Flexible, multiple-compartment drug container and method of making

IS 2 171 929 T3

DESCRIPTION

Flexible, multi-compartment medicine container and its manufacturing process.

The present invention refers to a sterile, flexible container used for storing and mixing drugs and diluent liquids in a sterile medium and for dispensing the mixtures therefrom of the type as defined in the pre-assembly of claim 1, and a method of its manufacture. More particularly, the package is manufactured from film tapes using modular compartment forming stations. The container is manufactured to include sacrificial ports through which the container is supported and transported through modular fill isolators.

Various drug (drug) solutions are commonly administered intravenously (through IVs) from sterile containers to patients. Often such solutions comprise a mixed combination of a liquid diluent, for example, an aqueous dextrose or NaCl solution, and a medicament. Desirably, the drug and diluent are stored separately in the container under aseptic conditions and are not mixed together until immediately prior to use to prevent degradation of the final product. Common diluent and drug packaging is often further complicated by the character of the drug which may be a powder sensitive to moisture contamination or a powder or liquid sensitive to degradation under exposure to light or oxygen.

Accordingly, various drugs, such as antibiotics, which are unstable over time in solution have been stored separately in gas and moisture impermeable vials, in containers, or the like before use. Before being administered to a patient, drugs stored in this way must be mixed, or diluted in, physiological solutions or diluents that are also preserved separately. Although capable of maintaining the stability and effectiveness of the drug, the storage of the separate component is a problem and involves the risk of bacteriological contamination during handling, mixing, and subsequent administration to a patient. Accordingly, medical packages have been developed that include a compartment for the storage of an unstable drug and a compartment containing a diluting liquid.

Immediately prior to IV administration to a patient, the compartments are placed in communication with each other so that the contents can be mixed together aseptically.

Multi-compartment packages are known, which allow separate storage of liquid diluents and drugs. Such packages are described, for example, in US Patent No. 4,608,043 to Larkin and US Patent No. 5,176,634 to Smith, et al. US Patent Nos. 4,608,043 and 5,176,634 are expressly incorporated herein in their entirety by reference. The compartments of the containers described in the preceding patents are separated from each other by breakable thermal seals. The seals are broken by manipulation of the container so that the contents of the compartments can be mixed together to thereby form a solution that is delivered to the patient through a standard IV arrangement.

Solution packages on the market today are generally made of materials comprising PVC plastic. PVC material is generally quite dark in appearance, making the contents of a container made of such material difficult to inspect. As a consequence, inspection of such containers for leakage and moisture contamination is quite difficult, as is verifying whether complete mixing of drug and diluent has taken place prior to administration to a patient. Additionally, various hazardous chemical agents are used in the manufacture of PVC material that must be disposed of in an environmentally safe manner. PVC containers must be carefully disposed of following use, because PVC emits toxic gas when incinerated and includes a toxic plasticizer that can leach into the surrounding environment if the container is buried in a landfill. This toxic plasticizer is also capable of leaching in IV solutions, making PVC containers unsuitable for use with various types of drugs.

The drug compartment of such multi-compartment packages is desirably protected from moisture and atmospheric gases as well as exposure to UV and ambient radiation to prevent degradation of the medication contained within. A known method of protecting the drug compartment from, for example, moisture and oxygen contamination is described in US Patent No.^°5,267,646 in the name of Inouye et al., In which the drug compartment is surrounded by a secondary compartment containing a desiccant and an oxygen absorber. Free oxygen and moisture vapor allow it to penetrate the secondary compartment material, and is absorbed by the desiccant and oxygen purifier before it is able to affect the material of the secondary compartment.

ES 2 171 929 T3 drug compartment.

Although this method is capable of providing some degree of protection for the drug compartment against free oxygen and moisture, the method requires an additional layer of material (a secondary compartment) that must be provided around the drug, making it more difficult to inspect the contents of the compartment. of medication before reconstitution. Furthermore, no protection is provided against the effects of UV or ambient light degradation of the contents of the drug compartment.

United States Patent No. 5,176,634 to Smith et al., Considered the closest prior art, describes a medical container that has multiple compartments separated by peelable gaskets that can be ruptured by manually applying pressure to the exterior of the container. The container is made up of two sheets of flexible materials that are sealed together along its perimeter. Separate drug and diluent compartments are formed in the container by breakable thermal seals. The back film is impermeable to water vapor and is constructed of a laminated material that has an inner layer of polypropylene, a middle layer of aluminum metallic tape and an outer layer of polyester film. The vapor impermeability of the back foil extends the shelf life of the product by reducing, by half, the permeation of diluent vapor from the container, and the permeation of the vapor from the atmosphere within the drug compartment. Further reduction in vapor permeability is provided for the peelable attached medicament compartment with a third lamina of laminated material which is identical to the rear film, on the front film of the package in the region of the medicament compartment. This third sheet of laminated material is sized to cover the drug compartment and, in combination with the back sheet, provides a vapor impermeable enclosure.

However, once the third vapor impermeable sheet is peeled out of the drug compartment, the drug compartment is no longer enclosed and therefore susceptible to vapor permeation from the atmosphere. Additionally, moisture vapor is able to migrate from the diluent compartment into the drug compartment through the peelable gasket material that separates them. Because the vapor-impermeable coating is routinely peeled off from the drug compartment during a hospital arrival inspection procedure, long-term storage of such packages is problematic. In cases where the drug is a powder, highly susceptible to moisture degradation, the shelf life of a container that has had its vapor impermeable coating removed is often no more than a few days.

In view of the above, it can be seen that there is a need for an improvement over prior art packages where there is a need for medical packages that are environmentally safe to manufacture and dispose of. Such packages should be capable of protecting powdered drugs and other sensitive drugs from humidity and atmospheric gases, while, at the same time, allowing easy visual access to the contents of the drug compartment. Protection from UV and visible spectrum radiation is also desired.

Simple frangible or peelable gaskets are used in several prior art multi-compartment packages to divide the drug and diluent compartments to exclude inadvertent delivery of components prior to mixing. Simple gaskets of this type are formed across the container in its width direction, and have a uniform cross-sectional thickness and length throughout the entire gasket. When the container is manipulated to break the joints, and therefore mixing the drug and diluent together prior to dispensing, the mechanical pressure of the liquid diluent against a joint is mitigated as soon as any portion of the joint is broken and allows the diluent enters the medicine compartment. Such a partial rupture of the linear seal often does not allow full delivery of the fluid contents of the diluent compartment to the medicament. Significant amounts of the diluent can remain in the diluent compartment, trapped in the corners defined by the side wall of the compartment and the left and right ends of the joint. Such partial breakdown can also result in incomplete mixing of drug with diluents and incomplete delivery of the mixed product to the patient.

It is therefore desirable to provide an IV container that has multiple compartments for the storage of diluents and medications in an individual package that has peelable gaskets that divide the compartments that are configured to rupture substantially completely along their entire length. for the complete mixing and mixing of the contents, and to ensure the supply of the full amount of the final mixed product.

IS 2 171 929 T3

It is further desirable that the container arrangement excludes the inadvertent supply of any of the components prior to mixing, but allows visual verification of the condition of the components following receipt of the container by a hospital pharmacy service, but prior to storage. and subsequent distribution. The ability for improved protection of the contents of one or more of the container compartments against moisture, oxygen permeation or light degradation is also desirable.

This need is fulfilled by the packaging of claim 1 and the method of claim 41.

The present invention provides a container having multiple compartments separated by peelable gaskets that can be broken by manually applying pressure to the exterior of the container. The container is made up of two sheets of flexible laminated materials, which are sealed together along their perometers. Separate compartments in the container are formed of peelable gaskets. In a first embodiment of the invention, three compartments are formed in the package, the first compartment contains a liquid diluent, the second compartment contains a powdered medicine that can be mixed with a liquid diluent by separating the peelable gasket that divides the two compartments. , and the third compartment is an outlet compartment from which the mixed medication solution is dispensed.

In one aspect of the invention, the container is constructed of a flexible back sheet and a flexible front sheet sealed to the back sheet along a common peripheral edge. A first peelable gasket extends between two sides of the common peripheral edge and removably joins the front and rear lamines to form a compartment containing a diluent. A second peelable gasket extends between the two sides of the common peripheral edge and removably joins the front and rear loamines to thereby form an outlet compartment and a compartment containing a drug that is intermediate of the outlet compartment and the compartment. of diluent. A clear, high barrier laminate film is sized to cover the drug compartment and is sealed to the front lamina. An opaque high barrier protective film is sized to extend over the clear high barrier laminate film and drug compartment and is removably sealed to the clear high barrier laminate film. The clear high barrier film and the opaque high barrier film, in combination, form a high barrier protective coating over the drug compartment.

In one embodiment, the opaque, high barrier protective film includes an inwardly directed layer of ethylene vinyl acetate polymer on its surface; a polyether polymer layer, having a higher melting temperature than the ethylene vinyl acetate polymer layer, on its outward facing surface; and a layer of opaque high bar aluminum metallic tape between the layers of ethylene vinyl acetate and polyether. The opaque high barrier protective coating is peelable attached to the drug compartment for easy removal and later inspection of the drug compartment contents.

In another aspect of the present invention, the clear, high-barrier laminate film comprises clear, moisture-barrier and oxygen-barrier laminate films provided between the opaque, aluminum metallic tape-containing protective film on the front lamina of the container, in the region of the medicine compartment. Specifically, the clear high barrier laminate film comprises an inner polypropylene layer adjacent to the front sheet of the package; an outer layer of polyester; and both a clear, transparent high moisture barrier and a clear clear high oxygen barrier, or both, disposed between the inner and outer layers.

In yet another aspect of the present invention, the peelable gaskets are constructed to present a characteristic curvilinear resistance with respect to hydraulic pressure on the gasket caused by manipulation of the container. The curvilinear strength characteristic is strongest in the center of the peel joint and tapers to either side. Separating the gasket is achieved by manipulation of the container creating pressure on the diluent in the first compartment which then hydraulically separates the gasket substantially completely along its length between the compartments that allow the diluent and drug to mix. A third compartment, adjacent to the second compartment and opposite the diluent compartment, contains an outlet port for distribution of the mixed fluid. A peelable gasket between the second and third compartments prevents administration of the contents prior to mixing of the contents of the first two compartments. After mixing, further manipulation of the container to exert pressure on the contents breaks the second seal substantially completely along its length allowing the medicated fluid to be distributed across the orifice.

IS 2 171 929 T3

In a further embodiment of the invention, an additional, sacrificial moisture vapor barrier compartment is constructed between the diluent and drug compartments, forming an additional peelable gasket in advance of the peelable gasket that separates the diluent from the compartment. of the medicine. Additionally, the sacrificial moisture vapor barrier compartment provides additional protection for the drug compartment against inadvertent rupture of the drug compartment seal.

In a still further aspect of the present invention, the drug compartment is protected from premature exposure to liquid diluent by folding the container over the region of the peelable seal formed between the drug and diluent compartments. The folding of the container presses the container material together in a region in front of the first peelable joint, reinforcing the joint against hydraulic pressure caused by inadvertent handling of the container. Once the package is folded, means are provided to maintain the package in a folded condition. In one embodiment, a tab is inserted into a retaining slot, where both the tab and the retaining slot are integrally formed, along with the container, from the packaging materials. The container can therefore be repeatedly unfolded for periodic inspection of the contents of the container, and folded again for storage.

In another aspect of the present invention, the opaque high barrier protective film is peelably attached to the clear high barrier laminate film to allow easy removal and inspection of the drug compartment. Only a portion of the surface of the clear high barrier laminate film is contacted by the opaque high barrier protective film, the bond strength being directly proportional to the area of ​​surface contact. The opaque, high-barrier protective film is affixed onto the clear, high-barrier laminate film by a formed gasket head that defines a regular series of generally circular non-contact areas. The strength of the peel joint formed in this way is easily adjustable by varying the number of non-contact areas.

In a still further aspect of the present invention, a method of forming a flexible container for combined administration and storage of drugs and diluents for IV solutions comprises the steps of sealing a transparent flexible front sheet to a vapor impermeable flexible back sheet, as well as along a common peripheric border; heating the front and rear loamines in a first localized area to fuse the heated portions of the adjoining surfaces together, thereby forming a first peelable joint that extends between two sides of the common peripheral edge; and heating the front and rear sheets in a second localized area to fuse the heated portions of the adjoining surfaces together, thereby forming a second peelable joint. The first peelable gasket separately joins the front and rear sheets to thereby form a first compartment containing a diluent. The second peelable gasket removably joins the front and rear sheets to thereby form an outlet compartment and a compartment for containing a medicament that was between the outlet compartment and the diluent compartment. The first and second sacrificial orifices are interposed between the front and rear loamines and are placed in communication with the diluent and drug compartments, respectively. The diluent compartment is aseptically filled with a diluent solution through its respective sacrificial orifice and the joint is completed along the periphery of the containers, in the region of the orifice. Likewise, the drug compartment is aseptically filled with a drug through its respective sacrificial port and because the port is sealed along the periphery of the package, following which the sacrificial ports are removed from the package. The formation and filling of the container is achieved without subjecting the container to a sterilization stage after the first stage of filling the compartment.

Specifically, the diluent and drug compartments are aseptically filled with pre-sterile diluent and pre-sterilized drug in a sterile environment. In one embodiment, the sterile environment is provided in an isolator within which the ambient atmosphere is maintained in a sterile condition.

In a further embodiment of the invention, the unfilled containers are placed on a transport stand which is then sealed against environmental contamination. The transport support, and the containers inside, are subjected to E-beam sterilization. The transport support, and the containers inside, are introduced inside the isolator through a UV decontamination tunnel that ensures the maintenance of a sterile environment inside the isolator.

IS 2 171 929 T3

These and other features, aspects, and advantages of the present invention will be more fully understood when considered with respect to the following detailed description, appended claims, and accompanying drawings where:

Figure 1 is a semi-schematic front view of an exemplary embodiment of the container provided in accordance with the practice of the present invention showing the arrangement of the compartments and the intervening curvilinear joints including an outlet hole and locking tabs. folded.

Figure 2 is a semi-schematic side cross-sectional view taken along line 2-2 of Figure 1 depicting the flexible sheets that make up the package, the thickness of the layers in the sheets is exaggerated for clarity. .

Figure 3 is a semi-schematic fragmentary cross-sectional view taken along line 3-3 of Figure 2, showing the configuration of the flexible sheets of a first embodiment of the container of the present invention without the Optional, transparent high barrier interlayer.

Figure 4 is a semi-schematic fragmentary cross-sectional view of the configuration of the flexible sheets of a first embodiment of the invention representing an optional, transparent, high-barrier intermediate film.

