ES2523379T3 - Container and closure for sterilized products or with low bacterial load without preservatives - Google Patents

Abstract

Container that can be closed again for sterilized products or products with low bacterial load without preservatives, suitable for limiting and / or reducing the growth of bacteria within said products, characterized in that it is made entirely of a thermoplastic material comprising an antibacterial composition dispersed therein, said antibacterial composition comprises at least silver ions and zinc ions supported on a solid support.

Description

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DESCRIPTION

Container and closure for sterilized products or with low bacterial load without preservatives

The present invention relates to a container and a relative closure element for sterilized products or products with low bacterial load without preservatives.

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

The present invention is further related to a primary packaging device of the aforementioned products, as well as to the use of the aforementioned device to limit and / or reduce the growth of bacteria within these products during use. Examples of products that can be stored in the containers of the present invention are pharmaceuticals, medical devices, cosmetic products, dietary and food products. Such products may be in the form of liquid, gel, suspension, paste, powder or granules.

Microorganisms, naturally present in large quantities and various species, can contaminate products packaged in sterile conditions or with low bacterial load (for example pharmaceutical products) once the consumer opens the container and can multiply very quickly, especially if the conditions Environmental factors are not such as to favor their growth and proliferation.

The presence of such microorganisms (for example, bacteria, fungi, yeasts, molds, etc.) negatively affects the hygienic, life and quality conditions of the packaged product, which leads to product degradation, agent proliferation pathogens and therefore to serious health risks of the end user of the product.

For these reasons, the packaging of pharmaceutical, cosmetic, dietary and food products should prevent product contamination by microorganisms present in the environment outside the container as much as possible once it has been opened for the first time, that is, after that the user has used the first dose of product and has closed the container again to store the remaining product thereof for subsequent administrations. Suitable resealable containers for containing products intended for use by parts (doses) at subsequent times are called multidose or multidose containers.

In order to reduce the risks associated with product contamination by microorganisms, formulations of products of the type mentioned in the prior art are generally mixed with preservative substances, suitable for limiting or preventing microbial growth that may develop within them. products while using them. Suitable preservatives for this purpose are, for example, benzalkonium chloride, sodium thiomersal, chlorexidine, methylparaben, ethylparaben, propylparaben, phenol, polyhexamethylene biguanide (PHMB), N-hydroxymethylglycinate, chlorbutanol.

However, the use of preservatives in the formulations of sterile products or with a low bacterial load is not desirable since their presence can also affect the health of the consumer in an unexpected way, generating unwanted reactions.

In order to obviate the use of preservatives, in the prior art it has been proposed to use containers provided with filters or other mechanical devices that prevent the passage of microorganisms. When the product is used, for example a eye drops, the filters or other mechanical devices present in the container allow the product to go outside and at the same time prevent the entry of microorganisms into the container.

Although this technical solution prevents contamination of the product inside the container and thus favors its storage under optimal conditions, it has the disadvantage of not preventing the user from using the contaminated product. From the second use, in fact, the product is forced to cross a filter or subsequent dispensing zone (for example, the drop dispensing tip in the case of a container of eye drops) contaminated by microorganisms, which in turn is contaminated .

An alternative solution to the addition of preservatives proposed in the prior art is that described in patent application WO0026100. This document describes the use of a closure element for containers intended to contain baby beverages, such as a bottle, made of plastic material mixed with an inorganic antibacterial agent, such as an antibacterial zeolite.

Containers having closure elements of the type described in WO0026100 ensure better hygienic conditions than containers having conventional closure elements; however, they are only suitable for containing products that do not require sterility or conditions with bacterial load

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particularly low (for example food liquids), as on the other hand are the necessary conditions for pharmaceutical or cosmetic products.

In fact, it is known that plastics generally used to make food containers have the disadvantage of allowing bacterial proliferation. Therefore, when using a device for closing an antibacterial material in containers made of plastic of the conventional type, the preservation of the product under the desired conditions of low bacterial load is not adequately ensured.

