Flexible, multiple-compartment drug container and method of making

ES 2 215 830 T3

DESCRIPTION

Flexible container and manufacturing procedure.

The present invention relates to a flexible storage container comprising a flexible backsheet and a flexible front sheet, and to a method for forming a flexible container.

The various drug (drug) solutions are commonly administered intravenously (IV) from sterile packaging to patients. Such solutions often comprise a mixed combination of a liquid diluent, eg, an aqueous dextrose or NaCl solution, and a drug. Desirably, the drug and diluent are stored separately in the container under aseptic conditions and are not mixed together until immediately before use to prevent degradation of the final product. The common packaging of the diluent and the drug is often further complicated by the character of the drug which can 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 in solution over time, have been stored separately in moisture-proof and gas-tight vials, containers, or the like before use. Before being administered to a patient, the drug stored in this way must be mixed, or diluted, in physiological solutions or diluents that are also preserved separately. Although they are capable of maintaining the stability and effectiveness of the drug, the storage of separate components is heavy 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 storing 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 aseptically mixed together.

Multi-compartment packaging is known, allowing 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 Pat. States Nos. 4,608,043 and 5,176,634. The compartments of the containers described in the preceding patents are separated from each other by frangible thermal seals. The seals are broken by manipulation of the container, so that the contents of the compartments can be mixed together to form a solution that is delivered to the patient through a standard IV device.

Solution packages on the market today are generally made of materials comprising PVC plastic. PVC material is generally quite dark in appearance, making it difficult to inspect the contents of a container made of such a material. As a consequence, inspection of such packages for leakage and moisture contamination is quite difficult as it is verified whether complete mixing of drug and diluent for administration to a patient has taken place. Additionally, various hazardous chemicals are used in the manufacture of PVC material that must be disposed of in an environmentally safe manner. PVC containers must be disposed of carefully following use, since PVC emits a toxic gas when incinerated and includes a toxic plasticizer that can infiltrate into the surrounding environment if the container is buried in a landfill. This toxic plasticizer is also capable of infiltrating 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 environmental radiation in order to avoid degradation of the medication contained within. A known method of protecting the drug compartment, for example, from moisture and oxygen contamination is described in US Patent No. 5,267,646 to Inouye, et al., Wherein the drug compartment It is surrounded by a secondary compartment that contains a desiccant and an oxygen absorber. Free oxygen and moisture vapor is allowed to penetrate the secondary compartment material, and is absorbed by the desiccant and oxygen scavenger before it is able to affect the drug compartment material.

Although this method is able to provide 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 is provided around the drug, making it more difficult to inspect the contents. from the medicine compartment before reconstitution. Furthermore, no protection against the effects of UV or degradation of ambient light is provided for the contents of the drug compartment.

US 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 seals 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 diluent and drug compartments are formed in the container by frangible heat seals. The back sheet is impermeable to water vapor and is made of a laminated material that has an inner layer of polypropylene,

ES 2 215 830 T3 a middle layer of aluminum foil and an outer layer of polyester film. The vapor tightness of the backsheet extends the shelf life of the product by halving the permeation of diluent vapor from the container, and permeation of vapor from the atmosphere into the drug compartment. Further reduction in a vapor permeability is provided for the drug compartment by peelable attachment of a third sheet of laminate that is identical to the back sheet, on the front sheet of the package in the region of the drug compartment. This third laminate sheet is sized to cover the drug compartment and, in combination with the backsheet, provides a vapor impermeable enclosure.

However, once the third vapor-impermeable sheet is peeled from the drug compartment, the drug compartment is no longer enclosed and is 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. Since the vapor-impermeable cover is routinely peeled from the drug compartment during a hospital entrance inspection procedure, long-term storage of such packages is problematic. In cases where the drug is a powder, highly susceptible to degradation by moisture, the shelf life of a container that has had its vapor-impermeable cover removed is often longer than a few days.

In view of the foregoing, it can be seen that there is a need for improvement over prior art packages, since medical packages are required that are environmentally safe in manufacture and disposal. Such packages should be capable of protecting dust and other sensitive drugs from moisture, humidity and other 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.

In various prior art multi-compartment packages, simple frangible or peelable seals are used to divide the drug and diluent compartments to prevent unexpected delivery of either component prior to mixing. Such simple seals are formed through the container in its transverse direction, and have a uniform thickness and cross-sectional length throughout the seal. When the container is manipulated in order to break the seals, and thus mix the drug and diluent together prior to delivery, the mechanical pressure of the liquid diluent against a seal is released as soon as a part of the seal is released. seal breaks and allows diluent to enter medication compartment. A partial rupture of the linear seal often does not allow full delivery of the fluid contents of the diluent compartment to the drug. 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 right and left ends of the gasket. Such a partial breakdown can also lead to incomplete mixing of drugs with diluents and incomplete delivery of the mixed product to the patient.

Therefore, it is desirable to provide an IV container that has multiple compartments for storing diluents and medications in a single container that has peelable seals that divide the compartments that are configured to substantially completely rupture along their entire length to combining and mixing the contents completely, and ensuring the supply of the full amount of the final mixed product.

It is also desirable that the container device prevents the unexpected delivery of some of the components before mixing, but allows visual verification of the condition of the components following the receipt of the container by the hospital's pharmaceutical services, but before storage and after distribution. Also desirable is the ability for improved protection of the contents of one or more of the compartments of the package against permeation of moisture, oxygen, or degradation by light.

