ITMI20101048A1 - CONTAINER AND RELATED CLOSURE FOR STERILE AND / OR LOW BACTERIAL PRODUCTS WITHOUT PRESERVATIVES - Google Patents

Description

Container and relative closure for sterile and / or low bacterial load products without preservatives

The present invention relates to a container and relative closure for sterile and / or low bacterial load products without preservatives.

In particular, the present invention relates to a container and relative closure suitable for limiting and / or reducing bacterial growth in a sterile and / or low bacterial load product without preservatives during use.

The present invention also relates to a primary packaging device for the aforesaid products, as well as the use of the aforesaid device to limit and / or reduce bacterial growth in the same products during use. Examples of products that can be stored in the containers of the present invention are pharmaceutical products, cosmetic products, dietetic and food products. These products can come in the form of liquid, gel, suspension, paste, powder or granule.

Microorganisms, present in nature in large quantities and various species, can contaminate products packaged in sterile conditions or with low bacterial load (for example, pharmaceutical products) after the opening of the container by the consumer and can multiply extremely quickly, especially if the environmental conditions are such as to favor their growth and proliferation.

The presence of these microorganisms (for example, bacteria, fungi, yeasts, molds, etc.) negatively affects the hygienic conditions, duration and quality of the packaged product, giving rise to the degradation of the product itself, the proliferation of pathogens and, consequently, to serious risks for the health of the final user of the product.

For these reasons, the packaging of pharmaceutical, cosmetic, dietetic and food products must avoid as much as possible the contamination of the product by microorganisms present in the environment after the first use.

In order to reduce the risks associated with the contamination of products by microorganisms, in the state of the art the formulations of the products of the aforementioned type are generally added with preservative substances, designed to limit or avoid the microbial growth that can develop inside the products themselves. during their use. Suitable preservatives for this purpose are, for example, benzalkonium chloride, sodium thiomersal, chlorhexidine, methylparaben, ethylparaben, propylparaben, phenol, polyhexamethylenebiguanide (PHMB), N-hydroxymethylglycinate, chlorobutanol.

The use of preservatives in the formulations of sterile and / or low bacterial load products, however, is undesirable, as their presence can also affect the health of the consumer in an unpredictable manner, generating unwanted reactions.

In order to avoid the use of preservatives, in the state of the art it has been proposed the use of containers equipped with filters that prevent the passage of microorganisms. When using the product, for example an eye drop, the filters in the container allow the product to go out and, at the same time, prevent the entry of microorganisms inside the container.

This technical solution, while avoiding the contamination of the product inside the container and thus favoring its conservation in optimal conditions, has the disadvantage of not preventing the use of the contaminated product by the user. From the second use onwards, in fact, the product is forced to pass through a filter contaminated by microorganisms, becoming contaminated in turn.

An alternative solution to the addition of preservatives proposed in the state of the art is that described in patent application WO0026100. This document describes the use of a closure for containers intended to contain children's drinks, such as for example a baby bottle, made of a plastic material with the addition of an inorganic antimicrobial agent, such as an antibacterial zeolite.

Containers having closures of the type described in WO0026100 ensure hygienic conditions that are superior to those of containers having conventional closures; however, they are only suitable for containing products that do not require particularly high conditions of sterility or reduced bacterial load (for example, food liquids), which are the conditions required for pharmaceutical or cosmetic products.

It is known, in fact, that the plastics generally used to make food containers have the disadvantage of yielding, at least partially, to the product some of the substances contained therein. Therefore, using a closure in antibacterial material on containers made of conventional plastic does not adequately guarantee the preservation of the product at the desired low bacterial load conditions.

In addition to the specific drawbacks described above, it is relevant that the antibacterial agents described in the state of the art are not always able to guarantee the desired bactericidal and / or bacteriostatic action against all types of microorganisms. In particular, the Applicant is not aware of any container for sterile or low bacterial load products, made of plastic material, capable of reducing and / or preventing the simultaneous proliferation of bacteria and fungi, such as Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger in accordance with the requirements established by the European Pharmacopoeia, the United States Pharmacopoeia and the Japanese Pharmacopoeia.