Apart from the specific drawbacks described above, it is important that the antibacterial agents described in the prior art are not always able to ensure the desired bactericidal and / or bacteriostatic action towards all types of microorganisms. In particular, the applicant does not know any container for sterile products or with a low bacterial load, made of a plastic material, capable of reducing and / or preventing the concurrent proliferation of bacteria and fungi, such as Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger according to the requirements set forth by the European Pharmacopoeia, the United States Pharmacopoeia and the Japanese Pharmacopoeia.

US 6179141 B1 describes a container according to the preamble of claim 1.

The object of the present invention is to overcome the drawbacks highlighted by the prior art.

Therefore, the object of the present invention is a resealable container according to claim

one.

A further object of the present invention is the use of said primary packaging device for packaging sterile products or with low bacterial load without preservatives, according to claim 14, and its use in combination with ophthalmic liquid according to claim 15.

In particular, the primary packaging device according to the present invention is a multidose dispensing device comprising a container, containing a sterile product and / or with low bacterial load without preservatives, and of the relative closure element. The device can be opened by the user to take a dose of the content and then be closed again to store the product until the next use. The device prevents product contamination by external microorganisms by taking one dose and between one dose and the next.

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

Figure 1 shows a schematic view of a container and a relative closure element according to a first embodiment of the invention;

Figure 2 shows a schematic view of a container and a relative closure element according to a second embodiment of the invention.

The applicant has surprisingly perceived that the use of a thermoplastic material where an antibacterial composition is dispersed to make a resealable container and the relative closure element make it possible to make a suitable packaging device to contain sterile or low-load products. bacteria that are preserved over time and also during the different stages of use (administration) of the product, avoiding the addition of preservatives of any kind to the formulation of the product to be preserved.

According to the present invention, the container is an enclosure where at least the inner surface is made of a material consisting of a thermoplastic resin comprising an antibacterial composition. Later in the present description, the terms "resin" and "thermoplastic material" are used as synonyms.

The interior surface of the container is understood as the surface that can come into contact with the product during the product packaging stages and subsequent use by the end user. Typically, the enclosure that composes the container is made entirely of said thermoplastic resin comprising an antibacterial composition.

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

The antibacterial composition is a chemical composition capable of exerting a preventive action on the proliferation of microorganisms and / or reducing the number of them where they are present. Later in the present description, such action will be indicated as "antibacterial action". For the purpose of the present invention, the term "microorganisms" refers to unicellular organisms classified as bacteria, fungi, yeasts, molds and spores.

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

The metal ions are supported on solid supports, such as ceramic structures based on zirconium phosphate and / or on aluminum silicate type supports (ceolites).

Examples of aluminum silicates that can be used for this purpose are: ceolite A, ceolite X, ceolite Y, ceolite T, sodalite, mordenite, analyte, clinoptilolite, cabazite, erionite and mixtures thereof. Preferably, zeolites A are used due to their greater ion exchange capacity. Especially preferred are zeolites A containing silver ions, even more preferably those containing silver and zinc ions at the same time due to the antibacterial efficacy against a greater number of microorganisms.

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

The ions with antibacterial action are deposited on said supports based on zirconium phosphate or aluminum silicate type by deposition and / or ion exchange reactions according to the prior art known techniques.

Generally, the content of metal ions with antibacterial action present in the zeolites is less than the ion exchange saturation capacity of the zeolites. Therefore, apart from containing metal ions that have a specific antibacterial action, the ceolites used for the purpose of the present invention may also contain other ions (metal and nonmetal), such as for example alkali metals, alkaline earth metals, protons and ammonium ions.

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

Ceolites containing metal ions are available in the market.

When it is desired to prepare a resin that incorporates two or more different metal ions, these can be supported on the same support (ceolite 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 an appropriate selection of the metal ions and the relative support.

