TW201811290A - Sterile liquid dispenser - Google Patents

Abstract

Dispenser of acqueous liquids through an interface membrane that is partly hydrophilic and partly hydrophobic, such that during each liquid-dose dispensing operaiton, air and liquid circulate alternatively in a capillary tube (18) downstream of the membrane. Said interface membrane (7) comprises a filtering material which incorporates biocide metal cations into its mass. Said dispenser comprises a porous plug (8) permeable to both liquid and air, which is placed upstream of the membrane along the fluid path and is made of a material comprising negative charge sites that can attract biocide metal cations from said membrane.

Description

Sterile liquid dispenser

The present invention relates to a liquid dispenser for conditioning a bottle of a product that must remain sterile (not only before the bottle is initially opened, but until the contents have been consumed and no product remains in the bottle).

A typical example of the present invention which is intended to meet the needs is to accommodate an aqueous solution that is discontinuously dispensed at a dose that is dispersed over a period of time, and is equipped with an air/liquid that uses the principle of filtration to prevent microbial contaminants from being transferred from the ambient air into the bottle. Multi-dose bottle for interface film.

Films of this type which are selectively permeable in two respects are also known. It preferentially allows the air or liquid to alternately pass in the downstream direction during the discharge of the liquid dose out of the bottle during the pressure difference applied to both sides thereof and to force the air back into the bottle to compensate for the volume of the dispensed liquid. Passing in the upstream direction during the suction phase. Applicants' prior patents describe how such films, which are referred to as bifunctional membranes (which are bifunctional from the point of liquid flow or gas flow transport), are used to ensure that liquids and air are placed in the continuation of the membrane and The capillary is designed to circulate alternately with the discharge of liquid. The film forming an interface between the closed volumes of the sterile bottles of the aqueous liquid (in particular, the aqueous solution of the pharmacologically active ingredient) is partially made of a hydrophilic material in the first area portion of the total interfacial surface area, and is the same The second portion of the total surface area is partially made of a hydrophobic material. In French Patent Application No. FR 2872137 (corresponding to International Application WO) In 2006/000897), such a film is described for a film that is placed across a single pipe to permit air and liquid to flow in either direction between the inside and the outside of the elastically deformable bottle that is squeezed to alternately discharge and pump. The principle of processing.

In this context, the present invention is directed to a liquid dispenser having microbial protection that has a high level of safety with respect to both microbial sterility and chemical toxicity in the application of sterile liquid dispenser bottles, over a period of time. Sterility must always be maintained in the sterile liquid dispenser bottles during the continuous dispensing operation within the consumption of the contents of the bottle. One of the primary objectives of the present invention is to achieve long gradual consumption periods, while another primary goal is to allow for multi-dose bottling of pharmaceutical or parapharmaceutical products in highly contaminated areas.

In view of these objectives, the present invention contemplates the use of a bifunctional hydrophilic/hydrophobic film that incorporates a biocide into its mass by means of ion oxidation. In particular, by ingesting macromolecules that combine positively charged metal ions (such as mineral polymers in the form of zeolites derived from the aluminosilicate family, which are well known in the prior art), contain unstable metals. The cations are used to introduce the agent. Silver ions (Ag+ or Ag++) are one of the most useful ions in the industrial production of antibacterial films embodied in accordance with the present invention.

In the liquid dispenser according to the present invention, the film is used as a permanent source of biocidal metal ions combined with a porous substance inserted upstream of the fluid path of the film, the substance being designed to retain biocidal ions, and the biocide is The substance is reached after extraction from the membrane during each pumping phase of dispensing the liquid dose, thus forming a secondary retention of active ions while providing a buffer for the delivery of the plasma to prevent the plasma from reaching the liquid receiving area inside the bottle. In practice, it has been observed that when not consumed on site, the retained ions are therefore in the row of subsequent dispensing operations. It is easy to be released during the out-of-stage period and carried back to the film.

Water/air interface films containing biocidal metal cations have been known for a long time, as exemplified in U.S. Patent No. 5,681,468, the entire disclosure of which is incorporated herein. However, it has never been suggested that the biocide can act in other ways than by attacking contaminated bacteria that emanate the liquid as it is located downstream of the film after it has passed through the film. It is also not proposed as provided in accordance with the present invention (i.e., in combination with a porous material that retains the same active ions as the active ions contained in the film and has a means for flowing fluid therethrough, thus ensuring alternating flow through The film is mounted through a film and through a dispenser in the downstream portion of the dispenser.

In a practical embodiment of the invention, the porous material is designed to be in the form of a plug mounted in the liquid distributor upstream of the membrane to provide a non-hermetic closure of the interconnecting conduit between the interior and exterior of the bottle. . Due to the porosity and position of the plug, the plug is advantageously designed to function as a flow conditioning buffer, which is known from the applicant's prior patents (based on its production along the bottle) The pressure drop of the liquid path).

However, in order for the plug to function as a sterility barrier to contaminants in a protective liquid as described in the present invention, it consists exclusively of a polymer having a negatively charged and thus capable of attracting the active site of the biocidal metal cation originally absorbed by the film. Made of materials. In view of this point of view, a preferred material is a polyolefin-based polymer copolymerized with a carboxylic acid compound. Depending on the relative proportions of the ingredients and the conditions under which the copolymerization is carried out, the polymer obtained still contains a substantial proportion of free carboxylic acid sites to be combined with the cationically contacting cations used as biocidal cations.

