, polypropylene, or a copolymer of ethylene or of polypropylene with up to 25% higher homologs of carboxylic acids or esters.

16. The device according to claim 11, wherein said capillary channel is formed within a material incorporating biocidal metal cations borne by mineral macromolecules.

17. The bottle according to claim 13, wherein the means for guiding the air aspired from the outside and any remaining liquid that has not been dispensed and is required to flow back to the downstream portion of the duct for the circulation of the fluids, which tend to direct the airflow to the hydrophobic part of the membrane are arranged in the center of said membrane.

Description

(1) In its general construction and as shown in all its elements in FIG. 1, the bottle equipped with a dispensing head appears to conform to the usual design for sterile packaging bottles. The bottle comprises a reservoir 2 accommodating the aqueous liquid to be dispensed in a sterile condition, surmounted by a dispensing device mounted in a sealing manner in the neck of the bottle 10. However, it differs therefrom by features specific to the invention that are distributed over its constituent elements, essential for dispensing, under ensured microbiological protection according to the invention, along the duct for the circulation of the aqueous liquid to be dispensed and of the air entering, compensating for the liquid expelled, namely mainly in the upstream portion of this duct, the porous insert 8 in the form of a plug occupying the internal space in the nacelle 4, and at the interface of these downstream and upstream parts of the membrane 7. It also differs therefrom in their relative assembly linked to the circulation of the fluids and to the resulting effects on the biocidal activity in the duct.

(2) According to the invention, the selective permeability membrane that the dispensing device contains is used for separating the flows of liquid and of air that pass through it, as a microbiological protection membrane by filtration and by the fact that its material contains mineral macromolecules bearing biocidal cations, for the destruction of the bacteria or similar microorganisms conveyed in the fluids that pass through it.

(3) In the example chosen to better illustrate the invention, the membrane is based on an organic polymer, more specifically in the present case based on polyester resin modified by a polyamide or polyethersulphone resin, into which the mineral macromulecules supporting the biocidal cations have been incorporated in the mass thereof, more particularly here a zeolite loaded with silver cations. It is hydrophilic and is rendered hydrophobic over only a part of its extent across the duct arranged in the dispensing device. For example, this is done via local exposure to irradiation under ultraviolet radiation, which modifies the structure of the polymer in situ, by radical crosslinking reactions between its constituents, while maintaining the properties of the biocidal cations of the zeolites.

(4) The membrane shown in FIG. 4 thus has a hydrophilic zone 22 preferentially allowing the aqueous liquid to pass through it in the presence of air, and a hydrophobic zone 23 preferentially allowing air to pass through it in the presence of water or of the aqueous liquid. The ionic load with biocidal effect is present both in the hydrophobic zone and in the hydrophilic zone.

(5) In operation, during the successive operations of dispensing the doses of liquid out of the bottle, spaced out over time, the structure of the membrane, in conjunction with the organization of the circulation through it of the fluids, tends to promote action that destroys the microorganisms and is exerted on the airflow within the hydrophobic material itself by contact between the air and the polymer loaded with ions at the surface of the pores, while conversely, in the hydrophilic part of the membrane, the biocidal ions are not consumed but entrained and conveyed further by the liquid passing through the membrane.

(6) Inside the duct for the circulation of the fluids, upstream of the membrane 7 on the side of the closed inner space of the bottle, there is a porous insert 8, the main role of which, according to the invention, is to retain the biocidal cations brought to it by each backflow of aqueous liquid constituted by the non-expelled remainder of the dose of liquid previously drawn off from the bottle, and to allow distribution to the membrane of the biocidal cations with which it has become loaded when a new dose of liquid is subsequently expelled from the bottle.

(7) In conventional examples within the context of ophthalmic applications, the length of the porous insert along the axis of the bottle is 9 mm and the diameter 9.6 mm. More generally, and by way of indication, the length of said insert can be comprised between 5 and 15 mm. The dimensions of the insert are adapted to the size of its receptacle.