In particular, studies by the applicant have shown that the best results from the point of view of efficacy to prevent, limit and / or reduce the proliferation of microorganisms that come into contact with the product stored in the containers object of the present invention they are obtained for thermoplastic resins where 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 0.04 <Ag / Zn <20, preferably in the range 0.15 <Ag / Zn <10 , more preferably in the range 0.31 <Ag / Zn <1.

This combination of ions is preferably supported on ceolithic structures, in particular on type A ceolites.

When added to the thermoplastic resins described above, the antibacterial compositions comprising silver and zinc ions make it possible to obtain a package that meets the requirements of antibacterial efficacy set forth by the European pharmacopoeia, the United States pharmacopoeia and the Japanese pharmacopoeia.

In particular, antibacterial compositions comprising silver and zinc ions, preferably supported on ceolites A, are capable of ensuring effective action to limit proliferation and reduce the number of microorganisms of Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger.

The antibacterial compositions may contain one or more zeolites and / or zirconium phosphate based supports exchanged with metal ions having an 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 ions with antibacterial action in the composition is obtained. As an alternative, it is possible to use a single support comprising two or more metal ions with antibacterial action.

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When two or more zeolites and / or zirconium phosphate-based supports are used, the antibacterial composition can be prepared by mixing the respective supports exchanged 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 techniques and equipment known in the field of thermoplastic material processing.

The incorporation of the antibacterial composition in the resin before forming the container and the relative closure element reduces the amount of possible assignment of the metal ions to the product contained therein.

The containers and the relative closure elements can be obtained in various shapes and dimensions.

The antibacterial composition is generally added to the thermoplastic material in such an amount as to have a total concentration of metal ions with variable antibacterial action in the range 0.01-10.0% by weight based on the weight of the thermoplastic material composing the container ( and the relative closure element), preferably in the range 0.01-7.0% by weight, even more preferably in the range 0.1-5.0% by weight.

Antibacterial compositions, those based on zirconium phosphate and those based on ceolites, can be dispersed as a solid (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 element) with the usual techniques for the processing of thermoplastic materials.

As an alternative, the antibacterial compositions can be combined with the thermoplastic resin during the melting operation.

The usual thermoplastic materials processing techniques include stretching (extrusion), molding, injection, blow injection, blow extrusion and blow-fill-seal.

The thermoplastic resin containing the antibacterial composition can also be extruded in the form of small pellets (granules), subsequently usable as a starting material to produce the containers and the relative closure elements with the aforementioned techniques.

While there is no intention in this report to refer to any specific theory, it is believed that the mechanism that is the basis of the antibacterial action in the containers object of the present invention is essentially related to the contact between the present surface antibacterial composition of the thermoplastic material from which the container and the product contained therein are made. In this case, the antibacterial efficacy depends in particular on the extent of the container surface in contact with the product and the duration of such contact.

While the concentrations indicated above for the antibacterial composition within the thermoplastic material from which the containers are made and the relative closure elements are generally sufficient to ensure the desired antibacterial action for a time compatible with the time of product use, in In some particular cases, however, the antibacterial performance of the container may not be sufficient for the intended use. This can happen, for example, if the container has walls with a reduced thickness and thus exhibits reduced amounts of ions of antibacterial composition on the inner surface in contact with the product.

In these cases it is possible to obviate the lower efficacy of the thermoplastic material comprising the antibacterial composition that makes containers with a 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 a eye drops) comprising a container 2 and the relative closure element 3. The device 1 also comprises a dropper 4, fixed on the closure element 3. Elements 2-4 of device 1 are made of a 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 with the sterilization of the product when packaging it must be preserved.

To ensure a more effective antibacterial action, a projection 6 (in the specific case having a tubular shape) associated with the closure element 3 is provided within the container. The projection 6 is also made of a thermoplastic resin comprising an antibacterial composition and therefore it also has an antibacterial action when its surface comes into contact with the product 5 contained in the container 2. The presence of the projection 6, in practice, increases the total area with which the product can contact during its period of storage inside container 2 during the use of the contained product.