This need is met by the packaging of claim 1, and the method of claim 17.

The present invention provides a container having multiple compartments separated by peelable seals that can be ruptured by manual application of 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 perimeters. Separate compartments in the package are formed by peelable heat seals. 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 distributed.

In one aspect of the invention, the package is made of a flexible backsheet and a flexible frontsheet sealed to the backsheet along a common peripheral edge. A first peelable gasket extends between the two sides of the common peripheral edge and removably joins the front and rear sheets to form a compartment containing a diluent. A second peelable sheet extends between the two sides of the common peripheral edge and separately joins the front and rear sheets to form an exit compartment and a compartment containing a drug that is intermediate between the exit compartment and the drug compartment. diluent. A clear, high-barrier laminate film is sized to

ES 2 215 830 T3 covers the medicine compartment and is sealed to the front sheet. An opaque, high-barrier protective film is sized to extend over the clear, high-barrier laminate film and the drug compartment and are separately 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 covering over the drug compartment.

In one embodiment, the opaque, high-barrier protective film includes an ethylene vinyl acetate polymer layer on its inwardly facing surface; a polyester polymer layer having a higher melting temperature than the ethylene vinyl acetate polymer layer, on its downward facing surface; and a high barrier opaque aluminum foil layer intermediate between the ethylene vinyl acetate and polyester layers. The opaque, high-barrier protective cover peelably attaches to the medication compartment to facilitate removal and subsequent inspection of the contents of the medication compartment.

In another aspect of the present invention, the clear high barrier laminate film comprises clear moisture and oxygen barrier laminate films provided intermediate between the opaque protective film containing aluminum foil on the front sheet of the container, in the region of the drug compartment. Specifically, the clear high barrier laminate film comprises an inner polypropylene layer adjacent to the front sheet of the container; an outer layer of polyester, and either a clear transparent high humidity barrier, a clear transparent high oxygen barrier, or both, arranged between the inner and outer layers. In yet another aspect of the present invention, the peelable seals are manufactured to exhibit a characteristic of curvilinear resistance to hydraulic pressure on the seal caused by tampering with the container. The curvilinear strength characteristic is strongest in the center of the peelable gasket and tapers to either side. Sealing gasket separation is achieved by manipulation of the container to create pressure on the diluent in the first compartment which then hydraulically separates the gasket substantially completely along its length between the compartments allowing the diluent and the medicine is mixed. A third compartment, adjacent to the second compartment and opposite the diluent compartment, contains an outlet port for dispensing the mixed fluid. A peelable gasket between the second and third compartments prevents administration of the contents before mixing 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, which allows the drug fluid to be distributed through the orifice.

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

Still a 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 fold of the container presses the container material together in a region ahead of the first peelable seal, thereby reinforcing the seal against hydraulic pressure, caused by unexpected 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 retention notch, where both the tongue and the retention notch are integrally formed, together with the container, from the container materials. The container can therefore be unfolded repeatedly 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 peelable attached onto the clear, high-barrier laminate film to allow easy removal and inspection of the drug compartment. Only a part of the surface of the clear, high-barrier laminate film is contacted by the opaque, high-barrier protective film, the fixing strength being directly proportional to the surface contact area. The opaque, high-barrier protective film is affixed onto the clear, high-barrier laminate film by a fabricated heat seal head that defines a regular series of generally circular non-contact areas. The strength of the peelable gasket thus formed can be easily adjusted by varying the number of non-contact areas.

In still a further aspect of the present invention, a method for forming the flexible container for the combined storage and administration of drugs and diluents for IV solutions, comprises the steps of sealing a flexible transparent front sheet to a flexible, waterproof back sheet. steam, along a common peripheral edge; heating the front and back sheets in a first localized area to fuse the heated portions of the adjoining surfaces together, thereby forming a first peelable gasket that extends between two sides of the common peripheral edge; and heating the front and back sheets in a second localized area to fuse the heated portions of the adjoining surfaces together, thereby forming a se4

ES 2 215 830 T3 peelable sealing gasket. The first peelable gasket separately joins the front and rear sheets to form a first compartment containing a diluent. The second peelable gasket separates the front and rear sheets to form an outlet compartment and a compartment for containing a medicament that is between the outlet compartment and the diluent compartment. The first and second sacrificial ports are interposed between the front and rear sheets and are positioned 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 seal is completed along the periphery of the container, in the region of the orifice. Similarly, the drug compartment is aseptically filled with a drug through its respective sacrificial port and this port is sealed along the periphery of the package, following which these sacrificial ports are removed from the package. The formation and filling of the container is achieved without the container undergoing a sterilization step after the first step of filling the compartment.

Specifically, the diluent and drug compartments are aseptically filled with presterilized diluent and presterilized 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 in a transport carrier which is then sealed against contamination from the environment. The transport carrier, and the packages within, are subjected to E-beam sterilization. The transport carrier and the containers inside are introduced into the isolator through a UV decontamination tunnel that ensures the maintenance of a sterile environment within the isolator.

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, in which:

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 intervention of curvilinear seals that include an outlet orifice and folded locking tabs.

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

Figure 3 is a fragmentary cross-sectional semi-schematic 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 describing an optional, transparent, high-barrier intermediate film.

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

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

Figure 7 is a semi-schematic front view of a further embodiment of the container provided in accordance with the present invention showing an additional peelable seal 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 at an intermediate stage of its manufacture showing the arrangement of the 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 including a cap in accordance with the present invention.