In accordance with a preferred embodiment of the present invention, the specific capacity of the polymeric material to retain metal cations can be increased by subjecting the polymer to radiation treatment intended to release other carboxyl groups.

The manner in which the dispenser according to the invention acts as a whole will be described below It is stated in the context of a sterile eye care solution dispenser bottle equipped with a flexible, elastically deformable wall for compressing the volume of the inner container. However, it should be understood that other means can be similarly ensured that there are two stages of pressure change at each liquid dose dispensing operation: first, the stage in which the liquid is pushed from the inside of the bottle by the capillary located upstream of the membrane and discharged to the outside. And, second, the stage in which the outside air is drawn into the bottle after the recirculation has not occurred. One example is a bottle with an axially acting bottom opposite the resilient return member or a bottle equipped with a pump system. Preferably, the dispenser will be a droplet dispenser, but it should be understood that the dispenser according to the present invention can be adapted to dispense individual doses larger than the droplets, and is suitable for other types of liquid dispensing capillary outlets, such as nozzles or fines. Droplet dispenser.

Initially, throughout the storage period prior to the first use of the bottle, the bottle remains hermetically sealed due to the sterile air blanket between the airtight closure and the liquid receiving area, leaving the film dry. It will only become wet by the liquid in the hydrophilic portion during the initial discharge of the liquid after the bottle has been opened.

The downstream portion of the dispenser includes a capillary in which liquid and gas alternately flow without mixing such that during dispensing, when the tube has completed directing fluid flow for outward discharge, the tube is temporarily occupied without discharge The remaining amount of liquid is retained. When the pressure difference between the two sides of the film stops affecting the direction of discharge, the air drawn from the outside causes the remaining liquid to flow back through the film. During the pumping phase, the reflux liquid passes through the hydrophilic portion of the membrane and enters the vessel to compensate for the passage of air through the hydrophobic portion of the volume of the dispensed liquid.

The region inside the dispenser according to the invention upstream of the membrane forms a conduit which, unlike the capillary tube, has a large cross section. The porous plug is placed inside the pipe, the polymer supply of the porous plug will react with the biocidal metal cation carried by the liquid and in particular free A negative charge that produces an ionic chemical bond in the active site in the form of a carboxyl group. Here, in the case where the porous plug is present in both the liquid phase and the gas phase, the liquid phase and the gas phase are in contact with the cells of the porous material of the polymer contained therein. This contact occurs over a large surface area that corresponds to the specific surface area of the porous material. When the dispenser is discharging liquid, the porous plug sufficiently retains biocidal metal cations to prevent chemical contamination of the remaining liquid in the bottle by biocidal cations. In addition, according to a process which contributes to the high biocidal activity in the liquid dispenser while protecting the remaining liquid from microbial contamination, it ensures that the biocidal cation grows with the liquid (specifically, between the membrane and the porous plug) Come and go.

Surprisingly, the inventors have shown that the dispenser according to the invention maintains high biocidal activity throughout its use as a discontinuous liquid dispenser. As will be explained in further detail, it has been shown that the dispenser according to the present invention, which is tightly mounted to provide closure of a vial to be used as a multi-dose liquid dispenser containing, for example, a sterile eye drop, is used throughout the life of the eye drop. It is efficient in terms of sterility. It is thus possible to safely use the eye drops in a much longer period of time than in the case of the current bottle without posing any danger to the patient.

Compensating for the entry of air through the effluent liquid and from the ambient air containing the microorganisms due to the contact biocidal action of the biocide in the pores of the hydrophobic portion of the membrane and, if necessary, by the filtration of the bacteria through the membrane Most of the time is sterilized. In addition, as needed, the biocide cations transported by the reflux of the remaining undischarged liquid remain in the plug at the end of each liquid dispensing operation, so there is always a usable de-stagnation in the plug and the remainder An active biocide of microorganisms in the air in some combination of liquids.

Further described tests confirm that the biocidal cations are gradually collected in the porous plug from the end closest to the membrane (referred to as the proximal end) towards the phase closest to the liquid remaining in the bottle. The opposite end (called the distal end) is gradually reduced so that the liquid does not contain any biocidal cations.

Additionally, after the first use of the liquid dispenser, the porous plug that absorbs the biocidal cation subsequently becomes the source of the cations, which may be partially from the liquid phase as the cation exits the interior of the bottle through the plug to bond the available sites on the film. extract.

The growth of the biocidal cation is thus produced in the fluid circulation conduit, and the growth of the biocidal cation is related to the growth of the liquid, which keeps a relatively stable amount of the biocidal cation during use to be used in the dispenser according to the invention to eliminate it Contact with microorganisms.

The principle of the invention thus appears to be on the one hand to produce a bifunctional water/air interface film and on the other hand to produce a non-hermetic plug such that during use, after the bottle has been opened for the first time to dispense the liquid, the film and the plug cooperate to The mobile ion bed is generated by the ions transported by the backflow of the undischarged liquid during the previous liquid dispensing operation (ie, during the intake phase), which are acted upon during each dispensing operation (ie, During the liquid discharge phase, the liquid stream extracted from the bottle is taken out of the plug.