(8) Its distance from the upper face of the membrane in question is of the same order of magnitude. Its porosity corresponds to an air flow rate of 3,000 ml/mn, as measured according to the “water flow” capacitive method, consisting of measuring the time taken to fill a given volume using a chronometer. Its volumetric mass density according to the example is of the order of 0.50 g.cm.sup.3.

(9) More generally, the porosity of the insert, which comprises a large number of open cells, preferably corresponds to an air flow rate comprised between 1,000 and 4,000 ml/min, measured according to the “water flow” capacitive method. Its volumetric mass density is preferably comprised between 0.20 and 0.80 g.cm.sup.3.

(10) Acidity Tests of the Porous Insert

(11) The porous insert intended for a bottle for ophthalmic liquid according to the example in question here is produced from an extruded polyethylene-based polymer filament that is subjected to compaction. The polymer comprises carboxyl groups initially to the extent that ethylene has been copolymerized with compounds having carboxylic acid functions, here constituted for example by higher homologues (with C4-C10 hydrocarbon chain) of carboxylic acid, in a proportion of 25% at most.

(12) At this stage it already comprises carboxyl sites left free by the polymerization reactions. This explains the test results reported below that make it possible to show the relationship between the effect on the cations and the acidity measured in the insert.

(13) The proportion of free carboxyl sites can be increased by exposing the product to a radiation capable of breaking the molecules of the polymer. Beta or gamma rays are suitable for this.

(14) By way of example, the compacted insert is subjected, in the presence of air, to an irradiation by gamma rays (Cobalt 60 source, 25 kGy). The radicals formed in the polymeric material during the irradiation react with air in order to form carboxyl anionic groups in particular.

(15) The content of carboxyl sites before and after irradiation is studied using acidity measurements that are carried out according to the principle of acidity or alkalinity assay from the European Pharmacopoeia 8.6 for polyolefins. These measurements are carried out by comparison with purified water, on warm water with non-irradiated inserts and on warm water with irradiated inserts.

(16) The results are shown in Table 1 hereinafter.

(17) TABLE-US-00001 TABLE 1 Purified Non-irradiated water inserts Irradiated inserts pH 6.8 5.5 5.0 Vh (ml) 1.2 1.5 2.4

(18) The decrease in the pH and the increase in the equivalent volume (Vh) at the end-point of the coloured indicator demonstrate the creation of a large number of acid sites in the irradiated inserts, hence a significant increase with respect to the case of the copolymer inserts with monomers having carboxylic functional groups not yet irradiated.

(19) The remainder of liquid reaching the reservoir receiving liquid inside the bottle reaches there sterile and free of biocidal cations. The proof of this is established by the tests hereinafter.

(20) Safety Testing for the Sterile Stored Liquid

(21) Tests were carried out in order to determine the quantity of silver ions found in the closed space, upstream of the membrane, of a first bottle containing a solution A and a second bottle containing a solution B, solutions described below, namely in the insert cut into three sections of equal thicknesses over its length, forming the proximal portion of the insert, the central portion of the insert and the distal portion of the insert, as well as in the solution in reserve, at different times of use of the bottles that correspond to a volume of solution extracted from the bottle by intermittent expulsions of drops.

(22) In these tests, two solutions in an aqueous medium known as eye drops are tested: a physiological solution A containing as active ingredient sodium chloride in an aqueous medium usually utilized as eye drops in the treatment of dry eye, and an ophthalmic solution B containing as active ingredient timolol maleate in an aqueous medium usually utilized as eye drops in the treatment of glaucoma.

(23) The results are shown hereinafter in Table 2 for solution A and in Table 3 for solution B.