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

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

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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 lid.

Figure 11a is a semi-schematic perspective view of the components of the rail cartridge of Figure 10, describing the rail cartridge in an exploded, ordered form, and ready 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 describing the packages loaded on the rails in accordance with the present invention.

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

Figure 13 is a flow chart of the sterilization and aseptic filling 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 the progressive stations of the process in accordance with the practice of the present invention.

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

Figure 15b is a semi-schematic partial perspective view of the arrangement of a powder filling wheel and conveyor belt showing the direction of travel of the packages under the filling wheel.

Figure 16 is a semi-schematic illustrated view of 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 seal to mix the diluent and drug.

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

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

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

Referring to Figures 1 and 2, schematic cross-sectional and front side views, respectively, are shown 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 package 10 can be viewed in any orientation, for purposes of explanation herein, the position of the package compartments relative to each other are described positioned in Figures 1 and 2. The package 10 is formed from a front sheet 12 and a back or back sheet 14 (shown only in Figure 2). The front and back sheets can be made of a single layer of flexible material or laminates of multiple layers of flexible material which are to be described in more detail below. The sheets 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 seals can vary in configuration and width. A configured seal, such as that described in the upper seal portion 16a and the lower seal portion 16b in Figure 1, can be used to provide grip areas for the user to manipulate the container and to secure the container, for example, an IV support shelf. Alternatively, the front and back sheets can be formed from a single sheet of film that is folded back and is sealed by means of a heat seal that extends around the peripheral portion of the package. The sheets sealed together are referred to herein 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 upper and intermediate compartments 18 and 20 are separated from each other by a first peelable seal 24, and the intermediate and lower compartments 20 and 22 are separated from each other by a second seal.

Peelable ES 2 215 830 T3 26. The peelable seals 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 sheets. A "peelable" gasket as the term is used herein means a gasket that is durable enough to allow normal handling of the still-peeled package, allowing separation of the front sheet from the back sheet in the region of the sealing gasket, under hydraulic pressure applied by handling the container, thus allowing the mixing and distribution of the container's contents. A peelable gasket is formed by partially melting together the polymer present in the adjacent layers of the front and back sheets. The sealing gasket is obtained by a heat sealing process that is carried out by varying the times, temperatures and pressures that is described in more detail below. Conversely, the peripheral edge seal 16 is significantly stronger than the "peelable" seals and will not rupture by pressures generated to separate the peelable seals. The configuration of peelable gaskets with a non-linear resistance to hydraulic opening pressure of a manipulated container, in contrast to a conventionally formed straight line gasket, substantially promotes complete peeling of the entire gasket during delivery. use of the container as will be described in more detail later.

In a typical application of 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, typically provided 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 tailored seat 32 which, when viewed from above, is configured as an ellipse with its focal ends flattened, and is disposed at approximately the center of the bottom edge of the container between the front sheet 12 and the backsheet 14. The flattened focal ends of seat 32 form flanges 34, best seen in Figure 1, which taper conically toward the flattened edges of seat 32. The flattened elliptical configuration creates a uniformly curved surface to which the front and rear sheets are firmly attached for example by a permanent heat seal (referred to herein as the "outlet seal") 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. Ribs 39 are provided in spaced relationship around body portion 38 of outlet port 30 to provide a surface that can be easily gripped when attaching an IV assembly to the container. In the illustrated embodiment, four ribs 39 are provided extending longitudinally from the surface of the body portion 38 of the container 10. Although four longitudinal ribs are described, one skilled in the art will recognize that various other types of surface hinge may be provided that will allow the hole to be easily grasped, such as circumferential ribs, transverse ribs, knurling or scoring the surface of the body portion, and the like.

The materials used in the front and back sheets of container 10 are selected based on the material that must be stored within. Preferably, at least one of the sheets is transparent to allow the contents of the container to be visually inspected and to allow the level of the solution in the container to be observed during dispensing. Suitable materials for making the transparent sheet are typically single-layer and multi-layer laminated polymer films.

In particular, if manufactured from a single or multi-layer laminated polymer film, the materials that comprise the front 12 and back 14 sheets of the package 10 are chosen for their clarity and transparency. Conventional polyvinyl chloride (PVC) container materials are generally quite dark in appearance, making it difficult to properly observe 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 mandatory that a nurse or any healthcare provider be able to tell, at a glance, that the fluid of any medication that is administered from a medical container is free of particulate matter.

First form of realization

In a first embodiment of the container of the present invention, which is described in fragmentary schematic cross-section in Figure 3, the front sheet 12 is made of a single layer transparent thermoplastic polymer film 44. In this embodiment, transparent 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 Wt% ethylene butylene styrene thermoplastic elastomer (SEBS), available from Shell Chemical Corporation under the ®® brand Kradon and carrying a G1652 trade designation. Kraton G1652 thermoplastic elastomer is a three-block copolymer with polystyrene end blocks and a poly (ethylene-butylene) rubber midblock. Subsequently, the transparent film 44 is formed from granules mixed in a commercial extrusion apparatus. The transparent polymer film 44 comprising the front sheet 12 can be made of various thicknesses, depending on the use for which the container is intended, and the durability required for this application.

Suitable thicknesses for the material comprising the front 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 (12 mils) thick.