The purpose of the present invention is to overcome the drawbacks highlighted by the state of the art.

The object of the present invention is therefore a resealable container for sterile and / or low bacterial load products without preservatives, suitable for limiting and / or reducing bacterial growth inside said products, characterized in that the internal surface of said container which can come into contact with said product is in a thermoplastic resin comprising an antibacterial composition.

A further object of the present invention is also a closure for containers which can be associated with a container of the aforesaid type, characterized in that it is made of a thermoplastic resin comprising an antibacterial composition.

A further object of the present invention is a primary packaging device for sterile and / or low bacterial load products without preservatives comprising the aforesaid container and the aforesaid closure.

A further object of the present invention is the use of the aforementioned primary packaging device to package sterile and / or low bacterial load products without preservatives.

In order to better understand the characteristics of the present invention, reference will be made to the following figures in the description:

Figure 1, schematic representation of a container and its closure according to a first embodiment of the present invention;

Figure 2, schematic representation of a container and its closure according to a second embodiment of the present invention.

The Applicant has surprisingly perceived that the use of a thermoplastic material in which an antibacterial composition is dispersed to create a resealable container and the relative closure allows the creation of a device (â € œpackagingâ €) suitable for containing sterile products and / or low bacterial load that are preserved over time and also during the various phases of use (administration) of the product, avoiding adding preservatives of any type to the product formulation.

According to the present invention, the container is an envelope in which at least the internal surface is made of a material consisting of a thermoplastic resin comprising an antibacterial composition.

By internal surface of the container, we mean the surface that can come into contact with the product during the phases of product packaging and subsequent use by the end user. Typically, the casing that constitutes the container is made entirely of the aforementioned thermoplastic resin comprising an antibacterial composition.

The thermoplastic material suitable for making the container of the present invention and the relative closure is a thermoplastic material comprising, or consisting of, a polymeric resin chosen for example from: polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polycarbonate (PC) and thermoplastic rubber (for example, poly-butadiene-styrene (PBS)).

The antibacterial composition is a chemical composition capable of preventing the proliferation of microorganisms and / or reducing their number where these are present. In the remainder of this description this action will be referred to as â € œ antibacterial actionâ €. For the purposes of the present invention, the term microorganisms refers to animal organisms classified as bacteria, fungi, yeasts, molds and spores.

The antibacterial composition present in the thermoplastic resin includes metal ions with antibacterial action. Metal ions with antibacterial action are selected from the group consisting of silver, copper, zinc, gold and their mixtures. Preferably, silver ions are used due to their higher antibacterial efficacy. Even more preferably, mixtures of silver ions and zinc ions are employed.

The metal ions are supported on solid supports, such as ceramic structures based on zirconium phosphate and / or on aluminosilicate supports (zeolites).

Examples of aluminosilicates that can be used for this purpose are the following: zeolite A, zeolite X, zeolite Y, zeolite T, sodalite, mordenite, analcite, clinoptilolite, cabazite, erionite and their mixtures. Preferably, A zeolites are used, due to their superior ion exchange capacity. Particularly preferred are the zeolites A containing silver ions, even more preferably those containing simultaneously silver and zinc ions due to the antibacterial efficacy against a greater number of microorganisms.

Examples of compositions containing metal ions supported on zirconium phosphate-based structures are described in US 5296238.

The antibacterial action ions are deposited on the aforesaid supports based on zirconium phosphate or aluminosilicate type through deposition and / or ion exchange reactions according to the techniques known in the art.