(24) TABLE-US-00002 TABLE 2 Quantity of silver ions in upstream portion of duct for circulation of fluids for solution A Time of use of the bottle First use 15 days 30 days 90 days Volume of 4 drops 1.67 ml 3.35 ml 10 ml solution A (0.15 ml) (approximately extracted 300 drops) In proximal 4.18 0.88 1.03 0.94 portion of the insert (ppm) In central 1.75 0.56 0.44 0.61 portion of the insert (ppm) In distal 0.81 0.26 0.31 0.22 portion of the insert (ppm) In the <0.001 ppm <0.001 ppm <0.001 ppm <0.001 ppm reservoir (ppm)

(25) TABLE-US-00003 TABLE 3 Quantity of silver ions in upstream portion of duct for circulation of fluids solution B Time of use of the bottle First use 15 days 30 days 90 days Volume of 4 drops 1.08 ml 2.17 ml 6.5 ml solution B (0.15 ml) (approximately extracted 200 drops) In proximal 7.73 2.08 1.81 1.34 portion of the insert (ppm) In central 4.95 1.36 0.91 0.63 portion of the insert (ppm) In distal 1.08 0.36 0.42 0.27 portion of the insert (ppm) In the <0.001 ppm <0.001 ppm <0.001 ppm <0.001 ppm reservoir (ppm)

(26) The results in these Tables 2 and 3 show on the one hand that silver ions are in fact retained in the insert and on the other hand that the quantity of silver ions retained in the insert diminishes from the proximal portion to the distal portion of the insert, whereas in the reserve of liquid the quantity of silver ions is below the detection threshold (0.001 ppm).

(27) The reserve of liquid is thus well protected by the biocidal cations from chemical contamination.

(28) The quantity of silver cations retained in the insert is large on first use, but it tends to diminish during prolonged use of the bottle, without however diminishing abruptly, which shows that a biocidal ion-exchange movement of takes place upstream of the membrane between the latter as a primary source of cations and the insert as a zone retaining biocidal cations conveyed by the back flow of liquid. The insert then becomes a secondary source of biocidal cations available to be used during withdrawals of liquid towards the membrane.

(29) Forced Contamination Tests

(30) Tests relating to the antimicrobial efficacy of the device by so-called forced tests of the antimicrobial efficacy over time are carried out on the one hand with a device D1 having an irradiated insert such as described with reference to the figures, with on the other hand a device D2 constituted like the device D1 except that the insert is not irradiated, in comparison with a device D3 the insert of which is made of irradiated polyethylene like the device D1, but the antimicrobial membrane of which is constituted by the same polymeric base material as that of the device of the invention but free of any biocidal agent.

(31) The forced biological contamination test consists of simulating a use of the bottle by expulsion of drops of liquid followed by inoculation with contaminant germs in a given significant quantity, the quantity of germs being subsequently found in one drop of expelled solution then being determined. The test results shown hereinafter in Tables 4 and 5 were determined according to the following protocol. After a bottle containing a sterile solution had been brought into use by expulsion of four drops of this solution, a large quantity of contaminant germs, here 10.sup.5 (one hundred thousand) germs, were inoculated into the orifice in the tip of the bottle, then the quantity of germs present in one drop of liquid expelled 6 hours (time T6) after this first inoculation was determined. The next day, i.e. 24 hours after the bottle was brought into use, one drop of solution is extracted from the bottle, followed by an inoculation of 10.sup.5 germs into the tip of the bottle, this manipulation being carried out three times a day, once in the morning, once at midday and once in the evening, in order to simulate a usual use of eye drops. One drop of solution is extracted 24 hours (time T24) after the last inoculation and the quantity of germs present in this drop is determined.

(32) 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' use of a given solution, then the forced contamination protocol is applied as above by inoculation of 10.sup.5 germs into the orifice in the tip and analysis of a drop of solution 6 hours later (at time T6), followed the next day by the manipulation for extraction of one drop followed by an inoculation, three times during the day, and the quantity of germs present in one drop extracted 24 hours (time 24) after this last inoculation is determined.

(33) The bottles with the physiological solution A and the ophthalmic solution B that were previously described for the examples in Tables 2 and 3 are tested.