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

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

In the exemplary embodiment, the backsheet 14 includes an inner sealing sealing layer 46 on its inwardly directed surface, comprised of an 80% / 20% w / w blend of polypropylene-polyethylene copolymer and thermoplastic elastomer. of styrene ethylene-butylene styrene having a thickness of about three to six mils (the 80:20 film). In a preferred embodiment, the film layer

80:20 interior gasket 46 is a 152.4 μm (six mils) thick composition, which is bonded by means of a suitable clear adhesive 48 to a 50 layer of high barrier capacity aluminum foil about 17.78 to 33.02 µm (0.7 mil to 1.3 mil) (preferably 25.4 µm or 1.0 mils). A high melt temperature outer layer 54 is provided on the outwardly facing surface of the backsheet, and is adhered to the high barrier ability aluminum foil layer 50 by means of a suitable transparent adhesive 52. In one form In the embodiment of Figure 3, adhesive layers 48 and 52 comprise a modified aliphatic polyester polyurethane adhesive, available from Liofol Co. ofCary, North Carolina, under the trade designation Tycel 7909. The aluminum foil layer 50 is suitably made from a commercially available 25.4 µm (1 mil) aluminum foil, such as Alcan 1145, available from Alcan Rolled Products Company of Louisville, Kentucky.

Because the heat sealing process used to form the peripheral edge gaskets and transverse peelable gaskets is capable of damaging the high barrier capacity aluminum foil layer, should that layer remain exposed, the high temperature outer layer 54 would be made up of a relatively high melt polymer and functions as a protective layer to prevent contact between the sheet layer and the heat patterns of a heat sealing apparatus. Additionally, the high temperature layer 54 serves as a heat seal release (also referred to as a mold release) since it does not melt or adhere to thick heat seal plates at the temperatures used to form the seals.

The high temperature outer 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 mils). In a preferred embodiment, the thickness dimensions of the multilayer laminate film 14 are 12.19 μm (0.48 mils) for the highest temperature outer polyester layer 54.25.4 μm (1 0.0 mils) for the 50 high barrier aluminum foil layer and 6.0 mils (152.4 μm) for the 80:20 inner film gasket layer 46.

The preferred material choices for the front and back sheets, which result in optimal performance of the peelable gaskets, have been found to incorporate a matching gasket layer on both sheets that comprises the 80:20 film. However, the front and back sheet adaptive gasket layers may alternatively comprise blends of polypropylene-polyethylene copolymer and styrene-butylene styrene thermoplastic elastomer having different relative percentages. The relative percentages used will depend on the characteristics of the various seals 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 the construction of the front and rear sheets of the container shell 10 of the present invention, as well as the layers of adaptive gasket on both sheets, are described in US patents. United States Nos. 4,803,102, 4,910,085, 5,176,634, and 5,462,256.

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

Referring in particular to Figures 2 and 3, an opaque, high-barrier protective film 55 is employed, in the illustrated embodiment, to cover the intermediate compartment 20. The film 55 interposes a barrier against the vapor of moisture and free oxygen permeation into the drug compartment. On

In the exemplary embodiment, the high-barrier protective film 55 comprises a multilayer laminate structure that includes a layer of high-barrier aluminum foil. The use of an opaque aluminum foil laminate further helps prevent the drug contained in the intermediate compartment 20 from being degraded due to exposure to visible light and UV radiation. Thus, in the present embodiment, the opaque aluminum foil comprising both the protective film 55 and the backsheet 14 prevents the 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 inwardly directed surface. In an exemplary embodiment, the gasket layer 56 is a co-extrusion soft coated resin comprising a modified ethylene vinyl acetate polymer available from Dupont Chemical Company under the trade designation Appeel 1181, provided in a thickness from about 5 .08 to about 10.16 µm (0.2 to about 0.4 mils). A layer of 58 aluminum foil, such as Alcan 1145, from about 17.78 to about 33.02 µm (0.7 to about 1.3 mils), (preferably, about 25.4 µm or 1.0 mils ) thick is adhered to the inner gasket layer 56 by means of a suitable transparent adhesive 57. An outer, heat seal release layer 60 comprising a polyethylene terephthalate (PET) film, such as Terphane 10.21, approximately 12.19 μm (0.48 mils) thick, forms an outwardly directed surface of the high barrier protective film 55 and is adhered on the aluminum foil layer 58 by means of a suitable transparent adhesive 59. Adhesive layers 57 and 59 of the present embodiment comprise a modified aliphatic 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 coextrusion coated resin, it is capable of providing a peelable gasket over a wide temperature range, when applied at a number of different materials. Materials to which such a coextrusion coated resin forms a peelable gasket include acrylonitrile-butadiene-styrene (ABS), high-density polyethylene (HDPE), high-impact polystyrene (HIPS), polypropylene (PP), polystyrene (PS), polyvinyl chloride (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 sheet 12, covering 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 condition of the drug powder within the intermediate compartment 20. In the exemplary embodiment, viewed Better in connection with Figure 1, the protective film 55 includes an extension tab 62 that can be grasped in order to peel the protective film 55 off the transparent front sheet 12. The contents of the intermediate compartment 20 are exposed in this manner and can be visually inspected.

As can be understood by referring to Figure 1, the high barrier protective film 55 is not attached to the container by a gasket over its total surface area; instead, the film 55 is partially sealed only to the underlying material. These unsealed portions of the high barrier protective film 55 define a regular series of generally circular raised cavities 51, which 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 capacity protective film 55, a heat seal is provided only on the surface contact regions of the heat seal bar and not in the regions where the bar material has been removed (the holes). Since pressure is also applied along with heat during the process, the high barrier protective film 55 adopts an imprint from the heat seal head, thereby giving rise to the raised, raised cavity surface.