Generally, the content of metal ions with antibacterial action present in zeolites is lower than the ion exchange saturation capacity of zeolites. Therefore, the zeolites used for the purposes of the present invention, in addition to containing the metal ions having a specific antibacterial action, can also contain other ions (metallic and non-metallic), such as for example alkali metals, alkaline earth metals, protons and ammonium ions .

The total content of metal ions with antibacterial action in the zeolite is generally variable in the range 2-25% by weight referred to the weight of the dried zeolite, preferably in the range 5-20% by weight. As known, the drying temperature of the zeolites can vary according to the thermal stability of the different zeolites and the type of counter-ions present; in the case of zeolite A, the reference drying temperature is in the range 400-800 ° C.

Zeolites containing metal ions are commercially available.

When it is desired to prepare a resin that incorporates two or more different metal ions, these can be supported on the same support (zeolite or zirconium phosphate structure) or on different supports.

The Applicant has unexpectedly observed that the antibacterial action exerted by the thermoplastic material comprising the antibacterial compositions described above can be intensified by suitably selecting the metal ions and the relative support.

In particular, the studies carried out by the Applicant have shown that the best results in terms of effectiveness in preventing, limiting and / or reducing the proliferation of microorganisms that come into contact with the product stored in the containers object of the present invention are obtained for thermoplastic resins. in which an antibacterial composition comprising silver ions and zinc ions has been dispersed.

Preferably, the weight ratio between silver ions and zinc ions (Ag / Zn) in the antibacterial composition varies in the range 0.15 <Ag / Zn <10.

This combination of ions is preferably supported on zeolite structures, in particular on type A zeolites.

When added to the thermoplastic resins described above, the antibacterial compositions comprising silver and zinc ions make it possible to create packaging that meets the antimicrobial efficacy requirements established by the European Pharmacopoeia, the United States Pharmacopoeia and the Japanese Pharmacopoeia.

In particular, the antibacterial compositions comprising silver and zinc ions, preferably supported on type A zeolites, are able to guarantee an effective action of limiting the proliferation and reducing the number of microorganisms Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger.

The antibacterial compositions can contain one or more zeolites and / or supports based on zirconium phosphate exchanged with metal ions with antibacterial action.

An antibacterial composition having a given concentration of one or more metal ions can be prepared by mixing different supports having different concentrations of metal ions, until the desired concentration of antibacterial ions in the composition is obtained. Alternatively, it is possible to use a single support comprising two or more metal ions with antibacterial action.

When using two or more zeolites and / or zirconium phosphate-based supports, the antibacterial composition can be prepared by mixing the respective exchanged supports with the metal ions (for example, one type of ion for each support) in solid form ( granules or powders).

The antibacterial compositions described above can be incorporated into thermoplastic resins using the techniques and equipment known in the field of processing thermoplastic materials.

The containers and their closures can be obtained in various shapes and sizes.

The antibacterial composition is generally added to the thermoplastic material in such a quantity as to have an overall concentration of metal ions with an antibacterial action varying in the range 0.01-10.0% by weight referred to the weight of the thermoplastic material that forms the container ( and the relative closure), preferably in the range 0.01-7.0% by weight, even more preferably in the range 0.1-5.0% by weight.

The antibacterial compositions, both those based on zirconium phosphate and those based on zeolites, can be dispersed in solid form (granular or powder) in the thermoplastic resin, also in the solid state (granules) by mechanical mixing. The mixture of thermoplastic granules and antibacterial composition is then transformed into the final product (container and / or closure) with the usual processing techniques of thermoplastic materials.

Alternatively, the antibacterial compositions can be joined to the thermoplastic resin, during the casting operation.

The usual processing techniques for thermoplastic materials include the processes of drawing (extrusion), molding, injection, injection-blow molding, extrusion-blow molding and Blow-fill-seal.

The thermoplastic resin containing the antibacterial composition can also be extruded in the form of small "pellets" (granules), which can subsequently be used as a starting material for the production of the containers and their closures with the above-mentioned techniques.