(34) In these tests, two contaminant aerobic bacterial stains were used: a strain P of Pseudomonas aeruginosa and a strain E of Escherichia coli.

(35) The results are shown in the following Tables 4 and 5:

(36) TABLE-US-00004 TABLE 4 forced contamination tests with physiological solution A Device D1 Device D2 Device D3: No Ag Insert Insert not cations in the Duration irradiated irradiated membrane. of Time of analysis use of the T6 T24 T6 T24 T6 T24 bottle Strain P 8 2 1,000 10 10,000 100,000 Immediate Strain P <1 <1 1,000 10 10,000 100,000 At 3 months (10 ml extracted) Strain E 100 <1 10,000 100 100,000 100,000 Immediate Strain E 10 <1 10,000 100 100,000 100,000 At 3 months (10 ml extracted)

(37) TABLE-US-00005 TABLE 5 forced contamination tests with physiological solution B Device D1 Comparative according device D2 with Device D3 with to the insert not membrane not invention irradiated initially loaded. Duration of Time of analysis use of the T6 T24 T6 T24 T6 T24 bottle Strain P <1 <1 1,000 10 100,000 100,000 Immediate Strain P <1 <1 100 10 100,000 100,000 At 3 months (6.5 ml extracted) Strain E <1 <1 1,000 100 100,000 100,000 Immediate Strain E <1 <1 1,000 10 100,000 100,000 At 3 months (6.5 ml extracted)

(38) The results of these Tables 4 and 5 show the high efficiency of the dispensing device according to the invention for maintaining the sterility of a liquid, sterile when placed in reserve, during a long usage through doses spaced out over time.

(39) The results reported here have the benefit, when departing from the normal conditions of use of bottles for ophthalmic drops, of showing that the microbiological quality of the liquid delivered by means of the device of the invention remains acceptable, even when an exceptionally heavy contamination has been artificially caused. It follows that it is possible to use the same device of the invention in applications involving conditions that are much more severe in terms of risk of contamination, for example for products that are to be spread on wounds, burns, for atopical skin products in the cosmetics field, etc. Thus packaging such products in multidose bottles becomes possible thanks to the invention. In addition, it is clear that such results could not be hoped for with the previously known systems.

(40) Tests with a Viscous Liquid

(41) The forced contamination tests are carried out here in order to be suitable for a viscous solution, thanks to the use of a membrane with an average pore diameter markedly greater than 0.2 μm, chosen here by way of example as 0.8 μm, considerably greater than the porosity of 0.2 μm usually accepted for a good bacterial filtration efficiency.

(42) A device according to the invention equipped with a membrane having an average pore diameter of 0.8 μm for use with a viscous solution V in comparison with a device according to the invention equipped with a membrane having an average pore diameter of 0.22 μm for use with a low-viscosity solution T is tested.

(43) The two solutions are based on hyaluronic acid in different quantities, dissolved in water buffered to a pH of approximately 7. For a total volume of an aqueous solution of 100 ml, the viscous solution V contains 0.30 g of hyaluronic acid and has a viscosity of 60 mPa.Math.s, whereas the low-viscosity solution T contains only 0.15 g of hyaluronic acid and has a viscosity of 3 mPa.Math.s.

(44) The forced contamination tests are carried out following the same protocol as previously described, and with the same two strains of contaminant germs, for an immediate use of the bottle and for a simulated use of 3 months. The results are shown in Table 6 hereinafter.

(45) These tests prove a high level of efficiency of the dispensing device according to the invention in terms of biocidal effect over time, in maintaining the sterility of the liquid in the bottle despite a markedly lower antibacterial efficacy by filtration.