Overall, it can be considered that the amount of biocidal metal ions that are effectively consumed during the eradication of biological contaminants is extremely small compared to the amount of ions displaced during each liquid dispensing operation, and the amount of ions displaced during each liquid dispensing operation. It is extremely small compared to the initial capacity of the film. The amount consumed depends on the degree of contamination of the ambient air being pumped. The greater the surface area in contact with the ion-charged material, the more efficient the air treatment will be. The amount of displacement depends on the flow rate of the liquid carrying the active cationic charge, or more precisely on the quality of the liquid displaced whenever there is a liquid return from the film to the plug and whenever there is a direct discharge of the liquid towards the film.

Based on these considerations, it is assumed that the constituent materials of the film and the porous plug remain unchanged, and the liquid dispenser according to the present invention is changed by varying the respective shapes and sizes of the film and the porous plug. It can be adapted to a variety of polluted environments, even under the harsh conditions of the total volume of the solution to be dispensed, the total period of use of the bottle, and the frequency with which the dispensing operation is repeated.

With regard to the film itself, the present invention advantageously provides that it should be made of a porous hydrophilic polymeric material that is uniformly supported by an ion-oxidizing biocide, the film being entirely made of the material, wherein one of the films partially spans the bottle The fluid circulation conduit between the interior and the exterior extends and a portion of the membrane exhibits regional hydrophobicity by an additional polymerization treatment that maintains its biocidal activity.

This provides a suitable volume to establish contact between the gas phase comprising air and the bioactive ion-filled polymeric material within the porous material across the entire thickness of the film. Likewise, the material of the hydrophilic substrate of the film is made finely uniform, and the material does not include the prior embodiment of a membrane filter made of a fiber-based material that retains charged particles between the fibers. According to the present invention, it is preferred to start with a polymer melt comprising a fusible particle of a masterbatch having an inorganic macromolecule containing a biocidal active ion.

Although conventionally, the filtration of bacteria requires no more than 0.2 μm of fine porosity, the presence of biocides in the film enables the presence of greater porosity (preferably about 0.3 μm or 0.4 μm, or more generally Maintaining a satisfactory level of sterility up to 0.5 μm, 0.6 μm or 0.8 μm or even 1 μm) is advantageous in terms of pressure drop and permits handling of viscous liquids. In practice, a preferred embodiment of the invention thus provides that the film should be manufactured such that it has an average pore size corresponding to filtration of microorganisms having a particle size greater than 0.3 μm to 1 μm and in detail between 0.3 microns and 0.6 microns. . After considering all of the cases, the film porosity can thus be adjusted to any value between 0.1 microns and 1 micron depending on the physicochemical properties of the liquid.

As indicated, macromolecules containing biocidal ions are advantageously And, more particularly, in a known manner and having an aluminosilicate type of metal ions (such as silver ions or similar metals in ionic form) bonded to the free portion of the polyoxyalkylene chain by means of polar covalent bonds Inorganic polymer. These inorganic polymers are preferably crystalline polymers. Although the concentration of the reactive ions in the film does not limit the conditions of application of the present invention, the concentration is preferably selected between 100 ppm and 100000 ppm, for example, from 0.2 micron to the silver ion containing over a useful area of about 3 square centimeters. The case of a film made of a 0.3 μm porosity aluminosilicate-based inorganic polymer.

Metal ions useful in the present invention also include copper and zinc ions, but silver ions have proven to be most advantageous within the industrial framework of the antimicrobial protection dispensers embodied in accordance with the present invention.

A second feature of the invention extends beyond the dispenser according to the invention to a sterile vial having the dispenser for the aseptic bottling of pharmaceutical and pharmaceutical products, in particular.

The invention also encompasses specific methods of making the film itself.

Advantageously, the dispenser designed to organize the fluid circulation completes the dispenser mounted on the dispenser bottle. Preferentially, the dispenser bottle has a reversibly elastically deformable wall to ensure that external air returns to compensate for the liquid dose discharged from the bottle and any remaining undischarged liquid is recirculated through the dispenser, the membrane together with the porous plug and tissue air And a liquid flow is mounted in the liquid dispenser in association with the member of the dispenser, and wherein the film is placed at the base of the dropper comprising the drop discharge capillary, with the base of the dropper (provided there The member is preferably placed on the film to direct any air entering the air and causing any remaining undischarged liquid from the downstream portion to flow back through the film to the upstream portion. Centrally distributed with liquid over the hydrophilic portion of the film.

Description of one embodiment of a dispenser bottle

By way of a non-exhaustive example, reference will be made to the use of the sterile liquid dispenser of the present invention in the maintenance of sterility in a dropper bottle as illustrated in Figures 1 to 4, which will now be in accordance with preferred features and advantages of the present invention. The invention is described more fully in the drawings: - Figure 1 is a longitudinal portion and an exploded view of different components of a bottle having a deformable wall that can be discharged in a continuous dose via a microbiologically protected dispenser according to the present invention; - the longitudinal portion of Figure 2 shows more particularly the dispenser after assembling a particular component of the dispenser to form a combined liquid dispensing head and after the outer air inlet is inserted into the neck; - Figure 3 illustrates the relationship with Figures 1 and 2 Illustrate the configuration of the surface of the dispenser basket opposite the nozzle base; - Figure 4 illustrates, in partial exploded view, the circulation of fluid back to the circulation conduit of the dispenser according to the present invention as represented in Figures 1 and 2.

