WO2008148176A1

WO2008148176A1 - Multi-layer high moisture barrier film for use in the production of pharmaceutical or medical thermoformed blister packs and a method for manufacturing such a film

Info

Publication number: WO2008148176A1
Application number: PCT/BE2007/000057
Authority: WO
Inventors: Michiel Willem Adriaan Van Den Berg; Johan Willy Declerck
Original assignee: Tekni-Plex Europe, Naamloze Vennootschap
Priority date: 2007-06-08
Filing date: 2007-06-08
Publication date: 2008-12-11

Abstract

A multi-layer high moisture barrier film for use in the production of pharmaceutical or medical thermoformed blister packs characterised in that the film (1) is manufactured by solventless lamination in five or more layers which from inside to outside are an inner layer (2), a layer of adhesive (3), a core layer (4), another layer of said adhesive (3) and an outer layer (5) respectively, whereby said inner, core and outer layers (2, 4, 5) consist of one or more polymers.

Description

Multi-layer high moisture barrier film for use in the production of pharmaceutical or medical thermoformed blister packs and a method for manufacturing such a film.

The present invention concerns a multi-layer high moisture barrier film or sheet designed for thermoforming pharmaceutical or medical blister packs.

Multi-layer high moisture barrier films are used in many industrial applications, but one particularly important application is their use for thermoforming pharmaceutical or medical blister packs. These blister packs are characterised in that they are combined of a thermoformed thermoplastic single-layer or multi-layer high moisture barrier film with a lidding foil . The blister pack is further characterised by combining one or, in most cases, several product cavities which may be separated by perforations to facilitate carrying one single unit dosage. These dosages usually come in the form of capsules, lozenges or tablets of a product meant for oral intake. Liquids and creams are also possible, however, as are other possibilities of administration such as topical, ocular, auricular or anal.

For administration the product is pushed out of a cavitythrough the lidding foil.

A pharmaceutical blister pack is therefore also called a "push-through package" or blister strip.

In the case of dosages of a solid product for oral administration, the thermoformed plastic of the package carrying the dosages is characterised in that it provides sufficient rigidity and thickness around the cavity in which the tablet is placed to prevent physical damage in transport on the one hand, but on the other hand the plastic is sufficiently collapsible or deformable to allow the patients or consumers to press the tablet through the lidding foil . This lidding foil is typically composed of aluminium which offers good barrier and push-through properties.

Peel-open blisters or so-called "child resistant" peel/push variants are also common.

It is known that pharmaceutical solid products for oral administration are often sensitive to water and/or oxygen, whereby excess ingress of water or oxygen in the blister cavities will significantly shorten the product expiry date. One way to avoid this, is to provide a blister pack containing one or more high moisture or oxygen barrier layers. These high moisture barrier layers can be polymer- based or metal-based, whereby the barrier performance is expressed by the Water Vapor Transmission Rate and/or the Oxygen Transmission Rate.

Several manufacturing techniques are known to exist in order to combine individual layers of material (metal-based or polymer-based) into a single film or sheet out of which the blister pack can be formed. Such techniques are coating, lamination and extrusion.

In the case of thermoforming, whereby the sheet is heated and formed into a mold by means of air pressure and/or vacuum and/or plugs, the barrier polymers are usually attached on a thermoformable rigid carrier layer such as Polyvinylchloride (hereafter PVC) , Polyethylene Terephthalate (PET) or Cyclic Olefin Copolymers (COC) . In order to obtain a suitable balance between rigidity against physical damage and acceptable push-through force, the thickness of the rigid carrier sheet is typically chosen in the range of 100 to 350 microns .

The words film and sheet are used interchangeably in this

■context; however sheet is sometimes preferentially used for thicker rigid polymers, and film for thinner flexible polymers.

Table 1. below provides an incomplete overview of the most common multi-layer high barrier sheet materials used to manufacture pharmaceutical and medical blister packs .

Table 1. Host common multi-layer high barrier sheets

It is further known that in order to manufacture these multi- layer high moisture barrier sheets a technique known as lamination can be used whereby two or more films are attached together by means of an adhesive.

