Patent Application
20160159541
The present invention is related to a high gas barrier and light proof, double-shell blister pack for medicinal contents, such as medication and analogous pharmaceutical products. The present invention also discloses a process for the production of this blister pack.
Blister packs are well known by those skilled in the art. They are produced on blister lines for the pharmaceutical industry to pack for example tablets and capsules by forming a packaging film to a cavity form, filling the tablet and sealing it by a lidding foil. If no gas barrier is needed, in particular no aluminum layer, usual films such as (PVC, PVDC/PVC, PP, PS, etc.) are easily thermoformable and constitute the bottom film of a single-shell blister in which cavities of a large variety of sizes can be thermoformed.
U.S. Pat. No. 5,011,019 discloses a single-shell blister pack with lid comprising an aluminium layer (
For blister packaging with total gas and light barrier requirements, laminates with an aluminum layer are required. The presence of such an aluminum layer considerably limits the depth of the cavities in a deep-drawing process since the elongation-at-break is conditioned by this aluminum layer. Therefore, a process called “stretch cold forming” is used. In this process, the periphery of a future cavity is maintained in place by clamping while the cavity is deep-drawn.
For single-shell blister packs with aluminum layer, it is state of the art that the bottom foil is formed and the lid foil is unformed. Forming tools form the Al laminate according to a cold forming process by means of plugs and a clamping. The multiaxial deformability is nevertheless limited. Single-shell blisters of this type are notably disclosed in EP 1 780 005 B1, EP 1 733 872 A1, WO 2007/042174 A1, WO 2007/057081 A1 and US 2010/0155288 A1.
A well-known example of a single-shell blister pack according to the prior art has the following structure: polyamide (PA) 25 μm/Al 45 μm/PVC 60 μm. This structure can be multiaxially stretch-coldformed by about 30%.
EP 0 637 285 B1 discloses a stretch-formed single-shell blister pack for freeze drying applications with a plurality of compartments made from a stretch-formable multilayer structure comprising a metal layer of 8 to 80 μm and a plastic support layer of biaxially oriented polyamide on each side having a thickness between 20 and 30 μm. The lid is not stretch-formed and comprises an aluminium layer from 15 to 25 μm. The blister pack is aimed for a process where a liquid is poured into the cavity and freeze dried, which requests a high resistance against temperature differences without curling and suggests the use of symmetrical film structures.
DE 102011001929 (Amcor) discloses a single-shell blister packaging using amorphous PET of a preferred thickness between 200 and 300 μm and a tensile strength at break much lower than 200 N/mm2 (MPa). Typical non-oriented PET (A-PET) for thermoforming exhibits a tensile strength at break between 55 and 75 N/mm2 (MPa) to allow thermoformability -see http://en.wikipedia.org/wiki/Polyethylene terephthalate. Furthermore, the multilayer structures disclosed in DE 102011001929 do not have two or more support layers of oriented polymer layer with a tensile strength at break higher than 200 N/mm2 (MPa), and in particular no aluminum layer sandwiched between those support layers.
The present invention aims to provide a double-shell packaging for medicinal contents exhibiting a total light barrier and a high gas barrier, wherein the only gas diffusion is limited to the edges.
The present invention also aims to optimize the size of the double-shell packaging by considerably reducing the ratio film laminate versus medicinal content by adapting the double-shell cavity size closely to the capsule or tablet size, thereby reducing the global size of the blister packaging and of the over-packaging with a logical positive effect on the global CO2 balance.
The present invention further provides a process for the production of a space-efficient double-shell blister according to the invention.
The present invention discloses a double-shell blister packaging for medicinal contents comprising one or more cavity(ies) of an optimized shape for the medicinal content, said double-shell packaging being the assembly of a first and a second multilayer structures sealed to each other via one or more seal layer(s), each multilayer structure comprising one or more aluminum layer(s) with a thickness of at least 20 μm, preferably 30 μm, and two or more support layers, wherein said two or more support layers have a tensile strength at break measured in machine and transversal direction of 200 N/mm2 or more, and an elongation at break of 50% or more, preferably 70% or more, measured according to EN ISO 527-3 published in 1995; sample type 2, part 1-6, each of said multilayer structures comprising cavities which, arranged face to face, enclose in use said medicinal content.
Particular embodiments of the present invention comprise one or more of the following features:
The present invention further discloses a process for the manufacturing of the blister packaging according to the invention, comprising the following steps:
The process according to the invention may comprise an additional step of cutting a weakening line or a tear notch into the first and/or second multilayer structure(s) to allow a push-through opening or a tear opening.
Tablet blisters are produced on blister lines for the pharmaceutical industry to pack a medicinal content, for example tablets and capsules, by forming a multilayer packaging film to a cavity form, filling the medicinal content and sealing it by a lidding foil. The presence of an aluminium layer with a thickness of at least 30 μm within the multilayer of the bottom and of the lidding foil guarantees a total gas and light barrier, if necessary.