Depending on the general configuration and all of the components illustrated in Figure 1, the bottle equipped with the dispensing head will appear to correspond to the conventional design of a sterile dispenser bottle. The bottle has a container 2 for storing an aqueous liquid to be dispensed in a sterile state, and an upper portion of the container 2 is fitted with a dispenser which is hermetically mounted in the bottle neck 10. However, certain features of the present invention are different, and such particular features relate to the full length of the circulation conduit for containing the aqueous liquid to be dispensed and for compensating the incoming air of the discharged liquid under the protection of the microorganisms secured according to the present invention (also That is, the basic components of the liquid are dispensed primarily at the upstream portion of the conduit, in the porous plug 8 that occupies the inner region of the basket 4, at the interface of the upstream and downstream portions of the membrane 7. The effects of fluid circulation assembly and biocidal activity in the pipeline are also different.

According to the present invention, a selectively permeable film constituting a dispenser is used to separate a liquid and air flowing therethrough to form a microbial protective film by filtration and by means of a component material thereof (including inorganic macromolecules containing biocidal cations), To remove bacteria or similar microorganisms that are transported through the fluid flowing therethrough.

In an example selected to best illustrate the invention, the film has an organic polymer substrate and, in the case of the present invention, more precisely a polyester resin substrate modified with a polydecylamine or polyether oxime resin, wherein The macromolecule supporting the biocidal cation (and more specifically herein a zeolite having a silver cationic charge) has been incorporated into its mass. The film is substantially hydrophilic and is made hydrophobic only over a portion of its surface area spanning the conduit formed inside the dispenser. For example, regional radiation is performed by ultraviolet radiation, which modifies the in situ structure of the polymer by a free radical crosslinking reaction between the polymer components while maintaining the biocidal cation properties of the zeolite.

The film illustrated in Figure 4 thus has a hydrophilic portion 22 and a hydrophobic portion 23, the aqueous liquid preferably passing through the hydrophilic portion 22 in the presence of air, preferably in the presence of water or an aqueous liquid. Part 23. Here, the biocidal charge is also present in both the hydrophobic portion and the hydrophilic portion.

During a continuous liquid dose dispensing operation that is dispersed over a period of time, the structure of the membrane structure in combination with the fluid circulation through the membrane structure tends to stimulate the interior of the hydrophobic material by contact between the air and the ionic polymer at the pore surface. The removal of microorganisms in the gas stream, on the contrary, in the hydrophilic portion of the membrane, the biocidal ions are not consumed, but are taken up by the liquid passing through the membrane and carried forward.

Film 7 on the inside of the fluid circulation pipe, on the side of the closed inner region of the bottle Upstream, there is a porous plug 8, which, according to the invention, functions primarily to retain the biocidal cations brought about by each reflux of the aqueous liquid comprising the liquid dose previously removed from the bottle without discharging the remainder, and The new liquid dose is returned from the bottle to return the biocidal cations contained therein to the film.

In a classic example of an ophthalmic application, the length of the porous plug along the axis of the bottle is 9 mm and its diameter is 9.6 mm. More generally, and for informational purposes, the plug can be from 5 mm to 15 mm in length. The size of the plug is adapted to the size of the container.

The distance of the plug from the upstream surface of the film is of the same order of magnitude. Its porosity corresponds to an air flow rate of 3000 ml/min measured according to the water flow rate method, which consists in using a timer to measure the time taken to fill the volume. The density of the plug is about 0.50 g.cm3 depending on the example.

More generally, the porosity of the plug having a large number of voids preferably has an air flow rate of from 1000 ml/min to 4000 ml/min measured using a water flow rate method. The density of the plug is preferably between 0.20 g.cm3 and 0.80 g.cm3.

Porous plug acidity test

A porous plug designed for use in a bottle containing an eye care solution according to the examples employed herein is made from extruded polyethylene polymer filaments that have been compressed. In the case where ethylene has been copolymerized with a carboxylic acid compound, the polymer initially comprises a carboxyl group which here comprises, for example, a higher homologue of a carboxylic acid in a ratio of up to 25% (having a C4-C10 hydrocarbon chain) .

At this stage, the polymer already has a free carboxylic acid moiety due to the polymerization reaction. This explains the test results given further, which results in an effect on the cation that can be correlated to the acidity measured in the plug.

The proportion of free carboxylic acid sites can be increased by exposing the product to radiation capable of decomposing the polymer molecules. Beta and gamma rays can be used for this purpose.

For example, in the presence of air, the pressed plug is subjected to radiation by gamma rays (Cobalt 60 source, 25 kGy). In particular, free radicals formed in the polymer during irradiation react with air to form carboxylate anion groups.

The percentage of carboxylic acid sites before and after irradiation was determined by acid metric according to the European Pharmacopoeia 8.6 for the acidity and alkalinity test principle of polyolefins. These measurements were made in comparison to purified water by water heated without a radiant plug and by water heated by a radiant plug.

The results obtained are given in Table 1 below.