Although it is not intended here to refer to any particular theory, it is believed that the mechanism underlying the antibacterial action in the containers object of the present invention is essentially linked to the contact between the antibacterial composition present on the surface of the thermoplastic material of which The container and the product it contains is formed. In this case, the antibacterial efficacy will depend in particular on the extent of the surface of the container in contact with the product and on the duration of such contact.

Although the concentrations indicated above for the antibacterial composition inside the thermoplastic material with which the containers and the relative closures are made are, generally, sufficient to guarantee the desired antibacterial action for a period of time compatible with the time of use of the product, in some particular cases, however, the antibacterial performance of the container may not be sufficient for its intended use. This may occur, for example, in the case in which the container has walls of reduced thickness and, therefore, has small quantities of the ions of the antibacterial composition on the internal surface in contact with the product.

In these cases, it is possible to obviate the lower effectiveness of the thermoplastic material comprising the antibacterial composition by making containers of suitable shape, such as those exemplified in Figures 1 and 2.

Figure 1 schematically shows a primary packaging device 1, suitable for containing ophthalmic liquids (for example, an eye drop), comprising a container 2 and the relative closure 3. The device 1 also includes a dropper 4, fixed on the closure 3. The elements 2-4 of the device 1 are made of thermoplastic resin comprising an antibacterial composition according to the present invention. Inside the container 1 there is a liquid product 5 whose aseptic characteristics obtained by sterilizing the product during its packaging are to be preserved.

To ensure a more effective antibacterial action, inside the container there is a protuberance 6 (in the specific case, tubular in shape) associated with the closure 3. The protuberance 6 is also made of a thermoplastic resin comprising a antibacterial composition and, therefore, also exerts an antibacterial action when its surface comes into contact with the product 5 contained in the container 2. The presence of the protuberance 6, in practice, increases the overall surface with which the product can come into contact during its storage period inside the container 2 while using the product contained.

A second embodiment of the technical solution exemplified in Figure 1 is represented in Figure 2. Figure 2 shows a primary packaging device 21 comprising a container 22 and the relative closure 23. The device 21 also comprises a dropper 24, fixed to the closure 23. The elements 22, 23 and 24 are made of thermoplastic resin comprising an antibacterial composition according to the present invention. Inside the container 22, there is a product 5 (for example, an ophthalmic liquid), whose characteristics of low bacterial load are to be preserved. According to this second embodiment of the invention, the container 22 can comprise inside one or more movable bodies 25 having at least the external surface made of a thermoplastic resin comprising an antibacterial composition according to the invention. The movable bodies 25, in particular the external surface containing the antibacterial composition, are in contact with the product 5. The movable bodies have dimensions such that they cannot exit the packaging through the opening of the dropper, which only allows the leakage of the product 5 for administration to the user.

In addition to the movable bodies 25, the container can also have protrusions 27, associated for example with the bottom wall of the container, which extend towards the inside of the container. Also in the case of the device shown in figure 2, the presence of the movable bodies 25 and possibly that of the protuberances 27 increases the overall surface with which the product can come into contact during storage inside the container 2, thus intensifying the ™ antibacterial action of the internal surface of the container 22.

The following examples of embodiment are provided merely for illustrative purposes of the present invention and must not be construed as limiting the scope of protection defined by the attached claims.

EXAMPLE 1

A first primary packaging device comprising a container and relative closure (packaging A) was prepared using a polyethylene resin for both components (container and closure). An antibacterial composition was dispersed in the resin comprising silver and zinc ions supported on a type A zeolite.

Zeolite A contained 5% by weight of silver ions, 12% by weight of zinc ions (percentages by weight referred to the weight of the exchanged and dried zeolite) and any residual ammonium or hydrogen ions (i.e., the original synthesis counter-ions of the zeolite).

The antibacterial composition was mixed with the resin in a quantity equal to 2% by weight referred to the total weight of the thermoplastic resin.