The expression “medicinal content” in the present invention has to be understood in its largest sense and comprises tablets, pills, capsules but also contents which are not strictly considered for medical use but requesting a high gas barrier.
A first target of the present invention is to create a double-shell gas-tight blister, comprising an aluminium barrier layer of at least 20 μm, preferably 30 μm, with a comparable cavity size as an ordinary double-shell thermoform blister (without aluminium layer as gas and light barrier).
To reach this target, the present invention uses a multilayer laminate comprising an aluminium layer with an increased multiaxial deformability of at least 35%, preferably of at least 40%. Two multilayer structures with increased multiaxial deformability can be cold-formed (stretch-cold forming) creating cavities in each part (top and bottom) that are arranged symmetrically to each other, those cold-formed parts being assembled by sealing after having been filled with their medicinal content. The size of such a double-shell configuration is considerably reduced compared to a single shell with a flat lid. The requested quantity of multilayer structure can be reduced by at least 50%, and preferably by at least 70%—see
A burst test to test multiaxial deformability is performed by preparing a strip with a width of 20 cm out of the multilayer structure, which is introduced under a calotte, in case of bursting during the test, the testing time has to be adjusted and the tests have to be repeated over the whole width of the strip. The measured values have to be averaged and the standard deviation is being calculated (see
The good formability of a standard cold-formed multilayer structure is achieved by supporting the weakest layer in the laminate, i.e. the aluminium foil, by means of at least two strong plastic layers. Oriented polyamide (oPA) film of 25 μm is generally used for that purpose as well as other plastics having a tensile strength at break in machine transversal direction of at least 200 N/mm2 and an elongation at break of at least 50%, preferably at least 70%, measured according to EN ISO 527-3 published in 1995, sample type 2, parts 1-6.
The present invention discloses the use of at least two or more of such stiff polymer films, either both on one side of the aluminium layer or sandwiching the aluminium layer.
Non-limitative examples of such stiff polymer layer are oriented polymer layer such as oPET's (>230 MPa in MD and TD), oPPS, oPS, oEVOH, or non-oriented aromatic polyamides (aramid) or PEEK. Preferred polymers are specific polyamide formulations developed for higher stiffness applications. An example for a typical structure of a final laminate according to the invention is (tie or adhesive layers are not mentioned here):
The use of such relatively thick multilayer structures requests high sealing temperatures on the jaws since the heat has to cross several layers before it reaches the seal layer. This creates a phenomenon called the “Hot Tack Issue” where the air in the cavity is overheated, thus increasing the pressure in the cavity. At that stage, the seal layer is still molten and air penetrates the periphery of the cavity leading to a poor seal and cross-diffusion barrier.
To overcome this problem, high-viscosity melt at the necessary seal temperature is needed. The most convenient seal layers are therefore combinations of a low seal temperature and high molecular weight, (high viscous seal layer), as thin as possible to avoid an insulation effect. Non-limitative examples for such films are PETG 35 μm, various LLDPE versions with densities between 0.902 and 0.925 g/cm3 or multilayer films based on it, as well as ionomers films/coatings. High MW lacquers or thin coatings (1-10 μm) are possible alternatives (see examples) as seal layer as well as highly mineral filled coatings since they have a high-melt viscosity. The key features for sealing layer are melting point determined by DSC and seal-initiation temperature which should be lower than 125° C., preferably lower than 120° C. and even lower than 115° C. if possible.
To determine the seal-initiation temperature (SIT), seal trials are started at a temperature low enough to avoid any seal (seal strength=0 N/15 mm), then the temperature is progressively increased (5 or 10° C. steps) and when a seal occurs, the strength is measured and the SIT is considered as determined above 2 N/15 mm seal strength.
The double-shell blister packaging according to the invention needs an opening mechanism chosen between peeling, pushing-through or tearing.
The tear-open solution can be achieved by the use of appropriate plastic that breaks easily and thin enough Al layers. Such plastic structures are mostly oriented or intrinsically brittle. As non-limitative examples, mention may be made of PETG, oPA, oPET, etc.
Another option to achieve “easy tear” is specific weakening by laser-cutting (in distinct areas and trough specific layers only) or mechanically (punching/scratching at specific area into specific layers only) at the blister production line after forming or during the laminate production process. These techniques are well known by those skilled in the art.
The peelable solution often uses seal layer composed of a matrix polymer and a dispersed-phase inorganic or organic material, that substantially weakens the cohesive strength leading to an easy opening. Well-known examples are e.g. polyethylene blended with poly-1-butene (PE/PB-1) or polyethylene with talcum added. For lacquers, debonding agents are used but adhesively-failing structures can possibly be used.