A decrease in pH and an equivalent increase in volume (Vh) as the coloring indicator changes indicate a large amount of acidic sites in the radiation plug, thereby forming a copolymer plug with a monomer having a functional carboxylic acid group that has not been irradiated. Substantially increased compared to the acidic site.

When the remaining liquid reaches the liquid receiving area inside the bottle, it is sterile and does not contain biocidal cations. Proof by the following test.

Safety testing for maintaining sterile liquids

The test has been carried out at different times during the use of the bottle (corresponding to the volume of the solution extracted from the bottle by intermittent discharge of the droplets) to determine the first bottle containing the solution A and the second bottle containing the solution B. The amount of silver ions found in the closed portion upstream of the film and in the solution remaining in the bottle, Solution A and Solution B are described below, wherein the closed portion corresponds to the longitudinal The plug is cut into three equal portions corresponding to the proximal end portion of the plug, the central portion of the plug, and the distal end portion of the plug.

In these tests, two known aqueous solutions for use as eye drops were tested: physiological saline solution A, which has sodium chloride as an active ingredient in an aqueous medium, which is commonly used to treat dry eyes and eye care. Solution B, which has timolol maleate as an active ingredient in an aqueous medium, is generally used for the treatment of glaucoma.

The results are presented in Table 2 below for Solution A and Table 3 below for Solution B.

The results of Tables 2 and 3 show that silver ions remain in the plug as expected, and the amount of silver ions remaining in the plug decreases from the proximal portion and toward the distal portion of the plug, while remaining in the liquid in the bottle. The amount of silver ions is less than the detection threshold (0.001 ppm).

The liquid remaining in the bottle is thus protected from chemical contamination of the biocide.

At the first use, the amount of silver cations remaining in the plug is extremely high, but tends to decrease during long-term use of the bottle, but not abruptly drop, this shows biocide ion exchange It occurs upstream of the film between the film which is the main source of the cation and the plug which is the storage area of the biocidal cation introduced by the reflux of the liquid. The plug then becomes a second source of biocide cations which are then used when the liquid is taken to the film.

Forced pollution test

Compared to a dispenser D3 made of irradiated polyethylene similar to dispenser D1 but having an antimicrobial film made of the same basic polymeric material as the dispenser of the present invention but not containing any biocide, Both the distributor D1 having the radiation plug as described with reference to the figures and the distributor D2 identical to D1 except for the radiation of the plug are subjected to a so-called forced antimicrobial effectiveness test and resistance against the dispenser over a period of time. Tests related to microbial effectiveness.

The forced biofouling test involves simulating the use of the bottle by discharging the droplets followed by inoculating the contaminating bacteria with a large given amount, and then measuring the amount of the bacteria found in the subsequently discharged solution droplets. The test results in Table 4 and Table 5 below were determined according to the following agreement. After opening the bottle containing the sterile solution by discharging four drops of the solution, a large amount of contaminating bacteria (here, 10 ⁵ (100,000) bacteria) was inoculated into the pores of the nozzle of the bottle. The amount of pathogen present in the droplets discharged 6 hours after the initial inoculation (time T6) was then determined. The next day, that is, 24 hours after the bottle has been opened, three times a day (once in the morning, once at noon, and once in the night), the solution is extracted from the bottle, and then 10 ⁵ bacteria are inoculated in the nozzle of the bottle. The routine use of simulated eye drops. The solution drops were taken 24 hours after the last inoculation (time T24), and the amount of pathogens present in the droplets was determined.

At the same time, a similar bottle was subjected to a forced contamination test by first extracting a solution droplet of a volume corresponding to a three month amount of a given solution. The forced contamination protocol described above was then applied by inoculating 10 ⁵ bacteria in the wells of the nozzle, and the solution drops were analyzed at 6 hours later (at time T6). The procedure was continued the next day by successively inoculation after three droplets were taken during the course of the day. The amount of pathogen present in the droplets extracted 24 hours after the last inoculation (time T24) was then determined.

The bottles were tested by the physiological saline solution A and the eye care solution B previously described for the examples in Tables 2 and 3.

In these tests, two contaminating aerobic bacterial strains were used: strain P of Pseudomonas aeruginosa and strain E of E. coli .

The results are presented in Tables 4 and 5 below:

The results of Tables 4 and 5 show that the dispenser according to the present invention maintains liquid sterility prior to opening, and then is highly effective in sterilizing the interior of the bottle during long-term use in dosages dispersed over a period of time.

By exceeding the normal condition of the use of the eye drop bottle, the results given herein have the advantage that it exhibits the microbiological quality of the liquid dispensed via the dispenser according to the invention even when artificially causing exceptionally harsh contamination. accept. Thus, the same dispenser as the present invention can be used in applications involving a much more serious risk of contamination, such as products to be sprayed onto wounds or burns, atopic skin in cosmetic surgery, and the like. Thus, thanks to the present invention, such products can be bottled in multi-dose containers. In addition, it is apparent that such results cannot be expected by previously known systems.

Test by viscous liquid

Here, the forced contamination test is adapted to be much larger by using an average pore size of 0.2 μm (for example, an average pore diameter of 0.8 μm is selected here, which is larger than the 0.2 μm porosity generally allowed to achieve good bacterial filtration effectiveness). More than a film to match the viscous solution.