In particular, it is known that dry bond lamination can be used to manufacture a multi-layer high moisture barrier sheet. In the case of dry bond lamination, the adhesive is prepared for production in suspension form, whereby the adhesive solids are dissolved in a liquid phase. The adhesive, which may have several components, is then coated on one of the sheet substrates and subsequently passed through an oven to evaporate the liquid phase. The coating of the adhesive is typically done via a gravure coating roll, equipped with a metering doctor blade. When the adhesive is dry and tacky, the substrate sheet carrying the dried adhesive and the second film are passed together through a set of heated nip rollers, exercising pressure.

The combination of heat and pressure will activate the adhesive, known as cross-linking, to form a permanent bond between the layers of the film.

There are two families of dry bond lamination: solvent-based and water-based. In the case of water-based dry bond lamination, the adhesive in suspension form has a water carrier as liquid.

In the case of solvent-based dry bond lamination, the adhesive solids are suspended in an organic solvent. In general, organic solvent suspended adhesives are easier to dry, but a disadvantage of them is that they raise environmental and operator safety concerns.

Another known technique is wet bond lamination, whereby the adhesive is prepared for production in suspension form and the adhesive solids are dissolved in a liquid phase. The adhesive, which may have several components, is coated on one of the -sheet substrates by means of a gravure coating roll, equipped with a metering doctor blade. Subsequently, both films are attached by passing them through the nip rollers, whereby the adhesive is still wet. In a last step, the laminated film is dried in an oven whereby the liquid part of the adhesive is evaporated through one of the sheets . In this case one of the sheets needs to be highly permeable for the liquid such as paper, and therefore this technique is not suitable for multi-layer high moisture barrier films.

Another known technique is solventless lamination, which differs significantly from the above mentioned techniques in that the adhesive technology is not based on an evaporation step. The adhesive is prepared by mixing two components into a paste, whereby the viscosity can be adjusted with temperature. The adhesive is then applied to one of the sheet substrates by means of a series of transfer rollers. The adhesive coating weight can thereby be controlled by adjusting transfer roller speeds and temperature/viscosity. These parameters need to be established for each type of substrate. After the first film has been coated with the adhesive, both films are brought together by passing them through the nip rollers. The higher temperature of the nip roller will accelerate the cross-linking of the adhesive layer to a polymeric film.

Polyurethane chemistry is typically used for these types of adhesives, whereby completion of the cross-linking may take one or more days, depending on the ambient temperature.

A disadvantage of this technique is that solventless adhesives are conventionally used with adhesive layers of restricted thickness (1 to 1.5 g/m²) for flexible films of 100 microns or less. This small layer thickness and the flexibility of the films, prevents the formation of gas bubbles when the adhesive is curing in the master reel because adhesive layers of restricted thickness are less sensitive to the formation of gas. However, thermoformable rigid barrier films require an adhesive layer with greater thickness (2 to 3 g/m²) so that solventless lamination at present is not a conventional technique for barrier films .

It is the object of the present application to present a multi-blister pack obtained by solventless lamination.

To this aim the invention relates to a multi-layer high moisture barrier film for use in the production of pharmaceutical or medical thermoformed blister packs characterised in that the film is manufactured by solventless lamination in five or more layers which from the inner layer to the outer layer are an inner layer, a layer of adhesive, a core layer, another layer of said adhesive and an outer layer respectively, whereby said inner, core and outer layers consist of one or more polymers .

Significant advantages are that a multi-layer high moisture barrier film according to the invention can be produced more cheaply because solventless lamination is a more energy efficient technique than dry bond lamination since no oven is required to evaporate the liquid phase of a dry bond lamination adhesive, less upfront capital investment is required for the lamination technique and since less floor space is required for the lamination machine installation.

Another advantage is that a multi-layer high moisture barrier film according to the invention exhibits higher chemical resistance to aggressive products than conventional barrier films . Significant advantages of a multi-layer high moisture barrier film according to the invention is that it is safer in production than solvent-based barrier films because no organic solvents are evaporated in the environment with a solventless lamination technique, thus raising no environmental and operator safety concerns .