EXAMPLE 2

A second primary packaging device comprising a container and relative closure (packaging B) was prepared with the same methods described in Example 1, using a polyethylene resin added with the same antibacterial composition of Example 1. The antibacterial composition It was mixed with the resin in a quantity equal to 5% by weight referred to the total weight of the thermoplastic resin.

EXAMPLE 3

A third primary packaging device comprising a container and relative closure (packaging C) was prepared with the same methods described in Example 1, but using a polyethylene resin added with an antibacterial composition consisting of silver ions dispersed on a structure zirconium phosphate ceramic. The concentration of Ag ions on the support was equal to 30% by weight referred to the total weight of the exchanged and dried support.

The antibacterial composition was mixed with the resin in an amount equal to 8% by weight referred to the total weight of the thermoplastic resin.

Antimicrobial efficacy test

The antimicrobial efficacy of A-C packaging has been tested in accordance with the provisions of the European Pharmacopoeia (â € œEfficacy of Antimicrobial Preservationâ €, Ph. Eur. Current Edition â € “5.1.3).

The effectiveness was evaluated in terms of logarithmic reduction of the number of viable microorganisms compared to the number of microorganisms introduced with the inoculum.

The acceptability criteria for parenteral and ophthalmic preparations defined by the European Pharmacopoeia are shown in Table 1. Acceptability criteria fully comparable to those of the European Pharmacopoeia are also defined by the United States Pharmacopoeia and the Japanese Pharmacopoeia.

Table 1

LOGARITHMIC REDUCTION

<Criteria>

Microorganisms 6 h 24 h 7 days 14 days 28 days evaluation

A 2 3 - - NR Bacteria

B - 1 3 - NI A - - 2 - NI Mushrooms

B - - - 1 NI NR = no reduction

NI = no increment

The results of the tests performed on A-C packaging are reported, respectively, in Tables 2-4.

The experimental data show that the antibacterial composition of packaging A and B, in which silver and zinc ions are present at the same time, is able to comply with the requirements of the European Pharmacopoeia of Table 1. The data also show that the efficacy of the composition increases as its concentration in the resin increases.

Packaging C, in which the antibacterial composition includes only silver ions supported on zirconium phosphate, is instead only partially effective against the bacteria and molds tested, not respecting the reduction values envisaged in the case of Aspergillus niger.

The examples show the effectiveness of the devices of the present invention in limiting and reducing the growth of microorganisms; in particular, the experimental results confirm that the container and the relative closure of Examples 1 and 2 can be used as packaging for the primary packaging of sterile and / or low bacterial load products without preservatives in compliance with the requirements established by the European Pharmacopoeia, by United States Pharmacopoeia and the Japanese Pharmacopoeia.

Table 2 - Packaging A

Value TO T R T R T R T R T inoculation 6h 6h 24h 2 4h 7g ig 1 4g 14g 28g CFU / ml

5.7x10 <6> 3.6x 2.9x 0.30 2.0x 4.46 0> 6.76 â € ”â €” 0 6538 10 <6> 10 <6> 10 <2>

4.5x10 <6> 1.8x <1.0x> 4.65 0> 6.65 0 9027 10 <6> 10 <2>

4, 9x10 <5> 4.6x - - 2, 0x 2.39 0> 5.69 0 10231 10 <5> 10 <3>

2, 3x10 <6> 3,5x - - 2, 0x 1,06 4,8x 1,68 2, 0 16404 10 <5> 10 <5> 10 <4> 10 <3> Table 3 - Packaging B

Value TO T R T R T R T R T inoculation 6h 6h 24h 2 4h ig ig 1 4g 14g 28g CFU / ml

5,7x10 <6> 4,4x 1,7x 0,53 <1,0x> 5, 76 0> 6,76 â € ”â €” 0 6538 10 <6> 10 <6> 10 <2>