Figure 5 is a semi-schematic fragmentary cross-sectional view showing the laminating configuration of the flexible sheets of a second embodiment of the container of the present invention depicting a second embodiment of an optional, transparent intermediate film. high barrier.

Figure 6 is a semi-schematic front view of the embodiment of the package of Figure 1, showing the package being folded for storage.

Figure 7 is a semi-schematic front view of a further embodiment of the package provided in accordance with the present invention showing an additional peelable gasket and intermediate compartment provided to protect the drug compartment against moisture vapor permeation.

Figure 8 is a semi-schematic front view of an exemplary embodiment of a container provided in accordance with the present invention in an intermediate stage of its manufacture showing the arrangement of sacrificial holes for filling the container.

Figure 8a is a semi-schematic side view of an exemplary embodiment of a container, detailing the arrangement and construction of the powder- and liquid-filled sacrificial orifices that include a lid in accordance with the present invention.

Figure 8b is a semi-schematic top view of the sacrificial orifices of Figure 8a detailing the configuration and arrangement of the orifice flanges.

Figure 9 is a semi-schematic plan view of an embodiment of a modular container manufacturing apparatus according to the present invention.

Figure 10 is a semi-schematic perspective view of a handling container provided in accordance with the present invention, including a container tray for receiving a rail cartridge and covered by a sealable film cap.

Figure 11a is a semi-schematic perspective view of the components of the rail cartridge of Figure 10, representing the rail cartridge in exploded form and easy for assembly.

Figure 11b is a semi-schematic perspective view of the fully assembled rail cartridge of Figure 11a.

Figure 12a is a semi-schematic plan view of the rail cartridge of Figures 11a and 11b depicting packages loaded on the rails in accordance with the present invention.

IS 2 171 929 T3

Figure 12b is a semi-schematic front view of the loaded rail cartridge of Figure 12a showing how the packages are held within the rails by the sacrificial holes.

Figure 13 is a flow chart of the aseptic filling and sterilization process for an embodiment of a package in accordance with an embodiment of the present invention.

Figure 14 is a semi-schematic plan view of one embodiment of a modular container filling apparatus showing progressive process stations in accordance with the practice of the present invention.

Figure 15a is a semi-schematic illustrated sectional view of a portion of a container conveyor belt in accordance with the practice of the present invention.

Figure 15b is a semi-schematic partial perspective view of the arrangement of a conveyor belt and powder filling wheel showing the direction of movement of the containers below the filling wheel.

Figure 16 is a semi-schematic illustrated view showing a peelable drug compartment cover that is removed for inspection of the drug prior to mixing and use.

Figure 17 is a semi-schematic illustrated sectional view demonstrating manipulation of the container to separate the first peelable gasket to mix the diluent and drug.

Figure 18 is a semi-schematic illustrated sectional view demonstrating manipulation of the container to separate the second peelable gasket to distribute the drug solution.

Figure 19 is a semi-schematic partial front view of an exemplary embodiment of a medical container showing the construction and arrangement of the curvilinear joints.

Figure 20 is a semi-schematic front view of a conventional peelable gasket showing, in imaginary, the progressive phases of incomplete rupture of the gasket.

Figure 21 is a semi-schematic front view of an exemplary embodiment of a curvilinear peelable gasket provided in accordance with the practice of the present invention showing, imaginary, the progressive phases of complete gasket rupture.

Referring to Figures 1 and 2, schematic front and cross-sectional side views are shown, respectively, of a preferred embodiment of a flexible, sterile package 10 provided in accordance with the practice of the principles of the present invention. Although the container 10 can be viewed in any orientation, for purposes of explanation here, the position of the compartments of the container with respect to each other is described as positioned in Figures 1 and 2. The container 10 is formed from the front plate 12. and a backing or backing sheet 14 (shown only in Figure 2). The front and rear laminates can be constructed of a single layer of flexible material or laminates of multiple layers of flexible material which should be described in more detail below. The loamines that make up the package may be provided separately and then sealed together at their common peripheral edge, forming an edge seal 16 that extends around the entire periphery of the package. Such peripheral gaskets can vary in configuration and width. A formed gasket, such as that depicted on the rear gasket portion 16a and the lower gasket portion 16b in Figure 1 can be used to provide gripping areas for the user to manipulate the container and for attachment of the container to, for example , a supportive IV. Alternatively, the front and back laminates can be formed from a single film sheet that is folded back and sealed by means of a gasket that extends around the peripheral portion of the package. The sheets sealed together are referred to here as the "shell" or "body" of the container.

In the present embodiment, the container 10 is divided into three separate compartments; an upper compartment 18, an intermediate compartment 20, and a lower compartment 22, each of which is sterile. The intermediate and upper compartments 18 and 20 are separated from each other by a first peelable joint 24, and the lower and intermediate compartments 20 and 22 are separated from each other by a second peelable joint 26. The peelable gaskets 24 and 26 extend between the two sides of the container, that is, between the right side 10a and the left side 10b that join the front and rear laminates. A "peelable" gasket as the term is used here is a gasket that is durable enough to allow normal handling of the container that was still peeled, allowing separation of the foil.

ES 2 171 929 T3 front from the back sheet in the region of the joint, under hydraulic pressure applied by manipulation of the container, allowing the mixing and distribution of the container's contents to be roasted. A peelable gasket is formed by a partial casting together with the polymer present in the adjacent layers of the front and rear laminates. The gasket is obtained by a thermic sealing process that is carried out with different times, temperatures and pressures that is described in greater detail below. Conversely, peripheral edge gasket 16 is significantly stronger than "peelable" gaskets and will not be broken by pressures generated to separate the peelable gaskets. The configuration of peelable gaskets with a non-linear resistance to the hydraulic opening pressure of a manipulated container, as contrasted to a conventionally formed liner gasket, substantially promotes complete peeling of the entire gasket during use of the container as described. in more detail later.

In a topical application for the container 10 of the present invention, the upper compartment 18 is filled with a liquid diluent and the intermediate compartment 20 is filled with a medicament, provided topically in powder form. The lower compartment 22 functions as a safety interface for an outlet port 30 and remains empty until the container is used. The outlet port 30 extends downwardly from a compliant chair 32 which, when viewed from above, was configured as an ellipse with its focal ends flattened, and is disposed approximately in the center of the bottom edge of the container between the front lamina 12 and rear lamina 14. The flattened focal ends of saddle 32 form flanges 34, best seen in Figure 1, which taper conically toward the flattened edges of chair 32. The flattened eloptic configuration creates a uniformly curved surface to which the front and rear sheets are firmly attached by, for example, a permanent gasket (referred to here as the "outlet gasket") 36 (shown in Figure 2). The outlet port 30 comprises a body portion 38 and a nozzle 40 that is configured for attachment to a standard IV delivery device. A cap (not shown) is provided to cover the nozzle and maintain its sterility. The cap is removed just prior to attachment of an IV set to the outlet port. The ribs 39 are provided spaced apart around the body portion 38 of the outlet port 30 to provide a surface that can be easily gripped when attaching an IV to the container. In the illustrated embodiment, four ribs 39 are provided which extend longitudinally from the surface of the body portion 38 of the container 10. Although four longitudinal ribs are shown, one of ordinary skill in the art will recognize that various other types of surface hinge can be provided that will allow the hole to be easily gripped, such as circumferential ribs, transverse ribs, knotting or shading of the body portion surface. , and the like.

The materials used in the front and rear sheets of container 10 are selected based on the material that should be stored inside. Preferably, at least one of the lamines is transparent to allow the contents of the container to be visually inspected and to allow the level of solution in the container to be observed during dispensing. Suitable materials for the manufacture of the transparent sheet are topically polymer films, laminated in multiple layers or in single layers.

In particular, whether constructed of a single or multi-layer laminated polymer film, the materials comprising the front 12 and back 14 laminates of the package 10 are chosen for clarity and transparency. Conventional polyvinylchloride (PVC) container materials are generally dark in appearance, making it difficult to properly view the interior of the container and determine the levels of any of the fluids contained within or the presence of particulate matter. This is a particularly dangerous situation when medication is administered intravenously. It is essential that a nurse or clone worker be able to report, at a glance, that the fluid of any medication being administered from a medical container is free of particulate matter.

The first form of realization

In a first embodiment of the package of the present invention, which is depicted in fragmentary schematic cross-section in Figure 3, the front sheet 12 was constructed of a single layer, transparent, thermoplastic polymer film 44. In this embodiment, clear film 44 comprises a blend of about 80% by weight of polypropylene-polyethylene copolymer available from Fina Oil and Chemical Company of Deerpark, Texas, having a trade designation of Z9450, and about 20% in weight of styrene ethylene-butylene styrene (SEBS) thermoplastic elastoomer, available from Shell Chemical Corporation under the trade name Kradon® and having a trade designation G1652. Kraton® G1652 thermoplastic elastomer is a three-block copolymer with polystyrene end blocks and a poly (ethylene-butylene) rubber center block. Subsequently, the transparent film 44 is formed from the mixed granules8

ES 2 171 929 T3 two in a commercial extrusion apparatus. The transparent polymer film 44 comprising the front film 12 can be constructed with varying thicknesses, depending on the use to which the container is put, and the durability required for that application. Suitable thicknesses for the material comprising lead sheet 12 can range from about 76.2 to about 381 µm (about 3 to about 15 mils). In a preferred embodiment, the transparent polymer film 44 comprising the front sheet 12 is 304.8 µm (2 mils) thick.

In addition to its clarity and transparency, 44 transparent polymer film (which may alternatively be referred to as the "80:20 film") is particularly suitable for the formation of both "peelable" joints and permanent edge joints along the periphery. of the container 10. As will be described in greater detail below, the 80:20 film, according to the invention, is capable of accommodating both lower temperature peelable gasket forming processes and higher temperature permanent gasket, without affecting the integrity of the material or its ability to provide an effective peelable joint.

For certain combinations of diluents and drugs, the back film 14 may have the same individual layer composition and configuration as the front film 12. Alternatively, multilayer films include layers that are impermeable to moisture and light, for example , may be preferred for the back foil to extend the shelf life of a filled container. In the embodiment of the container represented in Figure 3, a back laminate sheet is used, with three layers 14 that is impermeable to water vapor and light in order to preserve the effectiveness and activity of the binary components ( the medication and diluent not mixed, thus increasing the shelf life of the filled container.

In the exemplary embodiment, the back sheet 14 includes an inner gasket layer 46 on its inward-facing surface, constructed of an 80% / 20% w / w blend of polypropylene-polyethylene copolymer and thermoplastic elastomer of ethylene-butylene styrene styrene having a thickness of about three to six thousandths (the 80:20 film). In a preferred embodiment, the inner gasket 80:20 film layer 46 is a 152.4 µm (six mil) thick composition that is bonded by means of a suitable clear adhesive 48 to a layer of aluminum foil tape. high barrier 50 about 17.78 to 33.02 µm (0.7 thousandths to 1.3 thousandths) (preferably 25.4 µm or 1.0 thousandths). A high melt temperature outer layer 54 is provided on the surface facing the backsheet, and is attached to the high barrier aluminum foil tape layer 50 by means of a suitable transparent adhesive 52. In the form In the embodiment of Figure 3, adhesive layers 48 and 52 comprise a modified aliphatic polyester polyurethane adhesive, available from the Liofol Co. of Cary, North Carolina, under the trade designation Tycel 7009. The aluminum foil tape layer 50 is suitably constructed of a commercially available 25.4 µm (1 mil) aluminum foil tape, such as Alcan 1145, available from Alcan Rolled Products Company of Louisville, Kentucky.

Because the thermal sealing process used to form the peripheral edge gaskets and transverse peel gaskets is capable of damaging the high barrier aluminum foil tape layer, since the layer remains exposed, The outer high temperature layer 54 is constructed of a relatively high melting point polymer and functions as a protective layer to prevent contact between the metallic tape layer and the hot patterns of a thermal gasket apparatus. Additionally, the high temperature layer 54 serves as a heat seal release (also referred to as a mold release) because it does not melt or adhere to the heat seal plates at the temperatures used to form the seals.

The outer high temperature layer 54 is preferably a polyethylene terephthalate (designated herein as PET or polyester) available from Rhone-Poulanc under the trade designation Terphane 10.21, having a thickness in the range of about 10.2 to about 15.24 μm (0.4 to about 0.6 thousandths). In a preferred embodiment, the thickness dimensions of the multilayer laminate film 14 are 12.19 μm (0.48 mils) for the outer, higher temperature, polyester layer 54.25.4 μm ( 1.0 mil) for the 50 high barrier aluminum foil tape layer, and 6.0 mil (152.4 μm) for the 80:20 inner film gasket layer.

It has been found that the preferred material to choose for the back and front sheets, which results in the seventh performance of the peelable gaskets, is to incorporate an interfacial gasket layer on both sheets that comprise the 8:20 film. However, the interfacial joint layers of the front and back laminations may alternatively comprise polypropylene-polyethylene copolymer and elastomeric blends.

ES 2 171 929 T3 styrene ethylene-butylene styrene thermoplastics having different relative percentages. The relative percentages used will depend on the characteristics of the various gaskets contemplated for use in connection with a particular medical container, and the temperature and pressure parameters of the sealing process. Other types of flexible films, which may be useful in designing the front and rear sheets of the container shell 10 of the present invention, as well as the interfacial gasket layers on both sheets, are described in U.S. Patent Nos. 4,803,102, 4,910,085, 5,176,634, and 5,462,526.

In certain applications, particularly where the drug was in powder form, additional protection for the second or intermediate compartment 20 of container 10 is preferred. Such additional protection is provided to exclude the transmission of moisture, oxygen and / or light through of the film comprising the front part of the intermediate compartment to protect the drug powder from degradation. Additional protection of this type allows the container 10 to be stored, for substantial periods of time, without loss of medicinal efficacy.

Referring in particular to Figures 2 and 3, a protective, opaque, high-barrier film 55 is employed, in the illustrated embodiment, to cover the intermediate compartment 20. The film 55 interposes a barrier to moisture vapor permeation and free oxygen within the drug compartment. In the exemplary embodiment, the high barrier protective film 55 comprises a multilayer laminate structure that includes a layer of high barrier aluminum metallic tape. The use of an opaque aluminum metal tape laminate further helps prevent the drug contained in the intermediate compartment 20 from degrading due to exposure to visible light and UV radiation. Therefore, in the present embodiment, the opaque aluminum metallic tape comprising both the protective film 55 and the back foil 14 prevents penetration of UV and visible spectrum light into the intermediate compartment 20 of the package.