The cavities 51 allow the protective high barrier film 55 to be adequately sealed over the underlying material of the medical container but, at the same time, provide easy removal of the film 55 without the application of undue force. If the entire protective layer 55 is to be heat sealed on the surface of the container, a greater than desired amount of force would be required to fully peel it off. By reducing the surface area of ​​the gasket, less force (proportional to the sealing area) is required to remove the peelable aluminum strip. It is apparent from the foregoing description that the amount of force required to remove the peelable aluminum strip is inversely proportional to the number of cavities (51 of FIG. 1) formed in the film 55. Depending on the intended use of the medical container, a removable barrier high-capacity protective layer can be easily constructed more or less easily, simply by increasing or reducing the number of cavities 51 formed in the layer during the heat sealing process. .

In practical use, the filled container is received by the pharmacy services of the hospital, and is then stored for a period of time relative to what is necessary. Typically, prior to dispensing, the pharmacist removes the high barrier foil layer 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 in use at this time, it is returned to the pharmacy and redistributed at the next request. This removal of the high peelable barrier film 5 from the drug compartment 20 leaves the

ES 2 215 830 T3 contents of the drug compartment susceptible to degradation by moisture, light and permeable oxygen. It is desirable that the filled packages of the present invention be capable of being stored in the pharmacy services for periods of time of up to 30 days, before use, without the drug being severely degraded by exposure to humidity and free oxygen afterwards. the high barrier protective film on the medicine compartment has been removed. Accordingly, as shown in FIG. 4, in an embodiment of the present invention, a high barrier intermediate laminate transparent film 64 is optionally interposed between the protective film containing high barrier capacity aluminum foil. 55 and drug compartment 20. The transparent high barrier intermediate film 64 covers and protects the contents of the drug compartment 20, then the peelable protective film 55 is removed from the container, from at least one moisture vapor and free oxygen permeation for a substantial period that Depending on the activity of the contents of the drug compartment, it 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 covering 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. Categories range from high barrier ability (low permeability) to low barrier ability (high permeability). The category in which a polymer is classified can vary according to the penetrating gas. As used herein, the term "high barrier ability" when referring to moisture vapor permeability means a film with a permeability of less than about 1.5 g 125.4 µm / m²/ 24h / 10⁵Pa (g / mil / m²/ 24h / atm.) At 38 ° C, 100% RH As used herein, the term "high barrier capacity" when referring to oxygen permeability means a film with a permeability of less than about 50 cm³/ 25.4 μm / m²/ 24h / 10⁵ Pa (cm³/ thousand / m²/ 24h / atm) at 25 ° C, 100% RH

In an exemplary embodiment, the transparent high-barrier intermediate film 64 comprises a high-barrier, three-layer laminate structure that is significantly resistant to free oxygen and water vapor permeability to protect the contents of the compartment. of the medicine and increase the shelf life of the binary package. In one embodiment, intermediate film 64 includes an outer layer 66 of silica-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 high barrier protective film 55. The outer layer 66 is adhered to an interlayer 68 comprising a polyvinyl alcohol (PVA) (coated with SiOx) deposited with available silica from Mitsubishi Kasei under the trade designation Tech Barrier^TM S. On its inwardly directed surface, the transparent high-barrier intermediate film 64 includes an inner sealing layer 70 comprising a polypropylene-polyethylene copolymer, which can be blended with a styrene-butylene-styrene thermoplastic elastomer, in various relationships. However, a 100% polypropylene-polyethylene copolymer layer is preferable. The individual layers of the intermediate laminating film 64 are adhesively bonded to each other. However, for clarity, 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 seal layer 70 is securely attached to the outer surface of the container front sheet 12 by a suitable permanent thermal or ultrasonic seal, an adhesive pressure seal, or the like. The transparent high barrier intermediate laminate film 64 is dimensioned, horizontally and vertically, to cover the entire surface area of ​​the drug compartment and also extends to cover the peelable and permanent seals formed adjacent to the drug compartment.

As is the case with flexible plastic materials, the materials that comprise the front sheet 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. twenty. Thus, unlike polyvinyl chloride (PVC), and other similar materials, which are truly dark (translucent), the interlayer 64 of the present invention is substantially clear and transparent, allowing the contents of the drug compartment to be inspected. easily, while imparting considerable protection against degradation by moisture and free oxygen.

In particular, the barrier properties of 64 high-barrier transparent intermediate laminate film are substantially higher than those of conventional films, such as low-density polyethylene (LDPE), medium-density polyethylene (MDPE), linear low density (LLDPE), ethylene-vinyl acetate copolymers (EVA), or blends of these polymers, in areas important to package function, eg, moisture and oxygen permeability. The oxygen permeability of the intermediate layer 64 is approximately 10 cm³/ 25.4 μm / m²-24h / -10⁵Pa (10 cm³/ thousand / m²-24h / atm). Conversely, the oxygen permeability of EVA, LDPE, and MDPE copolymers, respectively, are approximately 2500 (EVA 5%), 8300 (LDPE), and 8500 (MDPE) cm.³/ 25.4 μm / m²-24h / 10⁵ Pa (cm³/ thousand / m²-24h / atm). The oxygen permeability of LLDPE is approximately the same or slightly higher than LDPE. Thus, the oxygen permeability of the transparent high barrier interlayer 64 is orders of magnitude less than the oxygen permeability of polymers typically used to construct binary medical packages.