4.5x10 <6> 2.7x <1.0x> 4.65 0> 6.65 0 9027 10 <6> 10 <2>

4, 9x10 <5> 4.4x - - 6, 0x 2.91 1, lx 4.65 0 10231 10 <5> 10 <2> 10

2, 3x10 <6> 8,2x - - 7,0x 3,51 1, lx 5,32 0 16404 10 <5> 10 <2> 10

Table 4 - Packaging C

T0 value T R T R T R T R inoculation 6h 6h 24h 24h 7g 7g 14g 14g CFU / ml

S. aureus 3.5x1 0 <6> 1.6x 1, lx 0.50 1, Ox 0.54 6.8x 2.71 6 5.77 ATCC 6538 10 <6> 10 <6> 10 <6> 10 <3>

P .aeruginosa 2,4x1 0 <6> 2,2x 1,6x 0,18 7, lx 0,53 2, Ox 1,08 4, 5x 1,73 ATCC 9027 10 <6> 10 <6> 10 <5 > 10 <5> 10 <4> C. albicans 5.4x1 0 <5> 5, lx - - 6.7x 0.91 6, Ox 1.95 ATCC 10 231 10 <5> 10 <4> 10 <3> A. niger 2.2x1 0 <5> 1.9x - - 1, Ox 0.34 1, Ox 0.34 ATCC 16404 10 <5> 10 <5> 10 <5>

Claims (11)

CLAIMS 1) Resealable container for sterile and / or low bacterial load products without preservatives, suitable for limiting and / or reducing bacterial growth inside said products, characterized by the fact that the internal surface of said container which can come into contact with said product it is in a thermoplastic resin comprising an antibacterial composition. 2) Container according to claim 1, characterized in that said antibacterial composition comprises metal ions with antibacterial action supported on a ceramic structure based on zirconium phosphate or on an aluminosilicate type support. 3) Container according to claim 2, characterized by the fact that said support of aluminosilicate type is a zeolite selected from the group consisting of zeolite A, zeolite X, zeolite Y, zeolite T, sodalite, mordenite, analcite, clinoptilolite, cabazite, erionite and their blends; preferably it is a zeolite A. 4) Container according to claim 2 or 3, characterized in that said metal ions are selected from the group consisting of silver, copper, zinc, gold and their mixtures; preferably they are silver ions. 5) Container according to claim 4, characterized in that said metal ions are preferably a mixture of silver and zinc ions. 6) Container according to claim 5, characterized in that the weight ratio between silver ions and zinc ions (Ag / Zn) varies in the range 0.15 <Ag / Zn <10. 7) Container according to any one of claims from 2 to 6, characterized in that said metal ions are present in variable concentration in the range 0.01-10.0% by weight referred to the weight of the thermoplastic material, preferably in the range 0.01-7.0% by weight, even more preferably in the range 0.1-5.0%. 8) Container according to any one of the preceding claims, characterized in that said internal surface comprises a protuberance which extends towards the interior of said container, said protuberance having a surface that can come into contact with said product made of a thermoplastic material comprising an antibacterial composition as defined in any one of the preceding claims. 9) Closure for container associable with a container according to claim 1, characterized in that it is made of a thermoplastic material comprising an antibacterial composition. 10) Closure according to claim 9, characterized in that said antibacterial composition is an antibacterial composition as defined in any one of claims 2 to 7. 11) Primary packaging device for sterile and / or low bacterial load products free of preservatives comprising a container according to any one of claims 1 to 8 and a closure according to claim 9 or 12) Device according to claim 11, characterized by the fact of comprising a movable body placed inside the container, said body having at least the external surface made of a thermoplastic material comprising an antibacterial composition 13. Device according to claim 12, characterized in that said antibacterial composition is an antibacterial composition as defined in any one of claims 2 to 7. 14) Use of a primary packaging device according to any one of claims 11 to 13 to package sterile and / or low bacterial load products free of preservatives, limiting and / or reducing bacterial growth inside them.