An advantage over water-based dry bond lamination barrier films is that a multi-layer high moisture barrier film by solventless lamination exhibits higher bond strength.

According to a preferred embodiment, the multi-layer high moisture barrier film involves a Polychlorotrifluoroethylene

(hereafter PCTFE) core layer, two layers of Polyurethane (hereafter PU) polymeric adhesive layers of equal thickness on each side of. the PCTFE core layer; and two layers of PVC of equal thickness attached to the other side of the PU adhesive layers forming the inner and outer layer of the film such that the material is symmetrical in a five layer composition: PVC / adhesive / PCTFE / adhesive / PVC.

An advantage of this embodiment is that the multi-layer high moisture barrier film does not curl preferentially to one side when heated.

Other possible embodiments are multi-layer barrier films whereby the inner layer and the outer layer are both made of PVC, Polypropylene (PP) , PE, COC, Polyethylene Terephthalate Glycol (PETG) , Amorphous Polyethylene Terephthalate (APET) , Polystyrene (PS) , a blend of Linear Low Density Polyethylene (LLDPE) with COC or an acrylonitrile-methyl acrylate copolymer grafted onto a nitrile rubber, which is commercially known as Barex®, and whereby the core layer is made ofPCTFE.

According to another preferred embodiment the multi-layer high moisture barrier film according to the invention is autoclavable in that the barrier film solely consists of layers of polymers that are known to be autoclavable such as

PP, COC or a blend of COC with LLDPE for the inner and outer layers and PCTFE for the core layer. The following structures can be made for steam sterilizable blister packs:

PP / adhesive / PCTFE / adhesive / PP COC / adhesive / PCTFE / adhesive / COC

[COC + LLDPE blend] / adhesive / PCTFE / adhesive / [COC + LLDPE blend]

An advantage of a high moisture barrier film or sheet structure according to this embodiment, made with solventless adhesives is that they can be sterilized by autoclave, preferably by steam sterilization at 121°C for 30 minutes, because the polymers used in this multi-layer structure are able to maintain dimensional stability at autoclave conditions, which is not the case for a high moisture barrier film manufactured by dry bond lamination.

The present invention also relates to a method for manufacturing a multi-layer high moisture barrier film by solventless lamination.

With the intention of better showing the characteristics of the invention, hereafter, as an example without any restrictive character whatsoever, some preferred forms of embodiment of a multi-layer high moisture barrier film according to the present invention for use in the production of pharmaceutical or medical thermoformed blister packs are described, with reference to the accompanying drawings, wherein:

figure 1 shows a schematic of the multi-layer high moisture barrier film structure in accordance with the present invention; figure 2 shows a schematic of the solventless lamination machine configuration for making a multi-layer high moisture barrier film according to the invention; figure 3 shows the multi-layer high moisture barrier film as re-wound on the master reel .

The multi-layer high moisture barrier film 1 for use in the production of pharmaceutical or medical thermoformed blister packs is represented in figure 1 and consists of five or more layers which, from the inner layer to the outer layer, are an inner layer 2, a layer of adhesive 3, a core layer 4, another layer of said adhesive 3 and an outer layer 5 respectively, whereby said inner layer 2 , core layer 4 and outer layer 5 consist of one or more polymers.

Preferably, the multi-layer high moisture barrier film 1 involves a PCTFE core layer 4, two layers of PU adhesive layers 3 of equal thickness on each side of the PCTFE core layer 4; and two layers of PVC of equal thickness attached to the other side of the PU adhesive layers forming the inner and outer layer 2, 5 of the high moisture barrier film 1 such that the material is symmetrical in a five layer composition: PVC / adhesive / PCTFE / adhesive / PVC. As mentioned, this embodiment offers the advantage that the multi-layer high moisture barrier film does not curl preferentially to one side when heated.

Other possibilities are that the inner layer 2 and the outer layer 5 are both PP, PE, COC, PETG, APET, PS, a blend of LLDPE with COC or an acrylonitrile-methyl acrylate copolymer grafted onto a nitrile rubber, which is commercially known as Barex®, and whereby the core layer 4 is PCTFE.