(46) TABLE-US-00006 TABLE 6 contamination tests with the solutions T and V Device according Device according to the invention to the invention with 0.22 μm with 0.80 μm membrane and membrane and solution T viscous solution T Time of analysis Duration of use of T6 T24 T6 T24 the bottle Strain P <1 <1 <1 <1 Immediate Strain P <1 <1 <1 <1 At 3 months (27 ml extracted) Strain E 2 <1 <1 <1 Immediate Strain E 2 <1 <1 <1 At 3 months (27 ml extracted)

(47) The above tests were carried out using a bottle equipped with a liquid dispensing head in which, according to the invention, the initial concentration of ionic load in the membrane, in silver cations, is of the order of several thousand ppm. Of course these are example cases, that can be adapted by modifying the estimated data depending on the conditions encountered in practice in each case of application of the invention.

(48) Continuation of the Description of the Figures

(49) According to a particular embodiment of the invention, the capillary channel is bored in a tip, itself produced from a material loaded with biocidal agent, here also supplied by an ion-supporting zeolite filler. The capillary channel 18 is thus produced in a tip of a dense polymeric material, not permeable by the liquid and air fluids, loaded with biocidal cations of silver that can be displaced by migrating from the mass to the surface. For example the tip can be made of polyethythene loaded with biocidal agent, in particular with zeolites supporting the silver cations.

(50) A dispensing head the tip of which is thus loaded with biocidal agent whereas the material constituting the nacelle is devoid thereof is sufficiently described in the Applicant's prior patent WO2010/013131, making more detailed description thereof unnecessary here.

(51) In order to complete the description of the device for dispensing liquid when applied to a bottle, with reference to FIGS. 3 and 4, it will be noted that upstream of the membrane in the wide part of the fluid-circulation duct provided by the annular shape of the nacelle 4, the free surface of the membrane is clear. However, supporting fins 16, 17 are formed on the nacelle, on the inside, to limit the stresses that could be exerted during operation on the periphery of the membrane where it is fixed bonded on a peripheral ring of the base of the tip provided with the capillary channel for expulsion of the liquid, but leaving the membrane free to curve away from the base 3 of the tip.

(52) Opposite the external face of the membrane viewed with respect to its hydrophilic nature, the base 3 of the tip 5 forms a supporting surface for the membrane during the liquid-expulsion phases, which joins the wall of the capillary channel 18 at the level of its flared nozzle 28.

(53) Around this nozzle, the free surface of the tip is scored with radial slots offering a wide cross-section for the passage of the liquid in proximity to the membrane on the outside of the bottle. The purpose of these radiating slots 31 is to collect the liquid leaving the bottle and guide it to the nozzle of the capillary channel 18 after it has passed through the membrane in its hydrophilic zone, but their role is also, with respect to the non-expelled remaining liquid that is aspirated back to the bottle in the air-entry phase compensating for the expelled liquid, to facilitate its being directed, under the pressure of the air to the hydrophilic zone 22, freeing the central hydrophobic zone 23 for the air that then arrives above.

(54) Furthermore, the surface of the base 3 has corrugations that tend to finely divide any path for the circulation of air arising at the outlet of the nozzle of the capillary channel of the tip, which tends to reduce the speed at which it then crosses the membrane, even when the latter is pushed away from the transversal surface of the base of the tip.

(55) In the preferred embodiment of a tip thus produced according to the invention, in particular in the case of a dropper tip, the corrugations dividing any air circulation path are present in the form of grooves 32, which are relatively narrow and not very deep, thus having a fine flow section, which are each annular and distributed in a concentric arrangement with respect to one another around the central capillary channel of the tip. These grooves 32 are cut into the surface of the base of the tip, in the sectors of the base retained by the slots 31 for guiding the flow of liquid, at the point where the surface of the base of the tip is rather reserved to act as a bearing support for the membrane when the latter is pushed by the internal pressure of the compressed bottle in order to expel liquid.