The high barrier protective film 55 is a multilayer laminate, constructed of an inner gasket layer 56, on its inward facing surface. In an exemplary embodiment, gasket layer 56 is a co-extrusion coated resin comprising a modified ethylene vinyl acetate polymer available from Dupont Chemical Company under the trade designation Appeel 1181, having a thickness of from about 5.08 to about 10 , 16 μιιι (0.2 to approximately 0.4 thousandths). A layer of 58 aluminum metallic tape, such as Alcan 1145, thick from about 17.78 to about 33.02 μιιι (0.7 to about

1.3 mil), (preferably about 25.4 µ or 1.0 mil) is adhered to the inner gasket layer 56 by means of a suitable transparent adhesive 57. An outer gasket release layer 60 comprising a polyethylene terephthalate (PET) film, such as Terphane 10.21, approximately 12.19 μιιι (0.48 thousandths) thick, forms the outward-facing surface of the high barrier protective film 55 and is adhered to the aluminum metallic tape layer 58 by means of a suitable transparent adhesive 59. Adhesive layers 57 and 59, of the present embodiment, comprise a modified alifaotic polyester polyurethane adhesive available from Liofol Co. under the trade designation Tycel 7909.

Because the inner gasket layer 56 of the high barrier protective film 55 is a co-extrusion coated resin, it is capable of providing a peelable gasket, over a wide temperature range, when applied to a number of different materials. . Materials to which such a co-extrusion coated resin forms a peelable gasket include acrylonitrile-butadiene-styrene (ABS), high-density polyethylene (HDPE), high-impact polystyrene (HIPS), polypropylene (PP), polystyrene (PS), polyvinylchloride (PVC), and the 80:20 film comprising the front sheet 12. The high barrier protective film 55 can therefore be releasably (peelable) attached to the outer surface of the front lamina 12, which covers the intermediate compartment 20.

Preferably, the high barrier protective film 55 is removable (peelable) from the container 10 prior to use, to allow examination of the state of the drug powder within the intermediate compartment 20. In the exemplary embodiment, best viewed In connection with FIG. 1, the liner 55 includes an extension tab 62 that can be grasped to peel the liner 55 out of the transparent front sheet 12. The contents of the intermediate compartment 20 are therefore exposed and can be visually inspected.

As can be understood by reference to FIG. 1, the high barrier protective film 55 is not attached to the container by a gasket over its entire surface area; furthermore, the film 55 was only partially sealed to the underlying material. These unsealed portions of the high barrier protective film 55 define a regular series of generally circular raised depressions 51, which

ES 2 171 929 T3 are the tactile residue of a heat seal bar into which a rectangular series of holes have been cut. When the heat seal bar is pressed onto the surface of the high barrier protective film 55, a themic seal is provided only over the surface contact regions of the heat seal bar and not in the regions where the bar material meets. has withdrawn (the holes). Since the pressure is also applied with heating, during the process, the high barrier protective film 55 takes an impression from the heat seal head, thereby giving rise to the high wavy textured surface.

The depressions 51 allow the protective high barrier film 55 to adequately seal on the underlying material of the medical package but, at the same time, provide easy removal of the film 55 without the application of undue force. Where all of the protective layer 55 is heat sealed on the surface of the container, an amount greater than the desired amount of the outside should be required to peel off completely. By reducing the gasket surface area, a lesser force (proportional to the gasket area) is required to remove the peelable aluminum strip. It is apparent from the above description that the amount of force required to remove the peelable aluminum strip is inversely proportional to the number of depressions (51 of Figure 1) formed in the film 55. Depending on the use to which the medical package is put, a more or less easily removable high barrier protective layer can be easily designed by simply increasing or decreasing the number of depressions 51 formed in the layer during the thermic sealing process.

In practical use, the filled container is received by a hospital pharmacy service, and is then stored for a period of time against necessity. Typically, prior to distribution, the pharmacist removes the layer of high barrier metallic tape 55 from the surface of the container, thereby exposing the drug compartment 20 so that the integrity of the contents can be visually verified. If the container is not put into use at the same time, it is returned to the pharmacy and distributed again, in the next order. Removal of the high barrier peelable film 55 from the drug compartment 20 leaves the contents of the drug compartment susceptible to degradation by moisture, light, and permeable oxygen. It is desirable that the filled containers of the present invention are capable of being stored in pharmacy services for periods of time greater than 30 days, before use, without the drug being severely degraded by exposure to moisture and free oxygen after it is used. You have removed the high barrier protective film over the medication compartment. As shown in FIG. 4, an intermediate, transparent, high-barrier laminating film 64 is interposed between the protective film containing a high-barrier aluminum metallic tape 55 and the drug compartment 20. The transparent high barrier intermediate film 64 covers and protects the contents of the drug compartment 20, after the peelable protective film 55 is removed from the container, from at least permeation of moisture vapor and free oxygen for a substantial period which, depending on of the activity of the contents of the drug compartment, can be as long as 30 days. In other words, the opaque, high-barrier protective film 55 in combination with the transparent, intermediate, high-barrier film 64 forms a high-barrier protective coating over the drug compartment.

Polymers are classified by the degree to which they limit the passage of penetrating gases, for example, oxygen or moisture vapor. The categories range from high barrier (low permeability) to low barrier (high permeability). The category in which the polymer is classified can vary according to the penetrating gas. As used herein, the term "high barrier", when referring to moisture vapor permeability, means a film with a permeability of less than about 1.5 g / 25.4 µm / m.²/ 24 n / 10⁵ Pa) (g / mil / m²/ 24hr / atm.) At 38 ° C, 100% RH As used herein, the term "high barrier" when referring to oxygen permeability means a film with a permeability of less than approximately 1 cm.³/ 25.4μm / m²/ 24 n / 10⁵Pa (cc / mil / m²/ 24 hr / atm.), At 25 ° C, 100% RH

In an exemplary embodiment, the transparent, intermediate, high-barrier film 64 comprises a three-layer high-barrier laminate structure that is significantly resistant to permeability to free oxygen and water vapor to protect the contents of the drug compartment. and increases the shelf life of the binary container. In one embodiment, intermediate film 64 includes an outer layer 66 of salyx-deposited polyethylene terephthalate (also referred to as SiOx-coated polyester or SiOx-coated PET), available from Mitsubishi Kasei under the trade designation Tech Barrier.^TM H, in contact with the sealing layer 56 of the protective high barrier film 55. The outer layer 66 is adhered to an intermediate layer 68 comprising a film of polyvinalic alcohol (PVA) (coated with SiOx) deposited with salice available from Mitsubishi. Kasei under the Tech Barrier trade designation^TM S. On its inward-facing surface, the transparent, intermediate, high-barrier film 64 includes an inner gasket layer 70 that

ES 2 171 929 T3 comprises a polypropylene-polyethylene copolymer, which can be mixed with styrene-ethylene-butylene styrene thermoplastic elastomer in various ratios. However, a 100% polypropylene-polyethylene copolymer layer is preferred. The individual layers of the intermediate laminate film 64 are adhesively bonded together. For clarity, however, these adhesive layers are not shown, but comprise a modified aliphatic polyurethane polyester laminate available from Liofol Co. under the trade designation Tycel 7909. The inner gasket layer 70 is securely attached to the outer surface of the the front film of the container 12 by an appropriate permanent ultrasound or thermal gasket, an adhesive pressure gasket, or the like. The transparent, intermediate high barrier laminate film 64 is sized, horizontally and vertically, to cover the entire surface area of ​​the drug compartment and also extends to cover the peelable and permanent gaskets formed adjacent to the drug compartment.

As is the case with the flexible, plastic materials that comprise the front film 12 of the container body, the three-layer laminate structure of the intermediate layer 64 is substantially transparent to allow inspection of the contents of the drug compartment 20. Therefore, unlike polyvinylchloride (PVC), and other similar materials, which are actually hazy (translucent), the interlayer 64 of the present invention is substantially clear and transparent, which allows the contents of the compartment to be easily inspected. medication, while imparting considerable protection against moisture degradation and free oxygen.

In particular, the barrier properties of the 64 high barrier transparent intermediate laminate film are substantially greater than those of conventional films, such as low-density polyethylene (LDPE), medium-density polyethylene (MDPE), low-density polyethylene linear density (LLDPE), ethylene-vinyl acetate copolymers (EVA), or mixtures of these polymers, in areas important for the function of the container, for example, permeability to moisture and oxygen. The oxygen permeability of the intermediate layer 64 is approximately 10 cm³/ 25.4 μm / m²/ 24 h / 10⁵ (10cc / mil / m²24hr / atm.). Conversely, the oxygen permeability of copolymer EVA, LDPE, and MDPE, respectively, are approximately 2500 (EVA 5%), 8300 (LDPE), and 8500 (MDPE) cm.²/ 25.4 μm / m²-24 h / 10⁵(cc / mil / m²-24hr / atm.). The oxygen permeability of LLDPE is approximately the same or slightly higher than LDPE. Therefore, the oxygen permeability of the transparent, high barrier interlayer 64 is several orders of magnitude lower than the oxygen permeability of polymers typically used to design binary medical packages.

Due to the barrier properties of the intermediate laminate film, the protective film containing peelable aluminum metallic tape 55 can be removed by a pharmacist for inspection on the contents of the container prior to distribution, and the container can then be stored during an additional period of time without the danger of oxygen- and moisture-induced degradation of the drug. Once the protective metal tape layer is removed, it is desirable that the container have a shelf life of approximately 30 days. After removal of the aluminum foil layer, the precise shelf life of a container that includes a clear, high barrier 64 laminate film necessarily depends on the moisture sensitivity of the drug contained in the drug compartment. Drugs with relatively low moisture sensitivity are capable of retaining efficacy for substantially longer periods of 30 days by virtue of being protected by the clear, high barrier laminate film 64. Additionally, drugs with extreme sensitivity to humidity, that is, those that would normally begin to lose effectiveness almost immediately after the removal of the aluminum metallic tape layer, can be stored for periods exceeding two weeks without losing effectiveness due to the moisture barrier properties of the clear high barrier film covering the drug compartment.

Although the intermediate barrier film 64 has been described in the exemplary embodiment as being affixed to the exterior surface of the drug compartment, it will be apparent to one of ordinary skill in the art that the intermediate layer can be sized to cover both the drug and the drugs. diluent compartments if desired. The manner of attachment of the intermediate layer to the outer surface of the container can also be varied without departing from the scope of the invention. Intermediate layer 64 can be permanently secured to the outer surface of the container by a suitable adhesive, as well as by permanent ultrasonic or heat sealing. Alternatively, intermediate film 64 may be removably provided on the surface of the container by adjusting the pressure and temperature characteristics of a heat seal, to render the seal peelable. In this case, film 64 could be peeled from container 10 as was the case with film 55.

It should be noted that in the exemplary embodiment, the drug is described as being

ES 2 171 929 T3 in the form of a dry powder. Dry powders of this type can be for example antibiootic compositions or antiemoetic compositions, with non-limiting examples of this type being: cefazolin, cefuroxime, cefotaxime, cefoxitin, ampicillin, nafcillin, erythromycin, ceftriaxone, methochloropramine and ticar / clav. However, a liquid drug can also be used in this system. Such a condition can arise when a liquid drug and a liquid diluent are not compatible for long periods of time and must be mixed just before being distributed to a patient. Furthermore, the medicament may be in the form of a colloid, crystalloid, liquid concentrate, emulsion, or the like. Additionally, the medication compartment does not need to be filled with a drug, by itself. Other medical compositions, such as lyophilized blood fractions, blood factor 8, factor 9, prothrombin complex, and the like, are equally suitable. While a single drug, and a single diluent compartment is described in the packaging of the present invention, packages having multiple compartments filled with different diluents and / or different drugs can be provided in accordance with the present invention.

The second embodiment

In a second exemplary embodiment of the present invention, which is depicted in schematic cross-section in Figure 5, an alternative construction is provided for the high barrier transparent intermediate laminate film (64 of Figure 4), which covers the medicine compartment.

As was the case with the first embodiment, depicted in Figures 2, 3, and 4, the clear high barrier intermediate laminate film 71 of Figure 5 may be provided in combination with an opaque, protective film that It contains high barrier, aluminum metallic tape (55 of Figures 2 and 3) disposed on the intermediate film 71 and therefore also on the drug compartment of the package. Accordingly, the intermediate, clear, high-barrier film 71 in combination with an opaque, high-barrier protective film, comprises a high-barrier protective coating disposed over the drug compartment. As described in greater detail below, the high barrier protective coating can include either a high moisture barrier layer, a high oxygen barrier layer, or both. The opaque protective film, containing aluminum metallic tape 55 is provided to prevent penetration of UV and visible spectrum light into the drug compartment of the container, if such protection is desired.

The alternative high barrier intermediate laminate film was constructed of a multilayer, thermoplastic, transparent polymer laminate, generally indicated at 71, with moisture and oxygen barrier properties. In the exemplary embodiment of Figure 5, the transparent, multi-layer, high-barrier film 71 comprises a sealant layer 72 on its inward-facing surface, constructed of 100% polypropylene having a thickness of about 76, 2 μm (3.0 thousandths). An oxygen barrier layer 74 is laminated to the sealant layer 72 by a first bonding layer 76 comprising a commercially available low-density polyethylene extrudate (LDPE) in combination with an initiator, and interposed between the barrier layer. oxygen 74 and sealant layer 72. Various flexible, polymeric films have been determined to be capable of providing adequate barriers to oxygen permeability, as further described below, but preferably, the oxygen barrier layer 74 of the multi-layer high barrier film 71 is constructed from a commercially available ethylene vinyl alcohol (EVOH) (EVOH) having a thickness of approximately 13.97 µm (0.55 thousandths).

Ethylenevinolic alcohol is indicated primarily for its barrier properties against oxygen permeability. In particular, its oxygen permeability barrier values ​​are topically in excess of four orders of magnitude greater than conventional primary bag films such as ethylene vinyl acetate (EVA), Surlyn¹®, medium and high density polyethylene (MDPE, HDPE). However, while providing a considerable barrier to oxygen permeability, ethylene vinyl alcohol alone may not provide sufficient protection from water vapor. Accordingly, a moisture barrier layer 78 is laminated to the ethylene vinyl alcohol oxygen barrier layer 74 by a second low density polyethylene (LDPE) bonding layer 80. Moisture barrier 78 is a transparent flexible film comprising an oriented high density polyethylene polymer (or HDPE) available from Tredegar Co. of Richmond, Virginia under the trade designation Monax.^TM, HD grade. The resulting composite barrier structure includes a polyester 82 (such as Terphane 10.21) gasket release layer (PET) on its outward facing surface, which in turn laminates to the moisture barrier. 78 by a third layer of low density polyethylene extrudate 84 adhesion.