The dispenser according to the present invention having a film having an average pore diameter of 0.80 μm was tested using a viscous solution V as compared with a dispenser according to the present invention equipped with a film having an average pore diameter of 0.22 μm using a low viscosity solution T.

Both solutions contain different amounts of hyaluronic acid dissolved in a buffered aqueous solution having a pH of about 7. For a 100 mL total volume aqueous solution, the viscous solution V contained 0.30 g hyaluronic acid and had a viscosity of 60 mPa.s, while the low viscosity solution T contained only 0.15 g hyaluronic acid and had a viscosity of 3 mPa.s.

For the immediate use of the bottle and the simulated use within 3 months, the forced contamination test was carried out using the same protocol as described above and by the same two contaminating bacteria strains. The results obtained are given in Table 6 below.

These tests show that the dispenser according to the invention has low efficiency in bacterial filtration. Many, but with a high biocidal effectiveness to maintain the sterility of the liquid in the bottle over a period of time.

The above test was carried out using a bottle equipped with a liquid dispensing head, wherein the initial concentration of silver cations in the film according to the present invention was about several thousand ppm. Naturally, these are examples, which can be adapted by modifying the numbers according to the actual conditions encountered in each case of the application of the invention.

Continued description of each figure

According to a particular embodiment of the invention, the capillary is formed by hollowing out a nozzle made of a biocide-containing material, which is also provided here by a zeolite ion exchange medium. Capillary 18 is thus formed in a dense polymer nozzle that is impermeable to liquid and air fluids and contains silver biocides that are capable of migrating from mass toward the surface. For example, the nozzle can be made of a polyethylene containing a biocide, and more particularly a zeolite supported by a silver cation.

The dispenser head which thus contains the biocide and the material comprising the basket does not contain a biocide is well described in the applicant's prior patent application WO 2010/013131, and no further description is necessary here.

In order to complete the description of the liquid dispenser when applied to a bottle, referring to Figures 3 and 4, it will be noted that in the widest portion of the fluid circulation conduit formed by the ring of the basket 4 upstream of the membrane, the freedom of the membrane The surface is unobstructed. However, the support fins 16, 17 are formed within the basket To limit any stress that may be applied to the periphery of the film during operation, wherein the film is adhesively secured to the peripheral crown around the base of the nozzle equipped with the liquid dispensing capillary, but the supporting fins allow the film to freely self-use from the nozzle The base 3 is convex outward.

Opposite the hydrophilic outer side of the film, the substrate 3 of the nozzle 5 forms a support surface for the film at the liquid dispensing stage, which engages the wall of the capillary 18 at the bell-shaped opening 28 of the capillary 18.

Around the orifice, the free surface of the nozzle has radial grooves that provide a large passageway for the passage of liquid near the outer membrane of the bottle. The radially disposed grooves 31 are designed to collect the liquid remaining in the bottle by directing it toward the orifice of the capillary 18 after it has passed through the hydrophilic portion of the film, but it is also designed to The gas is used to compensate for the remaining undischarged liquid being sucked back into the bottle during the discharge of the liquid, by releasing the central hydrophobic portion 23 to leave room for the incoming air and directing the remaining undischarged liquid to the hydrophilic under the thrust of the air. Sexual part 22.

In addition, the surface of the substrate 3 has corrugations that finely divide any air flow at the orifices of the capillary that begin at the nozzle, thereby reducing the velocity of air through the film as it is pushed away from the lateral surface of the substrate of the nozzle.

In a preferred embodiment of the nozzle thus produced according to the invention, in particular in the case of a dropper nozzle, the corrugations dividing the air flow are present in the form of shallow, relatively narrow grooves 32 having a small cross section, the grooves Each of 32 is annular and is disposed concentrically with respect to each other about a central capillary of the nozzle. The grooves 32 are formed in the surface of the nozzle base in portions of the substrate maintained by the liquid guiding grooves 31, wherein the surface of the nozzle substrate is actually designed to be pressed by the internal pressure of the compressed bottle Pressurization provides support for the film as it exits the liquid.

It will be understood that during use, the particular configuration of the surface of the nozzle opposite the membrane not only by facilitating the alternation between the liquid flow and the gas flow in the central capillary of the nozzle, but also by the arrows as shown by Figure 4 The fluid is directed over the return path to function in the guiding fluid cycle. The arrow f1 shows that the remaining undischarged liquid, which is first sucked back into the bottle, is offset from the direct axial path and directed to the hydrophilic portion 22 of the film. This prevents liquid from being projected onto the central portion of the film where the liquid wets the film material where the film material is hydrophobic. Thus, the air drawn back into the bottle is free to enter the hydrophobic material in the central portion 23 of the film, as shown by arrow f2.

If we now return to Figure 1 which is refined from Figure 2, additional details of the embodiment of the liquid dispensing head external to the sterile bottle can be observed. Although it is a standard bottle manufactured by the applicant's industry, it is still an embodiment of the invention due to the quality of the sterility maintained inside the bottle.