The peel and seal strength is given in N/15 mm. The test procedure generates a cross seal at appropriate temperature using sealing jaws of 10 mm, the sealing pressure is 50 N/cm2, +/−2 N/cm2, sealing time 0.5 sec. To measure the peel or seal force via a testing machine, the test velocity is 100 mm/min and the takedown angle 90°.
The push-through solution needs to take care on the tablet, which should not break, and therefore needs a cavity that must be sufficiently weak or breaking easily. This is an opposite requirement to the high-strength demand to achieve exceptionally high formability. Therefore, the push-through design feature can be achieved after forming, i.e. on the blister line. Laser ablation/cutting can be used to weaken the layers or scratching/punching can again be used to weaken the laminate in a certain region/area, enabling easy breaking of the laminate when pushing the tablet through.
Another advantage of the present invention is the sustainability of the double-shell blister pack since “thick” laminates lead to a higher CO2 emission than thin foils and one would expect a worse CO2 emission balance per square meter for the structures according to the invention than for the combinations used in a standard single-shell blister as they are thicker and heavier. Nevertheless, the blister pack according to the invention can pack up to 75% more tablets or capsules, as the cavity area size is up to 75% smaller leading to a better CO2 emission balance than for prior-art blisters (see Table 2).
Another aim of the present invention is to considerably reduce the so-called cross-diffusion. Cross-diffusion is the moisture and gas entering the cavity by diffusion through the seal layer (see
The calculations take into account the water-vapor transmission coefficients (g/m2/day) of the individual layer of the bottom and the lid foil on the inner sides (IS and sealing side of the Al foil)-see relevant layer for cross-diffusion in
The double-shell example B (PA25/PA25/Al/PE) achieves a cross-diffusion reduction of 27% compared to the single-cavity blister example B of the prior art. Important is the reduction in perimeter, where the cross-diffusion enters the cavity, by reduction of the blister-cavity size and minimizing the thickness of the seal layer. This is achieved by reducing the blister-cavity size and subsequently the perimeter through which cross-diffusion occurs by using an Al laminate with increased multidirectional deformability (approximately 40%) and by forming both lid and bottom foil creating a double-shell according to the invention. The cavities are formed in a blister line forming both lid and bottom foil. A scheme of a blister line for that purpose is shown in
The most important difference to a usual blister line is the second forming station for the lid and the possible presence of a second sealing station to heat the multilayer structure from both sides.
Further advantages of the present invention are:
The extremely low cross-diffusion rate of this type of packaging is evaluated at approximately 1.4*10−6 g water-vapor/day. On the contrary, the best thermoform blister typically has a cross-diffusion rate of approximately. 1*10−4 g water/day entering the cavity under 40° C./75% relative humidity outside of the blister and 40° C./0% rh. inside, wherein the blister tablet is considered as an infinite water absorption sink.
This low quantity of water-vapor diffusion is difficult to measure and it can only be performed by using several blisters having several cavities over long periods of time (half a year for example, 10 blisters with 10 cavities). Then, a difference of 0.1 mg can be measured. Examples: 1.4*10-6*10 blisters*10 cavities*183 days (half year)=0,026 g in half a year. And 1.83 g for the thermoform case, which corresponds to half a year at 40/75, is a typical storage condition for pharmaceutical companies (so called ICH conditions).
For the aluminium layer, soft temper types are used as multidirectional stretchability is required. Non-limitative exemples are: EN AW 8006, EN AW 8021, EN AW 8021A, EN AW 8021B, EN AW 8014.
The above-mentioned Al alloys can be milled, and after soft tempering, their elongation at break is above 8% and tensile strength is above 60 MPa. The surface of the Al foil must be homogeneous and free of oil. Optionally, the surface of the aluminium foil can be surface treated (corona, plasma, chemically, primer, washed with solvent MEK). The alloy should be fine grained with small and uniform grain sizes, there should be more than five, preferably seven, grain layers above each other across the thickness.
The so-called support layers are specific plastic layers which, due to their intrinsic stiffness or thickness, reach a tensile strength at break above 200 N/mm2 in machine and transversal direction, and an elongation/strain at break above 50% in machine and transversal direction. Furthermore, the strain hardening should have a substantially positive slope in the corresponding technical stress/strain curves. The determination of the tensile strength and elongation at break as well as technical stress/strain curves is performed by a (Zwick/Instron) tensile testing machine according to EN ISO 527-3 1995, sample type 2, part 1-6.
The following tables show examples of typical structures according to the invention for top and bottom of peelable double-shell blisters (examples 1 to 6) and tear-open blisters (examples 7 to 12). The commercial types of the polyurethane adhesives, primer, and coextruded tie layer as well as the support layer and the seal layers are specified below.
The layer thickness and weight of the various examples is reported in the following tables
(1)Forming depth
| Number | Date | Country | Kind |
|---|---|---|---|
| 13175849.2 | Jul 2013 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2014/064606 | 7/8/2014 | WO | 00 |