IS 2 171 929 T3

The multi-layer, high barrier polymeric laminate film 71 of the exemplary embodiment described in connection with Figure 5 is a high oxygen barrier and moisture impermeable flexible film which is suitable for designing the intermediate layer (64 of Figure 1) that covers the drug compartment (20 of Figure 1) of a medical container. All of the materials that comprise the laminate are substantially clear and transparent, and do not show any substantial coloration. Therefore, the composite film of the illustrated embodiment of Figure 5 is particularly suitable for covering the drug compartment of a medical container so that its contents can be easily inspected at a glance.

Higher transparency can be obtained for the multilayer laminate film 71 of Figure 5 as opposed to the SiOx-containing laminate film 64 of Figure 4. In particular, although transparent, the SiOx-containing film shows a Slight yellowish color, the absence of which in the multilayer laminate film 71 was thought to be the main reason for the higher transparency of the laminate film.

Additionally, the SiOx-containing material is relatively stiff and friable, and can crack during the primary container manufacturing, filling process, and / or handling. Due to its inherent stiffness, the barrier properties of a SiOx-containing film decrease if the SiOx film is stretched beyond 1% due to destruction of the SiOx film substrate. Additionally, the state of SiOx containing technology is such that the barrier properties of SiOx film will vary from point to point on the surface of the film. This is because currently available SiOx spraying processes are not capable of forming a uniform film of consistent thickness. This variability of barrier properties is topically greater than that exhibited by extruded polymeric materials, which have lower variability due to their inherent homogeneous character. The barrier properties of a homogeneous polymeric barrier film is primarily a function of film thicknesses, which can be controlled very precisely during the manufacturing process.

While preferred materials for the high barrier clear intermediate film would include both an oxygen barrier layer and a moisture barrier layer, alternative materials can be used to provide a drug compartment coating that is tailored for particular uses. For example, one of the high barrier layers can be omitted giving a high barrier intermediate film that includes only a moisture barrier layer, or only an oxygen barrier layer. In addition, the high barrier intermediate film can include a moisture barrier layer, as described above, in combination with a gasket release layer that is constructed of a high temperature cast iron material that also has barrier properties. to oxygen.

Table 1 is a non-limiting list showing exemplary film 71 of Figure 5 and four additional examples of multilayer films or laminates useful in the manufacture of various embodiments of a high barrier, intermediate layer according to the invention. In the oHDPE list it refers to an oriented high density polyethylene such as HD grade Monax, PE coated with polyvinylidene chloride refers to a product available from DuPont Chemical Co. under the trade designation 50M44, and Aclar^TM refers to polychlorotrifluoroethylene film available from Allied Signal Corporation and is also known under the trade designation ULTRX 2000.

(See Table 1 on the next page)

IS 2 171 929 T3

TABLE 1

<td>Laminate Layer Material 71</td><td>Thickness, thousand. X 25.4 μm</td><td>Description of Layer</td>

1.

<td>PET (outer layer)</td><td> 0,48</td><td>Thermal Joint Release</td>

<td>LDPE extrudate</td><td> 0,5-1</td><td>Cloak of Adhesion</td>

<td>oHDPE</td><td> 2</td><td>Moisture Barrier</td>

<td>LDPE</td><td> 0,5-1</td><td>Adhesion Layer</td>

<td>EVOH</td><td> 0,55</td><td>Oxygen barrier</td>

<td>Extrudate / LDPE Primary</td><td> 0,5-1</td><td>Adhesion layer</td>

<td>Polypropylene (100%) (inner layer)</td><td> 3</td><td>Sealant Layer</td>

2.

<td>PET</td><td> 0,50</td><td>Thermal Joint Release</td>

<td>Adhesive</td><td></td><td>Adhesion layer</td>

<td>OHDPE</td><td> 2</td><td>Moisture Barrier</td>

<td>Adhesive</td><td></td><td>Adhesion layer</td>

<td>Polypropylene (100%)</td><td> 3</td><td>Sealant Layer</td>

3.

<td>Polyvinylidene Chloride Coated PET</td><td> 0,50</td><td>Release of Thermal Board and Oxygen Barrier</td>

<td>Adhesive</td><td></td><td>Adhesion Layer</td>

<td>OHDPE</td><td> 2</td><td>Moisture Barrier</td>

<td>Adhesive</td><td></td><td>Cloak of Adhesion</td>

<td>Polypropylene (100%)</td><td> 3</td><td>Sealant Layer</td>

IS 2 171 929 T3

TABLE 1 (Continued)

<td>Laminate Layer Material 71</td><td>Thickness, thousand. X 25.4 μm</td><td>Layer Description</td>

4.

<td>PET</td><td> 0,48</td><td>Thermal Joint Release</td>

<td>Adhesive</td><td></td><td>Adhesion Layer</td>

<td>Clarify^TM</td><td> 2</td><td>Moisture Barrier</td>

<td>Adhesive</td><td></td><td>Adhesion Layer</td>

<td>EVOH</td><td> 0,55</td><td>Oxygen Barrier</td>

<td>Adhesive</td><td></td><td>Adhesion Layer</td>

<td>Polypropylene (100%)</td><td> 3</td><td>Sealant Layer</td>

5.

<td>Polyvinylidene Chloride Coated PET</td><td> 0,50</td><td>Thermal Joint Release and Oxygen Barrier</td>

<td>Adhesive</td><td></td><td>Adhesion Layer</td>

<td>AClar^TM</td><td> 2</td><td>Moisture Barrier</td>

<td>Adhesive</td><td></td><td>Adhesion Layer</td>

<td>Polypropylene (100%)</td><td> 3</td><td>Sealant Layer</td>

In accordance with the practice of the present invention, each of the multi-layer laminate films described above is contemplated as forming a clear, high-barrier coating on the medication compartment 20 of the medical package 10. Preferably, the back foil 14 of each such container is constructed of a multi-layer laminate structure that includes a film containing high moisture barrier aluminum metallic tape, comprising 80% / 20% w / w of film on its inward-facing surface, as described in connection with the embodiment of Figure 3.

Designing the backsheet 14 of the container from a high barrier opaque laminate film containing aluminum metallic tape allows the contents of the container to be protected from UV exposure and visible spectrum light that can degrade its contents. In practical use, the film containing peelable aluminum foil tape, which covers the drug compartment, is typically removed prior to distribution by a hospital pharmacy. Since high barrier intermediate films are clear, they do not provide protection against exposure to light and care must be taken to prevent the contents of the drug compartment from being inadvertently exposed to UV or intense visible light during storage of the drug. back pack. Consequently, the container is folded over on itself in the region of one of the peelable joints, so that the film containing aluminum foil tape (or backsheet) forms the outward-facing surface of the folded container and helps to protect the contents of the drug compartment from exposure to UV or intense visible spectrum light.

Returning to Figure 6, container 10 is shown to be folded along the line of one of the peelable joints or in front of one of the peelable joints. When folded this way, the material

ES 2 171 929 T3 of the front and back sheets of the bag are pressed together by the fold imparting additional protection to the joint. The pleat provides additional resistance to hydraulic pressure caused, for example, by inadvertently compressing the diluent compartment of the bag.

In accordance with preferred embodiments of the present invention, means are provided to secure the container in a folded condition to guard against accidental activation and to help protect the contents of the container from exposure to radiation by allowing it to be exposed only to ambient light. the back sheet containing aluminum metal tape.

Referring now to Figures 1 and 6, means for maintaining the bag in a folded condition suitably comprises a locking tab 28 formed from the primary bag material and extending from one side of the package, and a locking slot junction 27, configured to receive tab 28 when the bag is folded along a lone in the region of the first peelable seal 24 between the diluent and drug compartments. Once the container is folded, and the locking tab 28 is engaged with the attachment slot 27, the contents of the drug compartment are protected on both sides from incident radiation, by the rear lamina containing aluminum metallic tape.

Accordingly, it was understood that the configuration of the bag in a folded condition helps to provide protection for the contents of the drug compartment from radiation degradation while also protecting against inadvertent bag activation by increasing the strength of the peel seal throughout. from which the bag is folded. Additionally, the means for maintaining the bag in a folded condition is adaptable for easy attachment and detachment, thereby allowing the clear inner face of the medical container to be periodically exposed and allowing the contents of the medical container to be periodically accessed for inspection. visual of compartment integrity.

Referring to Figure 7, in an exemplary embodiment, additional protection is provided to the drug compartment by providing a sacrificial moisture vapor permeation path for moisture vapor that can develop in the liquid-containing diluent compartment. The sacrificial moisture vapor permeation path is provided by forming an additional peelable seal 25 across the medical container a distance cut in front of, or above, the peelable seal 24 that separates the drug compartment from the diluent compartment. Additional peelable gasket 25 is preferably disposed approximately 1/8 to 1 inch (3.17 to 12.7 mm) above peelable gasket 24, ie, in the direction of diluent compartment 18. The first peelable gasket 24 and the additional peelable gasket 25 together define an intermediate compartment 29, disposed between the diluent compartment 18 and the drug compartment 20. The intermediate compartment 29 is preferably empty.

When the mod pack is designed with the additional peelable gasket 25 and the intermediate compartment 29, a sacrificial moisture vapor permeation path is provided that protects powdered drugs in the drug compartment 20 from moisture permeation through the packaging material. from the diluent compartment. Although drug compartment 20 is covered by a variety of high barrier protective coatings, as described above, there is a path, for moisture to migrate from the diluent compartment to the drug compartment, through the primary packaging materials that comprise the first peelable joint

24. In the embodiment of the invention depicted in Figure 7, moisture vapor that can permeate through the primary packaging materials into the region of the additional peelable gasket 25, since the diluent compartment is trapped within the compartment. intermediate 29. Since the surface area of ​​the intermediate compartment 29 available for vapor permeation is much larger than the permeation surface provided by the peelable gasket 24, the moisture vapor in the intermediate compartment preferably escaped into the atmosphere, rather than migrating. through the first peelable gasket material 24 and into the drug compartment.

Thus, it can be seen that the additional peelable gasket 25 and the intermediate compartment 29 provide means to protect the dried medicament in the medicament compartment from being degraded by moisture.

Manufacture and assembly of the container

In accordance with the practice of the principles of the invention, the front 12 and rear 14 laminates of an exemplary embodiment of the package 10 face each other by an 80:20 film layer.

IS 2 171 929 T3

Although other interfacial films are within the scope and contemplation of the invention, in each of the embodiments described above, the inward facing layer of front sheet 12 comprises an 80:20 film, which is placed in contact with the 80:20 film layer facing inward of the backsheet 14.

The composition of the front and rear sheets 12 and 14 of the container 10, allow for the creation of the peripheral gaskets and peelable gaskets to use thermal sealing techniques. Dies or hot bars are used at different temperatures, pressures, and application times to bring interfacial portions of the materials and laminates used to temperatures near or above their melting point to allow migration of material across the interface to form. therefore a union of the desired resistance and characteristics.

For both a single layer film and a multilayer laminate film, comprising the front sheet 12 and the aluminum metal strip laminate comprising the back sheet 14, a process for manufacturing the container 10 of the illustrative embodiment, in connection with figure 8. The method comprises cutting the front and rear sheets of the container to the desired vertical container dimensions, but oversized in the horizontal dimension.

If container 10 is being constructed with a single layer front sheet 12, the protective layer containing high barrier aluminum foil tape 55 (of Figure 3) and the transparent high barrier interlayer (64 of Figure 4 or 71 of Figure 5), comprising the high barrier coatings for the drug compartment 20 are cut to size, placed over the area that will be the drug compartment, and are sequentially affixed to the front sheet of container 12. According to the invention, the high barrier transparent interlayer is first laminated onto the surface of the front sheet and the protective layer containing 55 aluminum metal tape superimposed thereon. .

Specifically, the transparent high barrier interlayer 64 or 71 is positioned over the drug compartment and is held in place by a pair of bars while being laminated onto the surface of the front sheet 12. The portion of the layer in contact with the bars it is therefore not accessible to, for example, the heat seal head, which results in a small portion of the film that is not sealed on the surface of the front sheet. The residue from the use of bars to secure the transparent high-barrier interlayer in position having an unsealed area in the contact footprint of the bar. In the embodiment illustrated in Figure 1, the contact surface of the bar is generally circular and results in two circular unsealed regions 41 that remain visible due to reverse printing caused by the pressure applied during the sealing process.

Following the lamination of the intermediate layer 64 or 71, the aluminum metallic tape layer 55 is applied on the surface thereof, using a heat seal die formed as described above.

Following the fixation of the aluminum foil tape layer 55 and the high barrier clear layer 64 or 71, the front and rear sheets are joined together and the exit hole 30 is inserted into its desired final position between the front and rear sheets. . The outlet port 30 of the illustrated embodiment is injection molded and has a composition of 40% FINA Z9450 polyethylene-polypropylene copolymer and 60% Shell Kraton^TM G1652 from styrene ethylene-butylene styrene thermoplastic elastomer. Following the insertion of the exit port, a heated die is used to create a seal between the exit port flanges 34 and the lower edge of the front and rear sheets adjacent to the flange.

The peelable gaskets 24 and 26 (and optionally the additional peelable gasket 25) dividing the compartments and the container 10 are then created using, for example, double hot rods comprising a front rod in alignment with a rear rod limiting the elements of the container between it to thereby form the joint. In an exemplary embodiment, the front bar contacting the pre-blended high barrier protective film 55, the intermediate films 64 or 71, and the front sheet 12, is maintained at a temperature in the range of about 118^°C (245^°F) up to approximately 129^°C (265^°F). The rear bar contacting the rear sheet 14 is maintained at substantially the same temperature as the front bar (in the range of about 118^°C or 245^°F to about 129^°C or 265^°F) and may optionally include a thin rubber coating to ensure uniform application of pressure. The double bars are pressed into contact with the front and rear blades with a pressure in the range from about 1.59 M Pa (230

ES 2 171 929 T3 psi) to about 2.35 M Pa (340 psi) and are held at that temperature and pressed for a period of time between about 1.5 to about 2.5 seconds. The peelable joints 24 and 26 as shown in Figure 2 can be made individually with a single double bar assembly, or simultaneously with a twin double bar assembly. The additional peelable gasket 25 can be easily accommodated by a triple double bar assembly.

A further refinement to the previously described embodiment of peelable joint formation involves configuring a joint head with a double joint bar configuration in which one end of the double bars are connected together by a transverse joint bar to describe an elongated U-shape, with square corners. When such a gasket head is pressed into contact with the front and rear sheets and is maintained in the temperature and pressure regime described above, an additional peelable gasket 25 is provided which extends the transverse peelable gaskets 24 and 26 and is arranged adjacent and parallel to the permanent peripheral gasket 16 which is formed along the edge of the container opposite the sacrificial holes. This additional gasket 25 is preferably formed when the package is manufactured to include a high barrier protective film disposed on the surface of the drug compartment.