Figure 2 shows a second embodiment of the technical solution exemplified in Figure 1. Figure 2 shows a primary packaging device 21 comprising a container 22 and the relative closure element 23. The device 21 also comprises a dropper 24, fixed to the closure element 23. Elements 22, 23 and 24 are made of a thermoplastic resin comprising an antibacterial composition according to the present invention. A

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product 5 (for example an ophthalmic liquid), whose characteristics of low bacterial load are to be preserved, is present within the container 22. According to this second embodiment of the invention, the container 22 may comprise one or more movable bodies 25 therein , which has at least the outer surface made of a thermoplastic resin comprising an antibacterial composition according to the invention. The movable bodies 25, in particular the outer surface containing the antibacterial composition, are in contact with the product 5. The movable bodies have dimensions such as not to leave the container through the dropper opening, which only allows the product 5 for user administration.

In addition to the movable bodies 25, the container may also have projections 27, associated for example to the bottom wall of the container, which extend into the container. Also in the case of the device shown in Figure 2, the presence of the movable bodies 25 and optionally of the projections 27 increases the total surface of the product with which it can contact, during storage inside the container 2, thereby intensifying the own antibacterial action of the inner surface of the container 22.

The following examples of embodiments are only given by way of illustration of the present invention, and are not intended to be limiting the scope of protection as it appears in the appended claims.

EXAMPLE 1

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

Ceolite A contained 5% by weight of silver ions, 12% by weight of zinc ions (weight percentages based on the weight of exchanged and dried ceolite) and optional residual hydrogen or ammonium ions (i.e. the original counterions of ceolite synthesis).

The antibacterial composition was mixed with the resin in amounts equal to 2% by weight based on the total weight of the thermoplastic resin.

EXAMPLE 2

With the same methods described in Example 1, a second primary packaging device was prepared comprising a container and the relative closure element (container B), using a polyethylene resin mixed with the same antibacterial composition as in Example 1. The Antibacterial composition was mixed with the resin in amounts equal to 5% by weight based on the total weight of the thermoplastic resin.

EXAMPLE 3

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

The antibacterial composition was mixed with the resin in amounts equal to 8% by weight based on the total weight of the thermoplastic resin.

Antimicrobial efficacy test

The antimicrobial efficacy of the A-C packages was tested according to the contributions of the European Pharmacopoeia ("Efficacy of Antimicrobial Preservation", Ph. Eur. Current edition -5.1.3).

Efficacy was assessed from the point of view of the logarithmic reduction in the number of vital microorganisms compared to the number of microorganisms introduced with the inoculum.

Table 1 shows the acceptability criteria for parenteral and ophthalmic preparations defined by the European pharmacopoeia. Acceptance criteria comparable to those of the European pharmacopoeia are also defined in the United States pharmacopoeia and the Japanese pharmacopoeia.

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Table 1

image 1

SR = no recovery SA = no increase

The results of the tests performed on the A-C containers are shown respectively in Tables 2-4.

Experimental data shows that the antibacterial composition of packages A and B, where silver and zinc ions are present at the same time, is able to meet the requirements of the European Pharmacopoeia of Table 1. Additional data show that the efficacy of the compound increases as its concentration in the resin increases.

It should be noted that the containers made with the same thermoplastic resin as in example 1 but containing the antibacterial composition in amounts equal to 1% by weight based on the total weight of the thermoplastic resin show an antibacterial efficacy comparable to that of the container A.

On the other hand, container C, where the antibacterial composition only contains silver ions supported on zirconium phosphate, is only partially effective against the bacteria and molds tested, not respecting the expected reduction values in the case of Aspergillus niger.

The examples show the efficacy 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 element of Examples 1 and 2 can be used as a container for the primary packaging of sterile products or with a low bacterial load without preservatives in accordance with the requirements set forth in the pharmacopoeia European, the United States Pharmacopoeia and the Japanese Pharmacopoeia.

EXAMPLE 4

The performance test was run on some samples of device A of Example 1 according to the guidelines of the European Pharmacopoeia for primary packaging devices of plastic material for pharmaceutical use. The test showed an average yield value of 12 ppm, lower than the maximum allowed value of 50 ppm.