An alternative structure of the multi-layer high moisture barrier film proposed is that the inner layer 2 is composed of a combination of PE, Ethylene Vinyl Alcohol Co-Polymer Resin (EVOH) and PE, the core layer 4 is a co-extrusion film of APET, PETG and APET (PETGAG) and the outer layer 5 is PCTFE .

The multi-layer high moisture barrier film 1 according to the invention is manufactured by a solventless lamination technique involving two separate laminating steps, for which an example of a machine configuration is shown in figure 2. The adhesive 3 is prepared by mixing two components into a paste, whereby the viscosity can be adjusted with temperature. By means of a series of transfer rollers 6, the adhesive 3 is applied to one of the sheet substrates, say, the inner layer 2, that has been unwound from reels 7 and passed through a corona treater 8 which modifies the serface tension by electric discharge in order to increase the bond strength. The adhesive coating weight can be controlled by adjusting the temperature (which directly influences the viscosity) and speeds of the transfer rollers 6. These parameters are established for each type of inner layer 2. After the inner layer 2 has been coated with the adhesive 3, it is brought together with the core layer 4 by passing them through nip rollers 9. The higher temperature of the nip rollers 9 will accelerate the cross-linking of the adhesive layer 3 to the inner layer 2 and the core layer 4 and this laminated film 10 is rewound onto the master reel 11.

The laminating step is repeated in order to bond the laminated film 10 by means of a second layer of adhesive 3 with the outer layer 5 in order to obtain the multi-layer high moisture barrier film 1.

It should be noted that the order of the laminating steps can be changed or that there is only one laminating step by for example providing two consecutive sets of transfer rollers 6 and/or nip rollers 9.

In order to prevent the formation of gas bubbles when the adhesive 3 is curing in the master reel 11, the concentric pressure 12 in radial direction on the multi-layer high moisture barrier film 1 needs to be sufficiently high. This will be the case if the film 1 would be thin and flexible, but in the present case of a multi-layer high moisture barrier film 1, the multi-layer high moisture barrier film 1 will be thicker, typically 100 to 350 microns, and thus the adhesive coating weight will be higher, typically 2 to 3 g/m², making the multi-layer high moisture barrier film 1 more sensitive to the formation of gas bubbles . This is also due to the increased rigidity of the multi-layer high moisture barrier film 1 which results in less concentric pressure 12 on the underlying film layers of the master reel 11. The minimum amount of concentric pressure 12 on the film that is required to prevent the formation of gas bubbles is obtained, however, by rewinding the master reel 11 with sufficient reel tension 13, as shown in figure 4.

The required amount of reel tension 13 is empirically obtained and depends on the type of polymers used in the multi-layer high moisture barrier film 1.

For a rigid multi-layer high moisture barrier film 1 - when the thickness is more than 150μm, and particularly when it is more than 200 μm, or when the polymer in the multi-layer high moisture barrier film 1 is mainly of a rigid material such as PVC, PET, PP, or COC, the concentric pressure 12 is increased by increasing the amount of reel tension 13. The smallest pressure 14 occurs at the circumference of the master reel 11 and the largest concentric pressure 15 occurs near the core

16 of the master reel 11. For this reason the core 16 of the master reel 11 must be chosen sufficiently strong in order to prevent the core 16 to collapse under the largest concentric pressure 15. The core 16 can be made of cardboard treated with polymers, but is preferably made of steel or plastic. In order to prevent gas bubble formation in the multi-layer high moisture barrier film 1 near the circumference of the master reel 11, a cheap lead-in film 17 made of PVC, PE, PET or waste film is attached at the multi-layer high moisture barrier film 1 and re-wound at the end of the master reel 11. In order to assure all of the multi-layer high moisture barrier film 1 is free of gas bubbles, the outer lead-in film

17 preferably consists of a minimum of 2% of the total length of the films 1, 17 rewound on the master reel 11.