In such a case, the thickness of the material experienced by the theoretical joint head will be different (thicker) in the region defined by the drug compartment 20 than the region defined by the material that comprises the permanent peripheral joint 16. The difference in material thickness between these two regions requires the gasket head to exert pressure against a compliant reinforcement, such as rubber, to ensure uniform gasket pressure across the interface. By forming the additional peelable gasket 25 within the periphery of the drug compartment, it avoids the requirement for a compliant reinforcement for the gasket head. The material thicknesses experienced by the thermal sealant will therefore be constant, ensuring a uniform, leak-resistant peelable joint.

Following the formation of the peelable gasket, the front and back sheets are joined together by a peripheral permanent gasket 16 that extends across the top, bottom, and along a continuous side of the container, such that It covers a portion of the peelable gasket 25 that extends the transverse gaskets 24 and 26, thereby ensuring leak-proof gaskets between the diluent, drug, and lower compartments. As best seen in Figure 8, on the opposite side of the container, the permanent gasket 16 was spaced outside the oversized edge of the front and back sheets and is provided intermittently along the desired edge of the final bag, it is That is, the joint is formed along the upper vertical portion 110a, a lower vertical portion 110b, and a central vertical portion 110c, thus defining spaces that intervene between the three vertical portions.

Sacrificial holes 102 and 104 are inserted between the front and rear foramina at positions along the edge of the oversized portion thereof adjacent the interstices in the permanent gasket. In a manner similar to exit port 30, the front and rear sheets are sealed to sacrificial ports 102 and 104 along tapered flanges 106 and 108, respectively, provided for that purpose. Sacrificial ports 102 and 104 are also injection molded and since they will be removed and disposed of in a state later in the process, they are designed from any inexpensive thermoplastic material available. In particular, the sacrificial ports can be constructed of 80:20 film "ground" material, plain propylene, or the like.

Sacrificial ports 102 and 104 depicted in greater detail in Figures 8a and 8b, with Figure 8a depicting the diluent fill port 102 and powder fill port 104, respectively, in side view and with Figure 8b showing represents the holes in a semi-schematic plan view. Sacrificial ports 102 and 104, respectively, include a cap 109 that has been inserted into diluent fill port 102 and is depicted as suspended above powder fill port 104.

Sacrificial ports 102 and 104 are an important feature of the present invention and, as further described below, provide a means for aseptically filling a single or multi-compartment container with powdered medicaments, liquid diluents, and the like. Additionally, the sacrificial ports are provided with structure to allow the ports and, therefore, the medical container must be supported and manipulated by automated robotic machinery.

As depicted in Figure 8a, sacrificial ports 102 and 104 each include two vertically spaced apart flanges, a lower flange 103 and an upper flange 105. Each of the

Flanges are generally rectangular in configuration (best seen in Figure 8b), with their long edges extending approximately 3mm, on either side, beyond the generally tubular rotating drum 107 of each respective sacrificial orifice. As can be seen in Figure 8b, each short side of the flange (or width) has the same dimension as the outer diameter of the rotating generally tubular hole filling drum (12mm). Each of the flanges 103 and 105 is constructed to a thickness of approximately 1.5 mm, and are positioned in vertical relationship, spaced apart from each other and with the intersection of each rotating bore drum with its respective tapered flange (106 and 108). The lowermost flange 103, in each hole is positioned approximately 4 to 5 mm above the intersection of the rotating drum of the orifice and the cenically narrowed flange of the hole, as long as the uppermost flange 105 is positioned so that its lower surface is approximately 4mm above the upper surface of the lower flange 103, thus defining a 4mm gap between the flanges and between the lower flange and the edge of the container.

In accordance with early practice, the generally tubular rotating drum 107 of each sacrificial port 102 and 104 has an outer diameter of approximately 12 mm and a length, or height that depends on whether it is a diluent fill port 102. or a powder fill hole 104. In the case of the diluent port 102, in an exemplary embodiment, the rotating drum has a height of approximately 13 mm, and in the case of the powder fill port 104, the rotating drum has a height of approximately 18 mm. It will be understood by those skilled in the art that the inside and outside diameters of the rotating filling drum are generally the same as those of a conventional plastic or glass drug vial. This configuration allows the rotating sacrificial orifice filling drums to be accessed by conventional drug vial filling apparatus.

Each of the generally tubular rotating drums is provided with a through hole, thereby defining a cylindrical configuration. In an exemplary embodiment, the diameter of each through hole is approximately 10.4mm, thus giving a cylindrical side wall thickness of approximately 0.8mm. The top edge of each rotating drum has a chamfer provided at approximately an angle of 45^° into the rotating drum.

A generally cylindrical cap (or plug) 109 is provided for each of the holes and is constructed with an outside diameter (10.5 mm) that is slightly larger than the inside diameter of each hole fill drum (10.4 mm). mm), so that when the cap 109 is inserted into a hole, the interface between the outside diameter of the cap and the inside diameter of the hole provides a tight seal. This gasket is required to prevent particles from entering the container prior to filling and to prevent powdered medications or liquid diluents from escaping after the container has been aseptically filled. As can be seen in Figure 8a, the bottom edge 109a of the cover 109 is beveled at approximately an angle of 45^°, to engage the chamfer of 45^° of each orifice rotating drum and assist in insertion.

In addition to the tabs 103 and 105 in the holes, a pair of tabs spaced apart vertically is also provided on the lid. In the exemplary embodiment of Figure 8a, a generally circumferential top flange 110 defines the top of the cap and has a thickness of about 1.0mm and a diameter of about 12.0mm to extend beyond the body of the cap. cap by about 0.75mm. The upper flange protrusion thus allows a "lift" mechanism to engage the lower portion of the upper flange 110 and provide a means to lift the lid vertically off its respective rotary bore drum. A lower flange 111 is provided to control the depth of insertion of the cap when the cap is inserted into the rotating bore drum or re-seated after a filling operation, for example. The lower flange 111 may be completely circumferential or, alternatively, it may be implemented as a partial flange defining a single lateral extension from the body of the cap. As was the case with the upper flange 110, the lower flange 111 is approximately 1mm thick and is constructed to extend outwardly from the body of the cap by approximately 0.75mm. The upper and lower flanges 110 and 111 are spaced apart vertically from each other, along the body of the cap, to define a space between them of approximately 3mm.

Accordingly, it will be seen that following insertion, each cap 109 adds approximately 5 millimeters to the total height of its respective sacrificial orifice. It will be noted that the diluent port 102 and the cap combination have a height of 18 millimeters, which is the same as the height of the drug port 104 without the cap being inserted. This particular feature allows the cap to be removed from the sacrificial orifice of the drug 104 and the container to be divided underneath a conventional, rotary powder filling mechanism, thus allowing the compartment orifice to

ES 2 171 929 T3 of the diluent remains sealed. Maintaining the sealed diluent compartment orifice at a height equal to or less than the height of a drug compartment orifice in the unsealed condition allows both holes to pass underneath and clean a powder wheel while it splits in a manner. lónea, efficient.

Turning now to Figure 8, permanent seals 110a, 110b, and 110c then extend toward the oversized edge of the container by seal extensions 110d, 110e, and 110f respectively. These gasket extensions are formed with a suitable width to allow the oversized portion of the container, including the sacrificial holes, to be cut out of the filled container after the manufacturing process has been completed without the danger of substantially weakening the peripheral gasket of the container. along the cut edge.

In particular, the oversized portions 110e and 110f are of sufficient width to allow the retention slot (27 of FIG. 1) and the retention tab (28 of FIG. 1) to be cut from the relatively stiff material of the extensions of joint 110e and 110f respectively.

The gaskets, and the gasket extensions, formed in the oversized portion of the container, define voids or channels 112a and 112b, in the container material intervening between the gaskets. Channel 112a allows communication between sacrificial port 102 and the interior of diluent compartment 18, while channel 112b allows communication between sacrificial port 104 and open drug compartment 20. As will be further described below, channels 112a and 112b are closed by a rear permanent gasket that joins the various spaced apart vertical seal portions (110a-f) on the oversized portion of the container.

Container manufacturing apparatus

In accordance with the principle practice of the present invention, a method and apparatus for manufacturing the container 10 of FIG. 8 will now be described in connection with FIG. 9. As will be apparent from the following description of a container manufacturing apparatus, both the apparatus and the process are adapted to be suitable for the manufacture of front and back laminating molecular containers comprising both single and multi-layer laminate films. layers. Additionally, it will be apparent from the following description that the number, shape, configuration and location of the various gaskets of the container 10 of Figure 8, can be easily changed, or indeed even omitted, due to the modular arrangement of the components of the package. apparatus.

Figure 9 is a semi-schematic plan view of an exemplary embodiment of a container manufacturing machine 120 provided in accordance with the present invention, showing the arrangement and placement of various joint forming stations and the arrangement and packaging configuration mainly film tape supply rolls.

The dough material for the front and back sheets of the container (12 and 14 of Figure 2, for example) is provided to the container manufacturing machine 120 in the form of supply rolls of respective dough film tape, 122 and 124, which are mounted on tape supply roll stations at the input end of the container making machine 120. From the tape material, for example, the lead sheet supply roll 122 is threaded through an oscillating station 123, which functions to hold the tape material in proper tension as the tape is pulled through the stations. remaining of the manufacturing machine 120. Following oscillating station 123, belt material is conveyed by vacuum feed wheels past a first belt cleaning station 125 and then through a series of optional barrier film application stations 126 and 127, arranged in series along the path of the tape. If the package (10 of Figure 1) is being constructed in the manner previously described, i.e. to include a single layer front film 12, a transparent high barrier intermediate film (64 of Figure 4 or 71 of Figure 5) and a protective layer containing high barrier aluminum metal tape (55 of Figure 3), the high barrier covers for the drug compartment 20 are first cut to size, then placed on the area that will be the drug compartment, and then sequentially attached to the front sheet of the container in barrier film application stations 126 and 127 respectively. In accordance with the invention, the high barrier transparent interlayer is first laminated onto the surface of the front sheet at application station 126 and the protective layer containing aluminum metal tape covered thereto at application station 127.

In a similar manner, the tape material that formed the back lamina of the container is threaded from

ES 2 171 929 T3 its respective dough tape supply roll 124 through a corresponding oscillating station 128, and is conveyed by vacuum feed wheels through a corresponding tape cleaning station 129.

When the continuous film of the front and back laminate tape material leaves their respective preparation states, the continuous films are fed coincident with each other and oriented so that the 80:20 surfaces of each continuous film face the 80:20 surface of the other. Once the continuous film tapes have been brought into registration, the tape material is continuously divided and moved longitudinally through the joint core 130 of the manufacturing apparatus 120. The sacrificial drug and diluent holes are located along the tape sandwich and are placed between the front and back foil film tapes, and the various gaskets are sequentially formed on the tape sandwich material to bond the tapes together and substantially manufacturing the container in an intermediate stage suitable for aseptic filling.

In accordance with the practice of the principles of the invention, the gasket core of the manufacturing machine 130 comprises a plurality of gasket presses and orifice insert stations, arranged in a series manner along the path of travel. of the container film tape sandwich. The first such station is a tight hole loading station 131, in which a tight hole, or outlet hole (30 of FIG. 8) is inserted into its proper position between the front and rear plates. A heated press, including a configured die, is compressed on the tape material to create a seal between the exit port flange (34 of Figure 8) and the eventual bottom edge of the front and rear sheets adjacent to the flange. , at the tight-bore gasket station 132. The fitted or outlet orifice 30 was comprised of a plastic material and is injection molded from a composition of 40% FINA Z9450 polypropylene copolymer and 60% Shell Kraton G1652 styrene ethylene butylene styrene thermoplastic elastoomer. Due to similarities between the composition of the material of the fitted hole 30 and the material of the gasket forming surfaces, inside the front and rear foil, it can be seen that the front and rear foils can be sealed to the fitted hole flange 34 using a Substantially similar thermal joint regime, as used for the formation of permanent peripheral joints, which must be described in greater detail below.

Following the insertion and sealing of the fitting hole 30 to the packaging material, the film tape sandwich is then divided to a sacrificial hole insertion station 134, where the sacrificial holes (102 and 104 in Figure 8) are inserted between the front and rear lamines, at positions along the respective sides of the container portions that will be the diluent 18 and drug 20 compartments. Sacrificial ports 102 and 104 are preferably injection molded from a 100% polypropylene material but can also be manufactured from a material having a composition similar to the composition of exit port 30. In a manner similar to the outlet port 30, the front and rear loamines are sealed to the sacrificial ports 102 and 104 along the tapered flanges 106 and 108, respectively, which are provided for that purpose.

Following the insertion of sacrificial holes 102 and 104, the front and back laminate film material are joined together by a permanent peripheral gasket (16 of Figure 8) that extends through what would be the top, bottom, and bottom. and a continuous side of the finished container. Along the opposite side of the container, the permanent gasket 16 is provided parallel to, but spaced out from the edge of the film tape sandwich strip, and is intermittently formed along the desired edge of the finished container. (110a and 110b and 110c of Figure 8).

Following the perometer gasket formation at the perometer gasket station 136, the container material is divided to a first optional drug sacrificial orifice gasket station 138. The front and back sheet material is sealed to the tapered flange 108 of the drug sacrificial orifice 104 by compressing the front and rear sheet material to the conically tapered orifice flange by a pair of concave conformable heated sealing dies. As was the case with the adjusted orifice die, the heated sealing die of the drug gasket station 138 is adaptively configured so that the eloptic bag having a configuration that is the mirror image of the sealing surface conically convex narrowed of the drug orifice.

Next, the tape material is divided to an optional second gasket station, sacrificial port of the diluent compartment 140, where the front and rear lamine material of the container is compressed and heat sealed to the tapered flange 106 of the container. sacrificial hole

ES 2 171 929 T3 of the drug compartment 102.

It will be appreciated that the order of sealing the sacrificial ports to the container is simply arbitrary and that the drug port seal station 138 can just easily follow the diluent port seal station 140 as vice versa. Additionally, the gasket stations for sealing the sacrificial holes to the container may precede the perimeter gasket station 136. Furthermore, an additional optional gasket station, peelable gasket forming station 142 which is shown in FIG. 9 as following sacrificial hole insert station 134 and preceding perimeter gasket station 136, is optionally provided for form peelable gaskets that cut and subdivide container 10 into a plurality of compartments. Alternatively, the optional peel seal station 142 may be configured to continue the sacrificial hole insert station 134, simply repositioning the peel seal station along the film tape path. It will also be apparent that a plurality of peelable gasket stations can be provided, if the package is to be manufactured with multiple compartments.