Due to the barrier properties of the intermediate laminating film, the protective film containing 55 aluminum foil can be removed by a pharmacist in order to perform an inspection on the contents of the

ES 2 215 830 T3 package prior to distribution, and the package can then be stored for an additional period of time without the danger of oxygen- or moisture-induced degradation of the drug. Once the protective foil layer is removed, it is desirable that the package have a shelf life of approximately 30 days. After removal of the aluminum foil layer, the exact shelf life of a container that includes a clear, high-barrier laminate film 64 necessarily depends on the moisture sensitivity of the drug contained in the drug compartment. . Drugs with relatively low moisture sensitivity are able to retain efficacy for periods substantially longer than 30 days by virtue of being protected by the clear high barrier laminate film 64. Additionally, drugs with extreme moisture sensitivity, that is, those that would normally begin to lose effectiveness almost immediately after removal of the aluminum foil layer, can be stored for periods of up to two weeks without losing effectiveness due to that the moisture barrier properties of the high barrier ability clear film cover the drug compartment.

Although the intermediate barrier film 64 in the exemplary embodiment has been described as being affixed to the outer surface of the drug compartment, it will be apparent to one of ordinary skill in the art that the intermediate layer may be sized to cover both the drug compartments as well as diluent, if desired. The way of fixing the intermediate layer to the outer surface of the container can also vary without departing from the scope of the invention. Intermediate layer 64 can be permanently attached to the outer surface of the container by a suitable adhesive, as well as by permanent heat or ultrasonic sealing. Alternatively, the intermediate film 64 may be removably provided on the surface of the container by adjusting the temperature and pressure characteristics of a heat seal in order to peel the seal. 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 medicament is described as being in the form of a dry powder. Such dry powders can be, for example, antibiotic or antiemetic compositions, without limiting examples such as: cefazolin, cefuroxime, cefotaxime, cefoxitin, ampicillin, nafcillin, erythromycin, cefriaxone, metclopramide and ticar / clav. However, a liquid medicine 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 as they are distributed to a patient. Furthermore, the medicament may be in the form of a colloid, crystalloid, liquid concentrate, emulsion, or the like. Additionally, the drug compartment does not need to be filled with a drug, per se. Other medical compositions are equally suitable, such as lyophilized blood fractions, blood factor 8, factor 9, prothrombin complex, and the like. Although a single drug and single diluent compartment is described in the package of the present invention, packages having multiple compartments filled with different diluents and / or different drugs may be provided in accordance with the present invention.

Second embodiment

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

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

The alternative high barrier capacity intermediate laminate film is constituted by a multilayer laminate of thermoplastic polymer, generally indicated at 71, with high barrier properties against humidity and oxygen. In the exemplary embodiment of Figure 5, the high barrier multilayer film 71 comprises a sealant layer 72 on its inwardly directed surface, consisting of

100% polypropylene that is approximately 76.2 µm (3.0 mils) thick. An oxygen barrier layer 74 is laminated to the sealant layer 72 by a first tie layer 76 comprising a commercially available low-density polyethylene (LDPE) extrudate in combination with a primer layer, and which is interposed between the layer. oxygen barrier 74 and sealant layer 72. Various flexible polymer films have been determined to be able to provide adequate barriers to oxygen permeability, as will be further described below, but preferably, the oxygen barrier layer 74 of the high barrier multilayer film 71 is constituted from a commercially available ethylene vinyl alcohol (EVOH) having a thickness of about 13.92 µm (0.55 mils).

Ethylene vinyl alcohol is indicated primarily for its barrier properties against the permeability of

ES 2 215 830 T3 oxygen. In particular, their oxygen permeability barrier values ​​are typically in excess of four odors ® of magnitude greater than conventional primary bag films, such as ethylene vinyl acetate (EVA), Surlyn, medium and high density polyethylene (MDPE, HDPE). . However, while offering a considerable barrier to oxygen permeability, ethylene vinyl alcohol alone cannot 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 adhesion layer of low density polyethylene (KDPE) 80. The moisture barrier 78 is a transparent flexible film. comprising an oriented high density polyethylene (or HDPE) polymer available from Tredegar Co. of Richmond, Virginia under the trade designation Monax^TM , HD grade. The resulting composite barrier structure includes a polyester heat seal (PET) release layer 82 (such as Terphane 10.21) on its outward facing surface, and which is laminated, in turn, to the moisture barrier 78. by a third adhesion layer of low-density polyethylene extrudate 84.

The high barrier capacity polymeric multilayer laminate film 71 of the exemplary embodiment described in connection with FIG. 5 is a high oxygen barrier and moisture impermeable flexible film which is suitable for construction of the intermediate layer (64 of Figure 1), which 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. Thus, the composite film of the illustrated embodiment of Figure 5 is particularly suitable for covering the drug compartment of a medical package, such that its contents can be easily inspected at first glance.

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

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

Although 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 cover that is adapted for particular uses. For example, one of the high barrier layers can be omitted by offering a high barrier intermediate film that includes only one moisture barrier layer, or only one oxygen barrier layer. In addition, the high barrier intermediate film may include a moisture barrier layer, as described above in combination with a heat seal release layer that is manufactured from a high temperature melt material that it also has oxygen barrier properties.