Additional tests were run on the same container samples to assess the amount of release of Ag and Zn ions from the device material. To this end, each device was filled with 10 ml of distilled water and stored sealed at a controlled temperature of 25 ° C or 40 ° C for 10 days. At the end of the storage period the concentration of Ag and Zn ions present in the water was measured using the methods to determine zinc and silver IRSA CNR 3320 and IRSA CNR 3070. The content of Ag ions in the distilled water was 0.006 micrograms / device, in samples stored at 25 ° C, and 0.002 micrograms / device in samples stored at 40 ° C. The ion content of Zn was 0.069 micrograms / device (25 ° C) and 1,167 micrograms / device (40 ° C). Ag and Zn ions were released into the product in insignificant amounts.

In general, the tests described show that the devices according to the present invention can be used as primary packaging devices for pharmaceutical use according to the criteria set forth by the European Pharmacopoeia.

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Claims (15)

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one.

Container that can be closed again for sterilized products or products with low bacterial load without preservatives, suitable for limiting and / or reducing the growth of bacteria within said products, characterized in that it is made entirely of a thermoplastic material comprising an antibacterial composition dispersed therein, said antibacterial composition comprises at least silver ions and zinc ions supported on a solid support.

2.

Container according to claim 1, characterized in that said support is a ceramic structure based on zirconium phosphate or a support of the aluminum silicate type.

3.

Container according to claim 2, characterized in that said aluminum silicate type support is a ceolite selected from the group consisting of ceolite A, ceolite X, ceolite Y, ceolite T, sodalite, mordenite, analyte, clinoptilolite, chabazite, erionite and mixtures thereof.

Four.

Container according to the preceding claim, characterized in that said ceolite is a ceolite A.

5.

Container according to any of the preceding claims, characterized in that said antibacterial composition further comprises copper and / or gold ions.

6.

Container according to any of the preceding claims, characterized in that the weight ratio between silver ions and zinc ions (Ag / Zn) varies in the range 0.04 <Ag / Zn <20.

7.

Container according to any preceding claim, characterized in that the weight ratio between silver ions and zinc ions (Ag / Zn) varies in the range 0.15 <Ag / Zn <10.

8.

Container according to any preceding claim, characterized in that the weight ratio between silver ions and zinc ions (Ag / Zn) varies in the range 0.31 <Ag / Zn <1.

9.

Container according to any of the preceding claims, characterized in that the total concentration of metal ions with antibacterial action is variable in the range between 0.01 and 10.0% by weight relative to the weight of the thermoplastic material, preferably in the range between 0, 01 and 7.0% by weight, even more preferably in the range between 0.1 and 5.0%.

10.

Container according to any of the preceding claims, characterized in that said thermoplastic material is a material comprising or consisting of a polymeric resin selected from: polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), poly (vinyl chloride ) (PVC), polycarbonate (PC) and thermoplastic rubber.

eleven.

Container according to any of the preceding claims, characterized in that its inner surface comprises a projection that extends into said container, said projection has a surface that can come into contact with said product made of a thermoplastic material comprising an antibacterial composition according to any of the preceding claims.

12.

Primary packaging device for sterilized or low bacterial load products without preservatives comprising a container according to any one of claims 1 to 10 and a closure element associated with said container, said closure element is made of thermoplastic material comprising an antibacterial composition according to any of claims 1 to 9.

13.

Device according to claim 12, characterized in that it comprises a movable body disposed within the container, said body has at least the outer surface made of thermoplastic material comprising an antibacterial composition according to any one of claims 1 to 6.

14.

Use of a primary packaging device according to claim 12 or 13 to package sterilized products or with low bacterial load without preservatives, which limits and / or reduces the growth of bacteria therein.

fifteen.

Use of a primary packaging device according to the preceding claims wherein said sterilized product is an ophthalmic liquid.

eleven