It will be apparent to one of ordinary skill in the art that the sequential, but independent plurality of the joining stations can be configured to operate automatically as the filmstrip is divided into their respective stations. Alternatively, the seal stations may be present on the packaging machine, but rendered inactive, so that their particular seals are not formed in a specific production cycle.

Following the sacrificial orifice seals, the container tape material is divided to a cutout zone seal station 144, which applies a permanent thermal seal to the container material that contacts and covers the intermittent portion of the permanent perimeter seal and extends to the edge of the film material of the container. The cutout zone seal regions (110d, 110e, and 110f of FIG. 8) are provided in the film region between the peripheral seal of the container and the tape edge to define a region of relatively low flexibility material having a relatively low flexibility. width sufficient to allow the retention groove (27 of Figure 1) and the retention tab (28 of Figure 1) to be balanced out of the relatively stiff material of the trim zone joints. Additionally, the trim zone joints function to add width to the peripheral joints (110a, 110b and 110c) so that the perimeter joints in this region are formed with a suitable width to allow this region of the container (including the holes sacrificial) are cut out of the container after the manufacturing and filling processes have been completed, without substantially weakening the peripheral seal of the container along the cutting edge and without compromising the integrity of the filled container.

As can be seen from Figure 8, cutout zone gaskets 110d, 110e, and 110f define voids or channels 112a and 112b, in the container material intervening between the gaskets. Channel 112a therefore allows communication between sacrificial orifice 102 and the interior of diluent compartment 18, while channel 112b allows communication between sacrificial orifice 104 and drug compartment 20, which allows both to be accessed. compartments through their respective sacrificial orifices. As will be described further below, channels 112a and 112b are closed by a rear permanent thermal seal that joins the cutout zone seal portions (110a-f) in these regions of the package.

Following the stages of the thermal sealing process, the container is divided through a hook-piercing station146 that forms an engaging recess in the upper center of the container. Following stations 147 and 148 separate the containers by cutting the tape of material at the first end of the hole (147), an upper trim station 148 cuts the container material at the hooking end after which the container is discharged from the manufacturing machine 120 and the construction of the container is substantially complete.

It will be apparent to one of ordinary skill in the art that the number and configuration of compartments comprising the package is uniquely determined by the number and location of the various thermal seals used to form the package. Additionally, depending on the number of packages contemplated for the final product, a suitable number of sacrificial holes are provided and placed along their respective material belt edges. It will be understood that the modular manufacturing process in accordance with the present invention is adaptable for the manufacture of medical packages that have a single primary compartment, or multi-compartment packages that have any number of compartments, simply providing additional peelable gaskets and additional sacrificial holes. with which to fill the compartments. For each configuration of the compartments and sacrificial orifices, the trim zone gasket presses on the trim zone gasket station 144 can be appropriately reconfigured by removing one press face and replacing another, which is configured

ES 2 171 929 T3 to provide one, three, four or similar channels or openings for connecting a plurality of sacrificial orifices to a plurality of compartments.

In a similar manner, it will be clear to a person skilled in the art that the composition of the front and rear sheets of the package can be changed by suitably replacing the front and rear sheet film supply tape rolls with other suitable materials. In particular, both the front and back foil supply rolls can be single layer 80:20 films so that the finished package is transparent on both sides. Due to the modular nature of the manufacturing apparatus, the clear barrier application station and the metal tape barrier application station can both become inoperable, as well as the peelable gasket forming station, configuring the container manufacturing machine as well. to provide a single compartment package which is completely transparent, and which may comprise a plurality of outlet ports, such as fitted holes and separate middle holes.

Accordingly, the container manufacturing machine according to the present invention is seen to be suitable for manufacturing a wide variety of medical containers, having a wide variety of sizes, and a variety of joint configurations and orifice locations. All packages manufactured are shown to be suitable for aseptic filling in accordance with the practice of the principles of the invention as well as suitable for use in combination with a terminal sterilization procedure, if so desired.

Board formation

The peelable gaskets formed during the manufacturing process described above are straight line gaskets that have a fine rectangular configuration. Although they will appear similar to conventional straight line joints, the peelable joints of this embodiment are improved because they show a more predictable rupture characteristic across production batches, that is, they show a characteristic of uniform resistance to handling pressure.

Without being limited by theory, it was thought that the peel ability of the gaskets is achieved by limiting the time, pressure and temperature to what is necessary to melt the interface between the inner layers of the front and rear laminates that have a melting temperature. lower than the intermediate and outer layers of the back lamina. The depth of structural alteration in the inner layers in the fusion zone is limited, imparting the peelable character to the joint while providing sufficient strength to prevent rupture in normal container handling.

Preferably, the activation force for the package of the present invention is hermetically controlled to provide package integrity under extreme handling conditions, even being easy to activate by all users. This effort or activation force is characterized by a burst pressure that is preferably about 0.028 ± 0.007 M Pa (4 ± 1 lbs. Pounds per square inch).

In order to achieve such uniformity in the burst pressure of a generally rectangular joint, it has been determined that the chromic parameter to be controlled is temperature. Uniform burst pressure response can be achieved by controlling the joint temperature to within ± 1^°C (2^° F). The commercially available production gasket apparatus is not capable of controlling variability in gasket temperature up to this desired range. However, the gasket time is capable of being controlled very precisely. Consequently, time is chosen as the control parameter and is adjusted to compensate for variation in gasket temperature. The gasket head time and pressure are monitored to ensure that it is within acceptable ranges as described above and the gasket time is adjusted accordingly. Although the contact pressure is preferably within the range of about 1.59 M Pa (230 psi) to about 2.35 M Pa (340 psi) it will be recognized by a technician in the art that the lower figure is in the range 1.59 M Pa o (approximately 230 psi) is provided for convenience in setting the parameters of a production gasket machine. As long as the pressure exerted by the gasket bars on the material is sufficient to force the gasket layers of material into contact over the desired gasket surface area, a peelable gasket will be formed given a suitable time and temperature. Indeed, it has been experimentally determined that variations in gasket temperature and time beyond those contemplated by the present invention result in gaskets that not only fail to display the desired uniform strength characteristic, but also fail to break completely along the way. along the length of the joint. Incomplete joint breakdown often results in residual thinner, for example, getting caught in 90-degree corners.^° where

ES 2 171 929 T3 the peelable gaskets contact the permanent peripheral gaskets of the container. Consequently, the diluent / drug mixture ratio may not be designated, and the drug delivery may be at a higher concentration than desired.

Examples of time, temperature and pressure settings, which formed peelable gaskets, in the 80:20 film of the illustrated embodiments, having a burst pressure of approximately 0.028 ± 0.007 M Pa (4 ± 1 psi) include pressure 1 , 62 M Pa (235 psi) temperature 125 ° C (257 ° F) and time = 1.9 seconds; and pressure = 1.62 M Pa (235 psi), temperature = 128 ° C (263 ° F), time = 1.75 seconds.

Higher temperatures and associated times and pressures are used to provide the permanent peripheral thermal gaskets and the outlet orifice gasket, which produce alteration of the structure affects in a greater proportion to or depth of the sealing layers. Such gaskets can be formed by heat sealing at a temperature of 143^°C (290^°F) and a pressure of up to 1.38 M Pa (200 psi) for approximately two seconds. These technicians in the art will recognize that various techniques for forming both peelable and permanent gaskets can be used in the construction of the container of the present invention. In particular, it will be apparent that by controlling the joint temperature to a higher degree (to within approximately 1^°Co ± 2^°F) also allowed the formation of peelable joints that have uniform blast pressure. Additionally, time is chosen as the control parameter for joint formation because it is capable of being precisely controlled. Precise control of temperature, pressure, or both will give the same result.

Furthermore, those skilled in the art recognize that the sequence for constructing the container 10 of the present invention is arbitrary and has been defined to accommodate a particular production process and a particular embodiment of the final container. Various alterations in the order of formation stages, as well as the position and orientation of the various components that comprise the container 10 can all be modified without departing from the principles of the present invention.

After the container brought to the manufacturing state exemplified in Figure 8, the container is now in a condition for aseptic filling with a drug, a diluent, both, or any desired combination of the foregoing. In an exemplary filling process, the particular embodiment of the container to be filled, in accordance with the invention, is one that incorporates both a single-layer or multi-layer laminate front laminate film as well as a single-layer rear laminate film. aluminum foil tape laminate and formed to comprise a diluent compartment 18 and drug compartment 20, both of which have peripheral edges left unsealed to fill through sacrificial holes provided respectively 102 and 104. This embodiment of the container was in the state of manufacture as depicted in figure 8. The primary container manufacture, which It includes the provision of an exit orifice and sacrificial orifices, it is achieved by the method and apparatus previously described.

For an aseptic filling process that is acceptable for medical purposes, the container to be filled must be provided in a sterile condition. Conventionally, package sterilization takes place in a separate processing area or facility due to the rather complex and extensive equipment and processes required to sterilize the material. A particular undesirable feature of the sterilization procedure is that the package must be transported to the sterilization facility for processing, following that the sterility of the package must be maintained during storage and subsequent transportation to an aseptic filling facility. The container must be introduced into the aseptic filling zone by means of a sterile transfer to prevent contamination of the aseptic zone by the container. Once introduced into the aseptic zone, the package can be filled aseptically, but must be further handled in a sterile manner.

In accordance with the practice of the principles of the invention, following the manufacture of the primary container, a plurality of empty containers are loaded into a handling container which is then sealed to protect the balls contained within from environmental contamination.

Returning to Figure 10, a handling container, generally indicated at 150 and referred to as "a support" here, functions as a transportable sterile containment isolator for sterilization, transporting and introducing into the aseptic zone, empty containers in a systematic manner. Support 150 comprises three components; a generally rectangular container tray 152, a sealable film lid 154, and a rail cartridge 162 for supporting a plurality of packages within the tray and which will be described in greater detail below in connection with Figures 11a &amp; 11b.

The generally rectangular container tray 152 was constructed of a polystyrene material

ES 2 171 929 T3 chosen to be able to withstand several sterilization cycles without significant degradation. Tray 152 is generally configured in the shape of a trough with its upper peripheral edge folded outward to form a peripheral, horizontally oriented rim 156 that extends beyond the sides of tray 152 for a distance of between about 6. 3 mm (1/4 inch) to approximately 25.4 mm (1 inch). Preferably, the flange 156 extends approximately 19mm (3/4 inch) beyond the sides of the tray, but any extension that provides rigidity to the tray 152 and a sufficient surface to support a joint is suitable. Two opposing bags 158 and 160 are formed at approximately the centers of the two opposing short sides of the tray and extend outward from the plane of the short sides. The bags 158 and 160 extend only partially downward along the sides of the tray and therefore form two opposing recesses into which the ends of the rail cartridge 162 can be inserted. The rail cartridge 162 rests on the bottom surfaces of the bags 158 and 160 and is therefore suspended above the bottom of the tray 152 at a height sufficient to allow the packages arranged on the rail cartridge to hang free within. of the internal volume of the tray. Accordingly, the bags 158 and 160, in combination with the rail cartridge 162, function to maintain a plurality of packages in a specific orientation during transport, storage, and UV sterilization.

Once the lane cartridge 162 has been loaded with packages and inserted into the bags 158 and 160, the tray 152 is environmentally sealed by heat sealing the plastic film lid 154 to the tray flange 156 in a different orientation. For purposes of illustration in Figure 10, the film cap 154 ​​is shown half through the sealing process, with a portion of the cap raised upward to show the rail cartridge 162 bundled within the tray 152. Film cap 154 ​​is positioned on flange 156 such that there is no "projection" of film cap material on the edge of the tray flange around the perometer of the tray. In an exemplary embodiment, the plastic film cap 154 ​​was constructed to have dimensions that allow the film cap to be positioned on the tray flange such that the film cap edge is inserted from the flange edge of the tray. tray around the entire periphery of flange. Additionally, the film cap gasket is applied to extend beyond the edge of the film cap 154, to ensure that no portion of the film cap edge has been left unsealed which will create a loose edge "flap". . Film cap orientation, placement and avoidance of loose edges is particularly important to the surface ultraviolet (UV) decontamination process performed on support 150 when the support is introduced into the aseptic zone. Cracks, caused by loose film lid edges and / or flaps, can cause local shadowing, when exposed to UV radiation, the shading effect of which can reject the UV decontamination process.

Once the film cover 154 has been heat sealed to the tray flange 156, the holder 150 defines a hermetically sealed environment that functions to isolate its contents from external contamination. The holder 150 is subsequently placed within a multi-bag wrap (not shown), which acted as a "dust cover", and is identified by an adhesive label that is placed on the wrap.

Turning now to Figures 11a and 11b, the support rail cartridge 162 is shown in its component form, ready for assembly, in Figure 11a and in a fully assembled condition in Figure 11b. Support rail cartridge 162 suitably comprises a plurality of injection molded polystyrene T-beams 163a, b, c, d, e, and f, arranged at spaced apart intervals to form longitudinally moving grooves 164a, b , c, and d between them. The polystyrene T-bars 163a-f are oriented with the T-face legs facing up (from the perspective of Figures 11a and 11b) and include press pins or elastomeric sockets 165 adapted to mate with corresponding receptacles 166 on a or more spacer plates 167. Spacer plates 167, like T-rails 163a-f, are constructed of an injection molded high impact polystyrene material such as FINA 825 manufactured and sold by Fina Oil And Chemical Company of Deerpark, Texas. The spacer plates 167 of the support rail cartridge 162 are provided to separate and maintain the T rails 163a-f at predetermined distances from each other. The spacer plates may include recesses 168 arranged to provide hand grips so that the end support rail cartridge assembly can be easily grasped, raised, and moved. Alternatively, a thin, flexible plastics assembly may be attached to extend the spacer plates 167, or some other well-known means may be provided whereby the support rail cartridge can be grasped and manipulated.

Once the support rail cartridge has been assembled, the manufactured packages can be loaded onto the cartridge according to the invention, in a manner depicted in Figures 12a and 12b.

IS 2 171 929 T3

In Figure 12a, which is a plan view of a loaded support rail cartridge, the finished packages 10, such as those depicted in Figure 8, are loaded onto the support rail cartridge 162 by inserting their sacrificial holes (102 , 104) within the grooves 164a-d formed between the T-rails of the cartridge 163a-f, in the manner depicted in FIG. 12b. The flange edges of the T-rails 163a-f are spaced a sufficient distance apart (approximately 13.0 mm) so that the central filling rotary drum 107 of each sacrificial hole is able to be accommodated between them, and are adapted to engage the sacrificial holes between the circumferential hole flanges (103 and 105 of Figure 8) such that each container 10 is grasped by the T-rail flanges below its uppermost circumferential sacrificial orifice flange 105 .