(56) It is understood that during operation, the particular configuration of the surface of the tip facing the membrane plays a role in the organization of the circulation of the fluids, not only by promoting an alternation between liquid flow and gaseous flow in the central channel of the tip, but also by guiding the fluids on their return path as shown by the arrows in FIG. 4. The arrows f1 show that the non-expelled remaining liquid that is returned first is diverted from a direct axial path and oriented towards the hydrophilic part of the membrane 22. It is thus prevented from being sprayed onto the central part of the membrane, where it would tend to wet the material of the membrane, which has a hydrophobic character in this area. The flow of aspirated air towards the bottle thereby has free access to the hydrophobic material of the membrane in its central portion 23, as shown by the arrows f2.

(57) Returning now to FIG. 1, together with FIG. 2, it is possible to observer other details of the realization of the head for dispensing liquid from a sterile packaging bottle which, while themselves being standard features of the bottles manufactured industrially by the Applicant, are nonetheless means involved in the implementation of the present invention due to their property of maintaining sterility in the bottle.

(58) In this respect, the presence of external peripheral ribs 15 on the nacelle 4, which ensure sealing against bacteria with the neck of the bottle 10 at the level of the porous insert 8 will be noted. The configuration of the cap 6 will also be noted, which is such that, when it is screwed (at 12) onto the neck of the bottle, it closes the external nozzle of the channel 18. Among other things, its role is to ensure a pressure drop downstream of the membrane that prevents the latter being wetted by the liquid contained in the bottle provided that the tamper-proof ring 26 has not been broken for a first use (first expulsion of a drop of liquid).

(59) Similarly, the shape of the nacelle 8 at its upstream end, inside the bottle, will also be noted. Its utility will become apparent firstly, in embodiments intended for dispensing eye drops with surface-active or viscous physico-chemical features, and in such cases the means shown will advantageously be exploited in combination with more specific embodiments of the invention, namely those providing for a membrane having a relatively coarse porosity leading to lower protection from microorganisms by filtration, while protection by biocidal effect is high. These means reside in the configuration forming arches 13 around a central pad 11 and being arranged in the bottle 2 beyond its neck 10. These have been fully described in patent application WO 2011/095877. They contribute to an organization of the circulation of the fluids that is favourable to the requirements of the present invention in the case of the same liquids.

(60) The test results reported above demonstrate an improvement in microbiological safety throughout the duration and under exposure to significant contaminants, which could not be expected simply from using a membrane loaded with biocidal cations. Nor could they be expected from such a membrane, which would also be partially hydrophilic and hydrophobic, inasmuch as such a membrane could not on its own ensure alternation of the flows of liquid and air which circulate from the bottle to the outside and vice versa.

(61) In the case of the invention, this alternate circulation is ensured by the fact that the partially hydrophilic and partially hydrophobic membrane forming the interface between the inside and the outside of the bottle is combined with a capillary channel for the expulsion of liquid and entry of air situated downstream of the membrane. It is also further ensured by the other means which contribute in a known manner to managing the alternation of the flows under the effects of pressure, and thereby to the regularity and the reproducibility of the masses and volumes conveyed.

(62) Finally, although the fact of applying the membrane loaded with biocidal ions in a conventional bottle by the Applicant is already inventive owing to the role that it is made to play in the transport of the active load on the back flow of the liquid created at each operation of dispensing a dose of liquid, nevertheless it would still not be possible to obtain the results demonstrated without adding the presence of an insert, made porous in order to act as a non-sealing closure stopper of the bottle, and if applicable, regulating the flow by its porous character as is conventionally the case, but which moreover is constituted by a polymeric material with anionic sites in its mass, having the effect of attracting metal cations that carboxylic sites in particular may have.

(63) Differences of behaviour in the ionic transfers can in fact be explained by considering that the membrane is a finely porous component having a relatively large extent across the duct for the circulation of the fluids and having a small thickness, whereas for its part, the insert has a relatively coarse porosity and it is thick, thus having a relatively great length along the circuit for the circulation of the fluids. Also considering that unlike the capillary channel on the downstream side, this insert occupies the neck of the bottle over a relatively extensive cross-section, like the membrane.