In this regard, it should be noted that there is an outer peripheral lug 15 on the basket 4 that allows the neck 10 to be opaque to the bacteria at the plug 8. It should also be noted that the cover 6 is configured such that it seals the outer aperture of the tube 18 as it is screwed (12) onto the bottle. The cover 6 is especially designed to ensure a pressure drop downstream of the film which prevents it from being wetted by the liquid contained in the bottle, as long as the protective guard ring 26 has not yet broken when the bottle is first used (first discharge of the liquid droplet).

For the same reason, attention should also be paid to the shape of the upstream end of the basket 8 inside the bottle. Its utility will first be seen in embodiments designed to dispense eye drops with surfactants or viscous physico-chemical properties. In such cases, the illustrated components will advantageously be used in combination with a more specific embodiment of the invention, i.e., providing a film having a relatively large porosity (resulting in a lower quality of protection by microbial filtration). Embodiment, this is due to the fact that it is according to the invention Higher biocidal protection is also needed. The components are in a configuration comprising an arch 13 surrounding a central disc 11 placed in the bottle 2 above the bottle neck 10. These are well described in the patent application WO 2011/095877. In the case of such identical liquids, the members promote fluid circulation organization corresponding to the needs of the present invention.

The test results given above indicate that in the long run and better microbiological safety during exposure to severe contamination, this safety cannot be expected from the simple use of a film containing biocidal cations. In the case where the film alone cannot ensure that the liquid and air flow from the bottle toward the outside and vice versa, it is not possible to expect such results from a partially hydrophilic and partially hydrophobic film.

In the case of the present invention, the alternating cycle is ensured by a combination of a partially hydrophilic and partially hydrophobic film providing an interface between the interior and exterior of the bottle and a drain and intake tube located upstream of the film. This alternating cycle is additionally ensured by other means that promote the control of the alternating flow of liquid and air under the influence of pressure and thus promote the regularity and reproducibility of the delivered mass and volume in a known manner.

Finally, even if the biocide film is applied to the applicant's standard bottle due to the effect of the transport active load imparting liquid reflux during each liquid dose dispensing operation, it is still an inventive step, but it is still impossible The results presented herein are obtained without the additional porous plug designed to provide a non-hermetic closure of the bottle, and it is not possible to adjust the flow as a natural consequence of its porous properties, where applicable, and the porous plug is also It is made of a polymer material that attracts an anion site (usually a carboxylic acid moiety) of a metal cation.

The difference in behavior in ion transfer can actually be explained by considering the fact that the film has a relatively large surface area across the fluid circulation pipe and a small thickness. The hole portion, while the plug has a relatively large porosity and a large thickness, and thus is relatively long relative to the fluid circulation loop. It can also be explained by taking into account the fact that, unlike the capillary on the downstream side, the plug (similar to the membrane) occupies a relatively large cross section of the bottle neck.

In addition, although individual cells of the film material are filled with little liquid or air, it can be observed that in the plug, both fluids are present in the chamber at the same time. In this case, oxygen in the air may affect the transfer of ionic charge in the chamber. Aerobic bacteria eliminate biocidal activity and therefore appear elsewhere rather than in the membrane chamber. Additionally, the air and liquid are in contact with a large surface area of the active material, which surface area corresponds to the specific surface area of the plug. The use of cationic charges to destroy bacteria is therefore even more effective.

Also, it is apparent that similar effects cannot exist in the loop downstream of the film because the nozzle material is dense and impermeable to both liquid and air. Thus, even if the material is an ionic polymer that initially contains silver ions, the plasma must also migrate to the surface to interact with the fluid. The surface of the nozzle that is in contact with the fluid is longer but has a smaller circumference around the capillary. In addition, the presence of air or water alternates, including during the reflow of the remaining undischarged aqueous solution.

The difference in the phenomena involved in the transfer of ionic charge between the bifunctional interface membrane and the porous plug of the closed vial is preferably controlled in the tissue circulating through the membrane to ensure that the hydrophobic portion of the membrane remains dry and the liquid is refluxed. Its hydrophilic part is even more pronounced. As long as the bottle is in storage and the film is allowed to dry before the first dispensing of the liquid, regardless of the position of the bottle, this is due to the excess pressure exerted on the downstream side by the hermetic closure of the capillary; such excess pressure is also present in On the upstream side, the membrane remains isolated from contact with the plug.

Regardless of the situation, during operation, the two porous sheets in the membrane and the porous plug Between the bodies, a mobile ion bed is generated which is derived from the biocidal ions introduced into the plug by the reflux of the liquid which was not discharged during the previous liquid dispensing operation, and the liquid stream extracted from the bottle at each dispensing operation is taken out of the plug. In practice, biocidal ions are therefore limited by the displacement from one porous body to another. Downstream of the film, there is no change in the discharged liquid.

Without requiring an exact understanding of what happens to the molecular and ionic charges, it is conceivable that in view of the large specific surface area of the plug and the large void volume and the thinness of the film, there is a direct access to the polymer material. The mechanism of the availability of active sites in contact with the fluid on the surface. The film is the primary source of sufficient biocide during manufacture so that it can supply the amount of ions needed to meet the needs of each application throughout the life of the bottle, i.e., until the initial liquid has no residue. On the other hand, plugging is a key component in the process of producing a dispenser due to its role as an additional source of active sites with ionic charges complementary to biocidal ions. After the bottle has been opened for the first dispensing operation, the stopper of the closed bottle begins to protect the internal sterile field and provides a second source of biocide that is stored at the end of the dispensing operation (air pumping phase) Until it is sucked in subsequent allocation operations. Thus, the ions drawn by the liquid from the bottle will be delivered to the membrane and remain there, except for the ions that are consumed by the bacteria present in the air as they pass through.