In the exemplary embodiment of the support rail cartridge depicted in Figures 12a and 12b, four slots 164a, b, c, and d are provided to receive the packages, with the packages loaded on the rail cartridge 162 in left and right orientations. right alternatives. Sacrificial holes 102 and 104 of each container are inserted into two of the slots 164a-f. As shown in figure 12b, a first container 10 'is loaded into the second and fourth slots (164b and 164d) and is oriented in a first horizontal direction, so that its hook end is oriented to the right, ( from the perspective of figure 12b), and its adjustment hole is oriented to the left. The second container 10 (the front container from the perspective of FIG. 12b) is loaded onto the rail cartridge 162 with its sacrificial ports 102 and 104 inserted into the first and third cartridge slots 164a and 164c. The second container 10 is loaded in a second horizontal direction with its fitting hole 30 oriented 180^° with respect to the first container. In the example of Figure 12b, the fitting hole 30 of the first container 10 is a on the right side when viewed from the perspective of Figure 12b. Additional containers are loaded onto the support rail cartridge 162 in a similar manner, with the horizontal orientation of the container alternating left and right; the sacrificial holes of the left-oriented containers inserted into the second and fourth slots, the adjustment holes of the right-oriented containers loaded into the first and third slots, as described above, until the support rail cartridge 162 is completely filled.

Turning now to Figure 12a, it will be understood that the particular design of the sacrificial hole flanges 102 and 104, in cooperation with the support rail cartridge 162, functions to maximize the package density of the packages within the tray. 152. As can be seen in Figure 12a, the sacrificial orifice tabs project only along the longitudinal direction of each container, and not along its width or thickness dimension. Consequently, as the support rail cartridge is filled, the thickness of any particular container is defined by the width of its rotating sacrificial orifice drum (approximately 12.00mm). As the containers are subsequently loaded onto the support rail cartridge, only the rotating drums for filling the sacrificial holes of alternative containers come into contact with each other. Alternating the horizontal orientation of consecutive containers, as well as alternating their slot offset position, also helps to improve the density of the container pack in a fully loaded lane cartridge. As can be seen from Figure 12a, providing a second set of slots allows the package density of the container to be substantially double, in contrast to a carrier rail cartridge system with only a single pair of slots.

It will be apparent to a person skilled in the art that the packages are loaded onto the support rail cartridge and are held within a systematically aligned orientation such that each alternate package is 180 °.^° opposed to the pre-package as well as being laterally deflected from the pre-package by the slot space of the cartridge. It will be understood that this alternative container orientation maximizes the density of the container pack along the length of the cartridge as well as defining specific orientations and locations of a plurality of containers with respect to the cartridge rails, for easy adaptation of the container. cartridge assembly to automatic loading and unloading system. The support rail cartridge and the container loading sequence allow the cartridge to be "shrunk" or temporarily mounted to robotic pick-and-place machinery. Additionally, recesses (or butterfly holes) 168 in spacer plates 167 allow an operator to easily insert and remove a fully loaded cartridge from the support tray without unduly tilting, thus minimizing the possibility of containers falling out of the box. lane.

Following loading, the support rail cartridge is placed within tray 152 with the ends of the T-rails 163a-f nested in bags a158 and 160 formed at the ends of the tray. The bags 158 and 160 support the support rail cartridge 162 within the interior volume of the tray and provide additional lateral support that prevents the cartridge from shifting during transport, sterilization, and storage.

IS 2 171 929 T3

The sealed support, which includes the empty packages inside, is rolled up in several bags and transported to a radiation sterilization facility where its contents are rendered sterile by an E-beam sterilization procedure, for example.

Container filling process

After the E-beam sterilization procedure and loading of the preceding holder is completed, the sterilized medical containers are transported to an aseptic filling facility, and the containers are aseptically filled in accordance with an embodiment of the invention as described. describes with reference to an exemplary process flow chart depicted in Figure 13 and an exemplary filling apparatus depicted in plan view, semi-schematic in figure 14.

The filling of the primary bag will take advantage of manufacturing technology developed in connection with integrated circuit manufacturing that is going to be more common in the medical industry. This technology generally involves a move away from filling the conventional container in class 100 aseptic environments, to filling the container within an "isolator" unit in which the environment is sterile. The main distinction between class 100 aseptic environments and "isolators" is the separation of the worker from the environment. An isolator is fundamentally a “mini environment” that includes the operation of filling the container and immediate machinery within a controlled space. The worker is separated from this space and faces the materials inside through glove holes and / or "semi-assemblies". By separating the worker from the environment, it is possible to create and maintain a small sterile environment, since the worker is typically the largest force of bio-contaminants.

The isolator is initially sterilized with a sterilant such as vaporized hydrogen peroxide (VHP). Inside the isolator, the ambient atmosphere is maintained in a sterile condition, supplying it with HEPA and ULPA filtered air. The ambient atmosphere within the isolator is also maintained at a higher pressure than the ambient atmosphere surrounding the isolator. The positive air pressure ensures that the air flow is always from the inside of the isolator to the outside. All components or sub-assemblies that will go into the isolator are both pre-sterilized and sterilized just prior to placing them in the isolator so that the sterile environment is maintained. Components are typically placed in isolators through doors or through inlet / outlet ports commonly referred to as RTPs (fast transfer ports). RTPs are designed to mechanically interlock in such a way that sterility is not compromised. Packages that carry sterile components to the isolator are sterile on the inside and include an RTP integral to the package.

Turning now to Figures 13 and 14, and with particular reference to Figure 13, before the holders are introduced into the fill line, the multi-bag wrap is removed from each charged holder under unidirectional HEPA filtered air to maintain a Low level of particulate matter and biological load on the outer surface of the supports. Following the removal of the wrapper from multiple bags, each backing is individually tested for hermetic integrity by pressure decay, again under unidirectional HEPA filtered air.

Turning now to Figure 14, in combination with Figure 13, assuming that each integrity of the holder has been maintained throughout the transport and beam sterilization at B, the holder is introduced into the fill line, generally indicated at 170 , being passed through a UV decontamination tunnel 172, within which the exterior of the support is surface decontaminated by UV radiation before the containers are removed from the container for filling. The bracket is inserted into the inlet end of the UV tunnel 172, where UV emitting lights surround the bracket and radiate the entire exterior surface to control potential contaminants as they are introduced into rear insulators of the fill line.

After the UV cycle is complete, the support is transferred through a chamber transfer port, into a support inlet chamber (not shown) in which the support film cap is opened and the cartridge is released. rail, which includes the containers, is removed from the support. Containers are removed from the cartridge rails and placed on vias from which they are divided on a swing pickup arm and positioned 177 to transfer into a first fill isolator 174, which in the exemplary embodiment of the invention is a medium. controlled environment for filling containers with, for example, powdered drugs. Although foregoing transfers can be achieved by the use of automated equipment, the transfer is typically performed manually, reaching into the support entrance station through "glove holes" or alternatively through the arms of a "semi- assemblies ”and handling the holder, cap and cartridge. During this time,

ES 2 171 929 T3 the empty rail cartridge and holder are transferred back into the UV chamber and the transfer door is closed prior to removal of the cartridge and holder from the UV chamber 172.

The pick and place arm 177 rotates a container into a position for loading onto a continuous belt conveyor mechanism, whereby the containers are fed into the powder fill isolator 174 and subsequently divided through the stages of operation. of the powder filling process. A portion of the continuous belt transport mechanism 176 is shown in Figure 15a and generally comprises a flat belt of a suitable flexible material, such as metal or plastic, and which forms a loop around the outer peripheral surface of a drive roll 171. The drive roller 171 is connected to a drive motor, such as a DC motor. conventional or stepped motor, causing the conveyor 176 to be divided into predetermined spaced apart states through the isolator. The conveyor belt 176 includes a series of spaced apart slots 175 that are cut into the belt material in a direction orthogonal to the direction of the travel belt. Each of the slots 175 has a width of approximately 12.4mm, to accommodate the rotary drum for filling sacrificial holes of the container. Consequently, the grooves 175 are configured wide enough to receive the rotating filling drum but are also narrow enough to engage the lower surface of a lower flange of sacrificial holes (103 of FIG. 8a).

A hole 173 is disposed between a pair of slots, and is provided entirely through the material of the conveyor belt 176. Each hole 173 has a diameter of approximately 11.0 mm and functions to provide a convenient receptacle to receive a cover of Sacrificial port (109 of Figure 8a) when a cap has been removed from a sacrificial port for filling. Although the hole 173 is depicted in the exemplary embodiment of Figure 15a as it is positioned equidistant between two slots 175, it will be apparent that the location of the hole (or cover receptacle) 173 may be provided somewhere in proximity to the holes. slots 175. If the roboetic pick and place equipment, for example, is used to remove the caps from the sacrificial holes, all that is required is that each cap receptacle 173 have a specific relationship to the slots 175 so that it is positioned. The lid receptacle 173 can be programmed into the robotics equipment.

Turning now to Figure 14, the packages can be removed from the rail cartridge and loaded onto the conveyor 176 by hand; reaching an operator within the isolator by means of a semi-assembly or flexible arm covers, accessed through gasketed orifices or, alternatively, containers can be loaded onto the conveyor belt 176 by an automated oscillating pick and place arm 177 that grabs each container and rotates it through approximately 90^°to join the sacrificial orifice tabs with the conveyor belt recesses.

Initially, conveyor 176 divides each container to a tare weight balance 178 (shown in Figure 14) in which the tare weight of each container is determined to provide a reference empty weight that correlates the weights. later checkpoints. The empty container can be removed from the conveyor 176 and placed on the tare weight balance either by hand or by means of an automated pick-and-place robotic arm 179. The container is then fed back onto the conveyor belt and divided into a substantial, in-line, rotating, aseptic powder filler 180. In the powder filler 180, a robotic arm 181 oscillates through a bow to engage the cap in the sacrificial hole of the drug compartment (104 of Figure 8). The cap is removed by grasping it by its removal tab (as described in connection with Figure 8a) and exerting a vertically upward force. After removal, the cap from the sacrificial port of the drug compartment is deposited into the cap receptacle (173 of Figure 15a) located between the sacrificial port slots on the conveyor belt. The lid of the drug compartment sacrificial port is now in a known location relative to the drug compartment sacrificial port, such that robotic machinery can now easily retrieve the cap for reinsertion into the drug compartment sacrificial port as will be described. additionally they continued. Following removal of the cap, the drug compartment is opened (unlocked) with a 0.2 micron jet of nitrogen or filtered air, introduced through the rotating drum of the sacrificial orifice of the drug compartment.

Turning now to Figure 15b, the conveyor belt then divides the container to a position where the sacrificial orifice of the drug compartment is below a conventional, generally circular dosing wheel 182 that automatically dispenses a predetermined amount of powdered drug. inside the medicine compartment however the open hole. Dosing wheel 182 is oriented in a direction orthogonal to the direction of

ES 2 171 929 T3 displacement of the conveyor belt 176 and the packages 10 hang from it. Accordingly, the reason why the drug compartment hole is higher than the diluent compartment hole is now apparent. So that the charge of all the powder contained in the dosing wheel is introduced into the medicine compartment without undue spillage, the orifice of the medicine compartment is sized to place its neck in proximity to the dosing wheel at a distance of approximately 1 , 0 millometers. In order for the diluent compartment hole, which includes the cap still attached, to clean the bottom of the dosing wheel after dosing has been completed and as the container is divided to the next station, the full height of the hole of the diluent compartment and the combination of the cap must be no greater than the height of the hole in the medication compartment with the cap removed, i.e. no greater than the space between the conveyor belt 176 and the metering wheel 182.

An alternative configuration can be invented with respect to the orientation of the containers and the deflection wheel. For example, in addition to linear displacement along their long axis, the containers could be inserted facing the dosing wheel, so that only the sacrificial orifice of the drug compartment passes under the bottom of the wheel arch. dosage. This particular orientation will allow the diluent orifice to avoid the narrow space between the conveyor belt and the bottom of the metering wheel arch and therefore exclude the need to provide sacrificial orifices of separate heights.

Turning now to Figures 13 and 14, following the powder fill, 0.2 micron filtered nitrogen gas or air is introduced into the headspace of the drug compartment and the conveyor belt 176 divides the compartment to a station of gasket 184. Although both air and 0.2 micron filtered nitrogen gas within the contemplation of the present invention, it was understood that the choice between these two gases, or other filter sterilized gases (inert or otherwise) would depend on the sensitivities of the particular drugs introduced into the drug compartment. Specifically, if a drug is extremely sensitive to oxidation, the headspace of the drug compartment is preferably filled with filter sterilized nitrogen, or a similar inert gas. At the gasket station 184 opposite the gasket heads they are brought together to either side of the container, thereby closing the channel (112b of Fig. 8) between the sacrificial orifice and the drug compartment. The gasket, thus formed, effectively continued permanent seals between the oversized edge gaskets 110e and 110f depicted in Figure 8, thereby sealing the drug compartment.

The cap is then reinserted into the sacrificial orifice of the drug compartment, and the powder filled container is divided up to a 186 gross weight balance where its gross weight is taken to verify that the proper amount of powdered drug has been distributed in. each container. Gross weight, as determined at station 186 is correlated to the weight of the empty container as determined at tare weight station 178. If the gross weight balance 186 determines that an improved amount of powdered drug has been introduced into the drug compartment of the container, the container is rejected and transferred to a reject lane cartridge for subsequent removal from the powder fill isolator 174 . If the weigher determines that the amount of powdered drug in the drug compartment is correct, the container is believed to have been filled correctly and divided to the next station, or stations, if further processing is desired.

In accordance with the practice of the principles of the invention, the additional compartments of a container can be filled by additional drugs or by diluents (in the next filling) in a subsequent isolator unit, or multiple subsequent isolator units. Although the first filling stage was described in connection with the introduction of a powdered drug into the drug compartment, it was understood that this was done in the context of a multi-compartment medical package that has separate compartments for a powder drug and a liquid diluent. However, it will be apparent that a single compartment medical container can be filled in accordance with the present invention, by any powdered drug, in the manner described above, or a liquid drug or diluent, in the manner described below.

With particular reference to FIG. 14, the partially filled multi-compartment container of the exemplary embodiment of the invention is now introduced to a second liquid fill isolator unit 190 for aseptic filling with a diluent.