(64) Moreover, whereas in the membrane the individual cells of the material are scarcely filled, whether by liquid or air, it will be observed that in the insert the two fluids are present simultaneously within the cells. Therefore, the oxygen in the air can have an effect on the transfers of ionic loads within the cells. The biocidal activity in the destruction of the aerobic bacteria is thus exerted there differently than in the cells of the membrane. In addition, air and liquid come into contact with a large surface area of active material, corresponding with the specific surface of the insert. This makes the use of the cationic loads in the destruction of the bacteria more effective.

(65) Clearly, a similar effect cannot take place at the level of the circuit situated downstream of the membrane since there, the material of the tip is dense and impermeable both to the liquid and to the air. Consequently, even if this material is based on an ionic polymer initially bearing silver ions, these ions must migrate to the surface in order to be active on the fluids. The surface of contact with the fluids at the level of the tip is long, but its perimeter around the section of the capillary channel is small. Moreover, it is alternately in the presence of either air or water, including during the back flow of the remaining aqueous solution that has not been expelled.

(66) The phenomena involving the transfers of the ionic loads between the bi-functional interface membrane and the porous insert capping the bottle are all the more clearly differentiated as the organization of the circulation of the fluids through them is better controlled in order to ensure that the membrane remains dry in its hydrophobic zone and that the back flow of liquid passes through its hydrophilic zone. While the bottle is in storage, before the first use consuming the liquid, the membrane remains dry regardless of the position of the bottle, thanks to an overpressure ensured on the downstream side by the sealed closure of the capillary channel; this overpressure also obtains upstream, so as to keep the membrane isolated from any contact with the porous insert.

(67) In any event, it is a fact that between the two porous bodies, being the membrane and the porous insert, during operation a bed is created, of mobile ions that are removed from the insert by the flow of liquid extracted from the bottle at each dispensing operation, from biocidal ions that have been brought there by a back flow of liquid not dispensed during the preceding liquid dispensing operations. In practice, the biocidal ions thus remain confined to movements from one to the other of the porous bodies. Downstream of the membrane, the expelled liquid is not affected.

(68) Without claiming to fully understand the phenomena that occur on the scale of the molecules and of the ionic loads, it is possible to envisage a mechanism involving the availability of the directly accessible active sites for contact with the fluids at the surface of the polymeric material, given the large specific surface area and of the large pore volume at the level of the insert and given the small thickness of the membrane. The membrane constitutes a primary source that would have been sufficiently loaded with biocidal agent during manufacture to be capable of generously supplying the quantity of ions required in order to satisfy the requirements of each application throughout the lifetime of the bottle until its initial liquid content is exhausted. For its part, during manufacture the insert is crucial as the source of active charged sites additional to that of the biocidal ions. From the time when the bottle has been opened for a first dispensing operation, the insert plugging the bottle enters into operation both in order to protect the sterile inner space and in order to constitute a secondary source of biocidal agent, which keeps in reserve the ions that have been brought there at the end of a dispensing operation (air aspiration phase), until they are taken up during a subsequent dispensing operation. Those which will thus be taken up by the flow of liquid removed from the bottle will be conveyed as far as the membrane and will be retained there, with the exception however of those which will have been consumed on the way by bacteria present in the air.

(69) The high quality of the sterility maintenance noted during the forced contamination tests goes far beyond the specific requirements in the case of bottles for eye drops and other ophthalmic liquids, that it has become customary to store under the protection of membranes filtering out the external microorganisms. Conversely, it shows that the technology of the invention retains its benefit as an alternative to the conventional methods even in this case, whereas generally it will be useful in many applications that do not require, or do not allow, fine bacterial filtration at the level of the membrane. Also, it is easily understood that the invention can be specifically implemented in embodiments suitable for large liquid capacities and long lifetimes in the case of discontinuous use and/or doses and forms of dispensing that are very diverse for the liquid expelled from the channel for alternate circulation of the fluids, by simple dimensional adaptations of the essential constituent elements of the device according to the invention.