Optionally, the blister packs made from the multi-layer high moisture or oxygen barrier film 1 are passed through an autoclave whereby they are sterilized, preferably by steam sterilization at 121°C for 30 minutes, provided said multilayer high moisture barrier film 1 is composed of known autoclavable polymers such as PP, COC, a blend of COC with LLDPE and PCTFE .

In the above description, multi-layer high moisture barrier film 1 and method for manufacturing such a film 1 specifically relates to a multi-layer high moisture barrier film for use in the production of pharmaceutical or medical thermoformed blister packs, but it is not excluded that such a multi-layer high moisture barrier film manufactured by solventless lamination can be used for other applications .

The present invention is in no way limited to the form of embodiment described by way of an example and represented in the figures, however, such a multi-layer high moisture barrier film designed for thermoforming pharmaceutical or medical blister packs and a method for manufacturing such a film according to the invention, can be realized in various forms without leaving the scope of the invention.

Claims

1 .- A multi-layer high moisture barrier film for use in the production of pharmaceutical or medical therrαoformed blister packs characterised in that the film (1) is manufactured by solventless lamination in five or more layers which from inside to outside are an inner layer

(2), a layer of adhesive (3), a core layer (4), another layer of said adhesive (3) and an outer layer (5) respectively, whereby said inner, core and outer layers

(2, 4, 5) consist of one or more polymers.

2 . - A multi-layer high moisture barrier film according to claim 1, characterised in that said layers of adhesive (3) are of equal thickness .

.- A multi-layer high moisture barrier film according to claim 1 or 2 , characterised in that said inner layer (2) and said outer layer (5) are of equal thickness.

.- A multi-layer high moisture barrier film according to any of the preceding claims, characterised in that said inner layer (2) and said outer layer (5) are both PVC and said core layer (4) is PCTFE.

. - A multi-layer high moisture barrier film according to any of the claims 1 to 3 , characterised in that said inner layer (2) and said outer layer (5) are both PP, PE, COC, PETG, APET, PS, a blend of LLDPE with COC or an acrylonitrile-methyl acrylate copolymer grafted onto a nitrile rubber, and whereby said core layer (4) is PCTFE.

6 .- A multi-layer high moisture barrier film according to any of the claims 1 to 3 , characterised in that said inner layer (2) is a co-extrusion of PE, EVOH and PE, said core layer (4) is a co-extrusion film of PETGAG and said outer layer (5) is PCTFE.

7 . - A multi-layer high moisture barrier film according to any of the preceding claims, characterised in that the film (1) is thicker than 100 microns.

8 .- A multi-layer high moisture barrier film according to any of the preceding claims , characterised in that said adhesive layers (3) are PU, exhibiting adhesive characteristics by mixing two components together.

9 .- Method of manufacturing by solventless lamination a multi-layer high moisture barrier film according to any of the preceding claims characterised in that said adhesive layers (3) are prepared by mixing two components into a paste and brought together by means of a series of transfer rollers (6) with said inner layer (2) , said core layer (4) and said outer layer (5) through nip rollers (9) and rewound onto a master reel (11) , whereby the concentric pressure (12, 14, 15) of said master reel (11) is adjusted by a tension force (13) , the magnitude of which depends on the total thickness and/or rigidity of said multi-layer high moisture barrier film (1) .

10.- Method of manufacturing by solventless lamination a multi-layer high moisture barrier film according to claim

9, characterised in that a lead-in film (17) made of PVC, PE, PET or waste film is attached to the end of said multi-layer high moisture barrier film (1) in order to increase the concentric pressure (12, 14, 15) of the master reel on said multi-layer high moisture barrier film

(1), whereby said lead-in film (17) is rewound on said master reel (11) and whereby the length of said lead-in film (17) is preferably at least 2% of the total length of the films (1, 17) on said master-reel (11) .

11.- Method of manufacturing by solventless lamination a multi-layer high moisture barrier film according to claim 9, characterised in that blisters made of said multi-layer high moisture barrier film (1) can be sterilized by autoclave, preferably by steam sterilization at 121°C for 30 minutes, provided said multi-layer high moisture barrier film (1) is composed of known autoclavable polymers such as PP, COC, a blend of COC with LLDPE and PCTFE .