In particular, at the completion of the powder fill process, and as indicated in the exemplary process flow chart of Figure 13, the partially filled container is moved from the powder fill isolator 174 to the powder fill isolator. liquid 190 through a transfer tunnel

IS 2 171 929 T3

192 which is connected between the two isolator units. Following the powder filling procedure described above, the container is removed from the conveyor belt 176 of the powder fill isolator 174, and placed on a transfer belt 194 that passes through the transfer tunnel 192 and joins the two isolator units. It will be understood by those skilled in the art that transfer tunnel 192 and transfer tape 194, in combination, provide an essential feature that promotes the modular nature of the isolator-based filling process of the present invention. Indeed, it can be seen that a plurality of isolators can be joined together by transfer tubes to add additional filling steps, perhaps with a plurality of ingredients to the process. The modular nature of the container construction process, by which single or multiple compartment containers can be manufactured, easily collides with the modular nature of the filling process. Since many fill isolators are required to fill the desired number of compartments, they can be easily joined together with transfer tubes to thereby realize a fully flexible fill and build line.

Turning now to the filling process and apparatus of Figures 13 and 14, the partially filled containers are introduced into the liquid fill isolator 190 through the transfer tunnel 192 and placed back on a continuous loop conveyor 196 which divides the container through the stages of the liquid filling process.

As was the case with the powder filling process described previously, each container is divided into a filling station 198 in which a robotic arm moves through an arc to grasp and remove the cap from the sacrificial orifice of the storage compartment. diluent and place it in a receptacle on the transport belt. The diluent compartment is then unblocked with a 0.2 micron filtered air or nitrogen jet and advanced to position the sacrificial orifice of the diluent compartment below the dispensing nozzle of a diluent filling machine. A predetermined amount of diluent, such as 5% Dextrose Injection diluent or normal saline is distributed into the container through the sacrificial orifice. The diluent has been topically premixed under qualified procedures in a separate mixing area and piped to the filling machine through 0.2 micron filters. It will be understood by those skilled in the art that the diluent may be introduced into the container in a single dispensing stage procedure or, alternatively, a double dispensing stage or a multiple dispensing stage may be used to more accurately control the dose and reduce turbulence.

Following the diluent dispensing step, the container is divided into a gasket station of the diluent compartment 200, where the diluent compartment headspace is first adjusted with 0.2 micron filtered air or nitrogen. The gasket station 200 comprises a gasket plate opposite a backing plate, which is then closed over the container to seal the channel (112a of FIG. 8) between the diluent compartment and its sacrificial orifice. In effect, the diluent compartment gasket continued to the permanent peripheral gasket between regions 110d and 110e of Figure 8, thereby completely sealing the now completed package from the sacrificial strip.

The filled container now exits the liquid fill isolator 190 through an exit tunnel passageway 202 and exit conveyor 204. The container is rinsed and dried to remove any residual diluent and / or medication from its outer surface and is trimmed to its ends. final dimensions by removing the oversized rim portion of the container that includes the sacrificial holes. As an optional part of the trimming process, the peripheral seal along the side of the container to be trimmed out can be reinforced thereby ensuring the seal of the drug and diluent compartments on all sides of the container. The manufacturing and filling of the container is now completed and the filled and finished container is folded along the joint between the drug and diluent compartments, rolled, and packaged in shipping containers.

The production process for the manufacture and filling of the container therefore only contemplates an individual sterilization procedure following the manufacture of the primary container. Consistent with early inventive practice, the construction of the container and the use of sacrificial ports communicating with the diluent and drug compartments allow the diluent and drug compartments to be subsequently filled aseptically, and sealed without the need for any additional sterilization procedures. Indeed, since the container of the present invention is not capable of being terminally sterilized by water vapor, due to the high sensitivity to humidity of powdered drugs and moisture barrier properties of the coating of the drug compartment, Aseptic filling methods, described above, is a necessary accessory for the manufacture of a sterile final product. The manufacture and filling of the container

ES 2 171 929 T3 according to the practice of the invention therefore allows the package to be manufactured from materials, including high barrier property laminates that are highly resistant to the effects of conventional steam sterilization. Once the requirement for downdraft sterilization is removed, modest packages can be designed to include such high-barrier laminates, thereby providing medical packages that are particularly suitable for long-term storage, and which can be efficiently manufactured at cost. low manufacturing.

Additionally, it was understood by those technicians in the field that the construction and use of the sacrificial orifices that communicate with the drug and diluent compartments provide a means to divide, retain, place and manipulate the container throughout the filling process. . The size of the sacrificial orifice openings is tailored to the container to be compatible with conventional drug vial filling equipment technology.

The sacrificial holes are designed with tabs so that the container is capable of being hung on a dividing mechanism, and two tabs are provided in each hole so that the container can be 'hung' by the robotic pick and place equipment to the stations. weighing out of line or transferred between isolators. Additionally, it was found that using sacrificial orifices, in connection with filling and medical container manufacturing processes, ideally promotes modularity in the manufacturing and filling sequence.

Use of the container

The use of the completed packages is substantially independent of the production technique employed. The triple compartment package 10 and the mixing system were received by healthcare personnel, topically a hospital pharmacy department, in the completed configuration shown in Figures 1 and 2. Referring now to Figure 16, in preparation for use of the container, the drug may be inspected by grasping the tab 62 on the protective layer containing aluminum metallic tape 55 and peeling the protective layer from the container to allow visual inspection of the intermediate compartment. 20 containing the powdered medicine. If the medication appears dry and in a normal condition, the solution can be mixed as shown in figure 17 by manipulating the container to compress the front and rear lamines in the area of ​​the upper diluent compartment 18. Mechanical pressure from the hydraulic forces created by manipulating the container, it breaks the peelable seal between the diluent and drug compartments (shown in the rupture condition as in 24 '). Additionally, the manipulation by shaking causes the mixing of the liquid diluent and the powdered medicine. Verification of mixing is done by visually observing the mixed solution through the clear, transparent front sheet. After mixing is complete, the peelable gasket between the medicine compartment and the lower safety compartment is broken as shown in figure 18 by compressing the front and back of the container again which creates hydraulic pressure in the container to break the seal. joint (shown in rupture condition as 26 '). The mixed solution is then dispensed from the container through outlet port 30 using a standard IV delivery device.

The arrangement of the container 10 precludes the supply of unmixed diluent through the outlet port 30. Additionally, the arrangement of the intermediate compartment 20 between the diluent compartment and the outlet port improves the likelihood of complete mixing and drug delivery to the patient. . For packages that include a liquid diluent and powdered drug, the breakdown of the first peelable joint between the diluent compartment 18 and the drug compartment 20 is ensured essentially prior to breakdown, of the second peelable gasket between medicine compartment 20 and lower safety compartment 22 since hydraulic forces developed in the diluent handling the container cannot be transmitted through the powder in the medicine compartment until the first gasket has been broken and mixing of diluent and powder has started. For these cases where a liquid medicine can be used, the relative size difference between the diluent compartment and the drug compartment and the placement of the small drug compartment between the larger diluent compartment and the safety or lower compartment ensures the development of hydraulic forces that break the first joint between the drug and diluent compartments before breaking the second seal leading to the safety compartment with only one care mononym.

In the exemplary embodiments of the container, shown in Figures 16, 17, and 18, the peelable gaskets are depicted as having a conventional, rectangular configuration such as the gaskets described in U.S. Patent No.^° 5,176,634 to Smith et al. The description of which is expressly incorporated herein by reference. In accordance with the principles of

ES 2 171 929 T3 the invention, the gaskets, although conventionally configured, are formed in the manner described above to provide a uniform predictable response to handling pressure and peel open at an applied force of approximately 0.028 ± 0.007 M Pa (4, 0 ± 1.0 psi). In a further embodiment of the invention, curvilinear peelable joints are provided which function for fully open peeling, along their lengths, under hydraulic pressure, and which are formed in substantially the same manner as the uniform peelable joints described above.

Turning now to Figure 19, which depicts a semi-schematic view of an exemplary embodiment of a curvilinear peelable gasket 86 provided in accordance with the practice of the invention. The curvilinear joint configuration is provided to solve two conflicting performance requirements imposed on peelable or breakable joints, used in connection with a binary medical container. The first performance requirement for a peelable, or breakable gasket is that it provides a relatively strong resistance to the force required by a user of the product to break or peel the gasket, in order to avoid inadvertent breakage of the gasket during normal handling. The second performance requirement is that the gasket is peeled substantially apart completely, during user activation, thereby avoiding any subsequent limitation of the flow path between the communication chambers. It has been noted that with conventional straight peelable gaskets there is a possibility for the gasket, both peelable and frangible, to peel apart incompletely during activation. This can allow significant amounts of both liquid diluent and mixed medication to remain trapped against the unopened joint lone portions.

Additionally, it has been indicated that for conventional straight peelable gaskets that when the force required for user activation increases, it also has the probability of incomplete gasket opening.

The operational use of a binary medical container requires that the peelable gaskets survive various impacts during the life of the product. Most of these impacts tended to occur while the product was folded along a joint line, with the peelable joints thus being well protected. However, significant impact events can occur after the product has unfolded and, during this period, peelable joints are susceptible to unforeseen activation with subsequent product activation. To reduce the risk of unanticipated activation, an effective binary medical package should be designed with peelable gaskets strong enough to withstand more inadvertent impacts, but fully withstanding intentional handling pressures.

Accordingly, the curvilinear peelable gasket 86 solves the two conflicting performance requirements by having a configuration that reflects the configuration made by a conventional straight peelable gasket as it begins to peel apart. As described above in connection with Figures 1 and 2, and as shown in Figures 19, the peelable gaskets extend the container horizontally, and have a length 88 sufficient to connect between the permanent gaskets 16 on the sides of the bag, therefore dividing the container into compartments. Each gasket 86 comprises a first, generally rectangular portion 90 defining the minimum width of peelable gasket 86 at its intersection with permanent gaskets 16 on the sides of the container. The dimension of the rectangular portion 90 in the height direction (the smallest dimension) is approximately 2.54 to 6.35 mm (1/10 to 1 inch) and preferably 3,175 mm (1/8 inch). This rectangular portion 90 is therefore configured as a conventional, rectangular (straight) joint. The peelable gasket 86 further includes a second curvilinear portion 92 comprising a curved section protruding from the rectangular portion 90, with the chord of the section coextensive with an edge of the rectangular portion, and with the arc of the section oriented to project into the compartment that provided the source of the gasket opening pressure. The convex edge of the arch 94 is generally radial and has a maximum chord depth that is approximately half the width of the rectangular portion 90 of the joint 86. The specific configuration, radius of curvature, and depth of the chord of the curvilonous section 92 will vary, therefore, with the length of the gasket, and the particular application to which the binary container is put, including the anticipated resistance to any inadvertent impacts. However, specific gasket configurations can be suitably calculated, by one of ordinary skill in the art, using beam theory and suitably determining the desired opening pressure for the gasket.

In operation, the convex guiding edge 94 of the peelable gasket 86 exhibits a compound resistance characteristic with respect to the hydraulic pressure of the diluent, or mixed medication, when a respective compartment is compressed. As shown in FIG. 20, conventional peelable gasket peeling characteristics show a curved peeling front, when the gasket is examined after it has been partially peeled open. This curved peel front indicates that the hydraulic pressure, which forces the joint opening, is greatest at approximately the center of the joint, and decreases uniformly, but according to a power law directed toward the joint.

ES 2 171 929 T3 out towards the edges of the joint. A conventional partially open peeled gasket would therefore have a concave gap pattern, with the deepest portion of the concavity being approximately in the center of the gasket. It can therefore be easily seen that conventional gaskets will naturally tend to open sooner in the central region of the gasket, and will tend to remain closed along the sides of the gasket, particularly where the peelable gasket contacts the edge gasket. permanent.

In accordance with early inventive practice, the curvilinear peelable gasket 86 of FIG. 19 provides a convex edge 94 having a configuration that is a mirror image of the concave gasket characteristics of a conventional gasket. As depicted in Figure 21, the strength characteristic of the curvilinear joint will bond the curvilinear pressure gradient of the diluent or mixed drug that is intended to peel the joint opening. The characteristic strength of the curvilinear joint 86 is strongest in the center, where the pressure is greatest, and decreases in a non-linear fashion, according to the decreasing pressure, towards the edges of the joint. In this way, the gasket causes it to peel open, evenly, along its entire length.

Although the curvilinear peelable gasket 86 has been described as providing a non-linear strength characteristic to hydraulic pressure having a curvilinear width, it will be apparent from a person skilled in the art that the nonlinear strength characteristics can be provided by other means. For example, a curvilinear strength characteristic can be obtained in a rectangular shaped straight peelable joint by varying the temperature or pressure of a thermal joint bar when the joint is formed. The thermal joint temperature can be made hotter in the center and can be lowered non-linearly towards the ends of the joint, thus providing a peelable joint that is stronger in the center, by virtue of the joint that is not permanent. Alternatively, a curved sealing bar can be used to give the same effect, with the sealing bar being designed to have a convex contact face that presses against the binary medical container during the peelable gasket manufacturing process. Although such a gasket may exhibit a conventional linear configuration, its center portion should be compressed together much tighter during the sealing process. The application of pressure would result in the central portion of the joint being the strongest, with the joint strength decreasing in a non-linear (curved) manner towards the ends. All that is required is that the peelable gasket have a non-linear strength characteristic that substantially unites the non-linear pressure characteristics of diluent, or mixed medication, when a respective compartment is compressed.

Additionally, thorough mixing of diluent and drug, and complete delivery of mixed solution through the outlet port to a standard IV delivery device is enhanced by the non-linear peel characteristics of the joints of the present invention. As described above, the nonlinear resistance of the peelable gasket to hydraulic pressure ensures that the gasket opens substantially along its entire length and therefore ensures that substantially all of the liquid diluent is capable of entering the compartment of the gasket. medicine and mix it with the drug contained inside. Following mixing, the non-linear peel characteristic of the second gasket ensures that the gasket is peeled open substantially completely along its length allowing access of mixed solution to the outlet port and IV delivery system.

Those skilled in the art will recognize that the primary discussion of embodiments comprising a liquid diluent and an individual powdered medicament do not limit the scope of the invention. The use of liquid drugs in the intermediate compartment or a plurality of compartments for liquid and powder drugs, should be mixed with the diluent, can be employed using the present invention. Multiple sacrificial ports and communication channels between the sacrificial ports and a respective compartment can easily be provided in accordance with the practice of the early invention. In addition, depending on the susceptibility of any of the components that comprise the contents of the multiple compartments to moisture or free oxygen contamination, these compartments can be protected by additional applications of a clear, high-barrier laminate containing transparent SiOx on the surface. léamina front of the container in these regions of the compartment. Such high barrier laminates may be provided with or without being combined with a peelable coating of high barrier laminate containing aluminum metallic tape.

The foregoing descriptions of exemplary sterile, flexible packaging embodiments are for illustrative purposes. Due to variations that will be apparent to those skilled in the art, the present invention is not limited to the particular embodiments described above. Such variations, and other modifications and alterations are included within the scope of the invention as described in the following claims.