Table 1 is a non-limiting list showing the exemplary film 71 of Figure 5 and four additional examples of multilayer films or laminates useful in the manufacture of various embodiments of a clear, high-performance barrier interlayer. according to the invention. In the list, oHDPE refers to a high density polyethylene, such as PET coated with HD grade polyvinylidene chloride Monax 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 ULTRAX 2000.

TABLE 1

Material Laminate layer 71 Thickness, mil x 25.4 pm Layer description

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>Adhesion Layer</td>

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

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

ES 2 215 830 T3

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

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

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

.

<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>Barrier Layer</td>

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

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

.

<td>Chloride coated PET polvinyl</td><td> 0,50</td><td>Thermal Joint Release and Oxygen Barrier</td>

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

<td>OHDPE</td><td> 2</td><td>Barrier Layer</td>

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

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

.

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

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

<td>Aclar ™</td><td> 2</td><td>Barrier Against Moisture</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>

.

<td>Chloride coated PET polvinyl</td><td> 0,50</td><td>Thermal Joint Release and Oxygen Barrier</td>

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

<td>Aclar ™</td><td> 2</td><td>Barrier Against Moisture</td>

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

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

ES 2 215 830 T3

In accordance with the practice of the present invention, each of the multilayer laminating films described above are viewed as forming a clear covering against the high barrier capacity over the drug compartment 20 of the medical package 10. Preferably, the backsheet 14 of each such package is formed of a multilayer laminate structure that includes a film containing aluminum foil with a high moisture barrier capacity, comprising film of 80% / 20% w / w on its inwardly directed surface, as described in connection with the embodiment of Figure 3.

The construction of the container backsheet 14 of a high barrier laminate film containing opaque aluminum foil, 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 peelable aluminum foil-containing film, which covers the drug compartment, is typically removed prior to dispensing by a hospital pharmacy. Since high barrier intermediate films are clear, they do not provide protection against light exposure and care must be taken to prevent the contents of the drug compartment from being unexpectedly exposed to UV or intense visible light during subsequent storage of the drug. container. Accordingly, the package is folded back on itself in the region of one of the peelable seals, such that the aluminum foil-containing film (or backsheet) forms the outwardly facing surface of the folded package and helps protect the Drug compartment contents from exposure to UV or intense visible spectrum light.

Returning to Figure 6, container 10 is shown folded along the line of one of the peelable seals or prior to one of the peelable seals. When so folded, the material of the front and back sheets of the bag is pressed together by the fold, thus imparting additional protection to the seal. The pleat provides additional resistance to hydraulic pressure caused by, for example, unexpected pressure on the diluent compartment of the bag.

In accordance with preferred embodiments of the present invention, means are provided to secure the container to a collapsed condition to protect against further activation and to help protect the contents of the container from radiation exposure by allowing the backsheet containing the aluminum sheet is exposed to ambient light.

Referring now to Figures 1 and 6, the 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 container, and a matching mating notch 27 , configured to receive the tab 28 when the bag is folded along a line in the region of the first peelable seal 24 between the diluent and drug compartments. Once the container is folded, and the locking tab is engaged with a matching notch 27, the contents of the drug compartment are shielded on both sides from incident radiation by the backsheet containing aluminum foil.

Accordingly, it will be understood that the configuration of the bag in a folded condition contributes to providing protection for the contents of the drug compartment from degradation by radiation, while at the same time protecting against unexpected bag activation by increased resistance. of the peelable gasket along which the bag is folded. Additionally, the means for maintaining the bag in a folded condition can be adapted for easy attachment and detachment, thereby allowing the clear inner face of the medical container to be exposed periodically and allowing the contents of the medical container to be periodically accessible for visual inspection of the integrity of the compartment.

Referring to Figure 7, in an exemplary embodiment, additional protection is provided for 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 the formation of an additional peelable seal 25 through the medical container a short distance prior to or above seal 24 that separates the drug compartment from the diluent compartment. . The additional peelable seal 25 is preferably disposed approximately 1/8 to 1/2 inch (3.17 to 12.7 mm) above the peelable seal 24, ie, in the direction of the diluent compartment18. The first peelable seal 24 and the additional peel seal 25 together define an intermediate compartment 29, disposed between the diluent compartment 18 and the drug compartment 20. Intermediate compartment 29 is preferably empty.

When the medical package is constituted with the additional peelable seal 25 and the intermediate compartment 29, a sacrificial moisture vapor permeation path is provided which protects the powdered drugs in the drug compartment 20 from moisture permeation through of the container material from the diluent compartment. Although the drug compartment 20 is covered by one of a variety of high-barrier protective covers, as described above, there is a path for moisture to migrate from the diluent compartment to the drug compartment, through the materials. of the primary package comprising the first peelable seal 24. In the embodiment of the invention described in Figure 7, moisture vapor that can permeate through the primary packaging materials in the region of the additional peelable seal 25, from the diluent compartment is trapped within the compartment. intermediate 29. Since the surface area of ​​intermediate compartment 29 available per

ES 2 215 830 T3 the vapor permeation is much larger than the permeation surface provided by the peelable gasket 24, the moisture vapor in the intermediate compartment will preferably escape into the atmosphere, instead of migrating through the material from the first peelable seal 24 and into the drug compartment.

Thus, it can be seen that the additional peelable seal 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 sheets of an exemplary embodiment of container10 are bonded together by an 80:20 film layer. Although adaptation films are within the scope and contemplation of the invention, in each of the embodiments described above, the inward facing layer of the front sheet 12 comprises an 80:20 film that is positioned in contact with the layer. 80:20 inward facing film of backsheet 14.