The high sterility quality observed during the mandatory contamination test is therefore maintained far beyond the specific needs of eye drops and other eye care liquid bottles that are typically protected by membrane filters designed to prevent microbial entry. It is shown that the technique of the present invention is an effective alternative to standard methods even in the present case, and more generally, it will be applicable to a wide variety of applications that do not require or permit fine bacterial filtration through a film. It is also conceivable that the present invention may comprise a suitable amount of liquid and by simple size adjustment of the basic component parts of the dispenser according to the invention. Embodiments of a highly diverse manner of long term discontinuous use and/or dosage and liquid dispensed from an alternate fluid circulation conduit.

Claims (17)

A dispenser for dispensing an aqueous liquid at a dose dispersed over a period of time, the aqueous liquid being dispensed from a closed upstream liquid receiving region to an open downstream region by means of a capillary tube, the capillary entering the ambient air, partially hydrophilic One of the partially hydrophobic interface films, such that during each liquid dose dispensing operation, air and liquid alternately circulate in the capillary, thereby producing a recirculation of one of the remaining undischarged liquid, characterized in that the interface film contains will kill The biometal cation is incorporated into one of the masses of the filter material, and the dispenser comprises a porous plug permeable to both liquid and air, the porous plug being placed upstream of the film along the fluid path, And made of a material comprising a negatively charged portion that attracts biocidal metal cations from the films. The dispenser of claim 1, wherein the biocidal metal cation comprises a silver cation. A dispenser according to any of the preceding claims, characterized in that the biocidal metal cations in the film are supported by inorganic macromolecules of the zeolite type incorporated into the mass of the base film material. A dispenser according to any one of the preceding claims, characterized in that the negatively charged sites capable of attracting biocidal metal cations are carboxylate anionic groups. A dispenser according to any one of claims 1 to 4, characterized in that the porous plug has a density of from 0.2 g.cm3 to 0.8 g.cm3. A dispenser according to any of the preceding claims, characterized in that the plug has a polyolefin polymer substrate, preferably selected from the group consisting of polyethylene, polypropylene and ethylene or polypropylene with up to 25% carboxylic acid or ester. a copolymer of a higher homologue. A dispenser according to any one of claims 1 to 6 wherein the plug comprises a compressed fibrous material. A dispenser according to any one of the preceding claims, characterized in that the negatively charged sites capable of attracting biocidal metal cations are the result of radiation of the porous plug by beta or gamma rays in the presence of oxygen. A dispenser according to any of the preceding claims, characterized in that the material comprising the film has an average pore size of from 0.1 micron to 1 micron. A dispenser according to claim 9 which is characterized in that the material comprising the film has an average pore diameter of from 0.04 μm to 0.8 μm. A dispenser according to any one of the preceding claims, characterized in that the capillary is formed in a material incorporating one of the biocidal metal cations, in particular supported by inorganic macromolecules. A bottle for containing a sterile aqueous liquid which will be dispensed by a dose dispersed over a period of time by expelling a liquid dose from the bottle and compensating for external air to enter, characterized in that the bottle is equipped with A dispenser for the liquid according to any one of claims 1 to 11, wherein the plug of the dispenser is installed to provide a non-hermetic closure of the interior of the bottle, the closed area thereby Bottle inside. A bottle according to claim 12, which has a reversibly elastically deformable wall to ensure return of external air to compensate for the liquid dose discharged from the bottle and any remaining undischarged liquid to be recirculated through the dispenser, the film Mounted in the liquid dispenser together with the porous plug in association with a member for tissue air and liquid flow through the liquid dispenser, and wherein the film is placed at a base forming a dropper of a droplet discharge capillary And providing a member to direct any incoming air and causing it to flow back to the downstream portion of the fluid circulation conduit The base of the dropper of any remaining undischarged liquid is opposite, the member directing the gas flow toward the hydrophobic portion of the film preferably placed in the center of the film, and in the hydrophilic portion of the film The liquid is distributed on top. A bottle according to claim 12 or 13, wherein the stopper is designed to participate in the organization of the fluid circulation by forming a flow regulator. A dispenser for maintaining a sterile aqueous liquid as defined in any one of claims 1 to 11 or for use in any one of claims 12 to 14 A bottle of a method for producing a film containing a biocidal cation, wherein, during a first step, the film is made of a porous hydrophilic polymer that penetrates all of its mass and has such a The biocidal cation is thereafter rendered hydrophobic by the polymer over the entire thickness of a portion of the film by an additional polymerization treatment that maintains the biocidal activity of the biocide. The method of claim 15, characterized in that the material is shaped by melting the hydrophilic polymer and the fusible particles of the masterbatch containing the biocide-containing inorganic macromolecule. In the film, the shaped material exhibits uniform porosity throughout its mass. The method of any one of claim 15 or claim 16, wherein the initial hydrophilic polymer is made hydrophobic by a radical cross-linking reaction between the components, the free The radical crosslinking reaction is initiated by irradiating the film with an ultraviolet ray region.