The composition of the front and rear sheets 12 and 14 of the container 10, allows the creation of peripheral gaskets and peelable gaskets using heat sealing techniques. The hot bars or dies are used in the differentiation of temperatures, pressures and application times to bring the adaptation portions of the laminated materials used to temperatures near or above their melting points to allow the migration of material through the interface to form a link of the desired strength and characteristics.

For any single layer film, or multilayer laminating film, comprising the front sheet 12 and the aluminum foil laminate comprising the back sheet 14, a method for manufacturing the container 10 in the form of 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 the container 10 is being formed with a single layer front sheet 12, the protective layer containing aluminum foil of high barrier capacity 55 (of Figure 3), and the transparent intermediate layer of high barrier capacity (64 of Figure 4 or 71 of Figure 5), comprising the high barrier capacity covers for the medication compartment 20 are cut to size, placed over the area that will be the medication compartment, and sequentially attached to the front sheet of the container 12. According to the invention, the transparent interlayer with high barrier capacity is laminated, first, on the surface of the front sheet, and the protective layer containing aluminum foil 55 placed on top of this.

Specifically, the transparent high barrier interlayer 64 or 71 is placed over the drug compartment and held in place by a pair of rods while being laminated onto the surface of the front sheet 12. The portion of the layer in Contact with the rods is therefore not accessible to the heat seal head, resulting in a small portion of the film not sealing on the face of the front sheet. The residue from the use of rods to fix the high barrier transparent interlayer in place in an unsealed area that has the impression of rod contact footprints. In the embodiment illustrated in Figure 1, the contact surface of the rod is generally circular and results in two regions with circular seals 41 that remain visible due to the reverse printing caused by the pressure applied during the sealing process.

After lamination of the intermediate layer 64 or 71, the aluminum foil layer 55 is applied on its surface, using a heat seal die configured as described above.

After the fixing of the aluminum foil layer 55 and the high capacity barrier transparent layer 64 or 71, the front and rear sheets are coincident and the outlet hole 30 is inserted in the desired final position between the front sheets to and rear. The sealing hole 30 of the illustrated embodiment is injection molded and has a composition of 40% FINA Z9450 polyethylene-polypropylene copolymer and 60% Shell Kraton styrene ethylene-butylene styrene thermoplastic elastomer.^TM G1652. Following the insertion of the exit port, a hot die is used to create a seal between the tabs of the exit port 34 and the lower edge of the front and back sheets adjacent to the flange.

The peelable seals 24 and 26 (and optionally the additional peelable seal 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 rod rear that forces the elements of the container between them to form the seal, in this way. In an exemplary embodiment, the front bar that is contacted with the combined high-barrier protective film 55, intermediate films 64 or 71, and front sheet 12, is maintained at a temperature in the range of about 118 °. C (245 ° C) to about 129 ° C (265 ° F). The back bar that contacts the backsheet 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 can optionally include a fine rubber coating to ensure uniform application of pre15

ES 2 215 830 T3 sion. The double bars are pressed into contact with the front and rear sheets with a pressure in the range of about 1.59 MPa (230 psi) to about 2.35 MPa (340 psi) and held at this temperature and pressure for a period of time. time between about 1.5 to about 2.5 seconds. The peelable gaskets 24 and 26 as shown in Figure 2, can be manufactured individually with a single double bar assembly, or simultaneously with a double double bar assembly in pairs. The additional peelable gasket 25 can be easily fitted by a double, triple bar assembly.

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

In such a case, the material thicknesses experienced by a heat seal head will be different (thicker) in the region defined by the drug compartment 20 than the region defined by the material comprising the peripheral seal. permanent 16. The difference in material thickness between these two regions requires that the head of the heat seal exert pressure against a compliant bearing, such as rubber, in order to ensure uniform seal pressure across the interface. The formation of the additional peelable gasket 25 within the periphery of the drug compartment makes obvious the requirement for compliant support for the gasket head. The thickness of the material experienced by the heat sealant will therefore be constant, ensuring a uniform, peelable, leak resistant gasket.

After formation of the peelable gasket, the front and back sheets are joined together by a peripheral permanent heat seal 16 that extends across the top, bottom, and along a continuous side of the container, such that it overlaps a portion of the peelable seal 25 that extends into the transverse seals 24 and 26, thereby ensuring leak-proof seals between diluent, drug and lower compartments. As best seen in Figure 8, on the opposite side of the container, the permanent seal 16 is spaced from the oversized edge of the front and back sheets and is provided discontinuously along the desired edge of the final bag, that is, the gasket is formed along the upper vertical portion 110a, a lower vertical portion 1 10b, and a central vertical portion 110c, defining therefore the intervention spaces between the three vertical portions.

Sacrificial holes 102 and 104 are inserted between the front and rear sheets at positions along the edge of their oversized portion adjacent the interstices in the permanent heat seal. In a similar way to the outlet port 30, the front and rear sheets are sealed to the sacrificial ports 102 and 104 along the tapered flanges 106 and 108, respectively, provided for this purpose. Sacrificial ports 102 and 104 are also injection molded and since they will be removed and discarded at the last stage in the process, they are manufactured from any inexpensive thermoplastic material available. In particular, the sacrificial holes may be formed of 80:20 film "regrind" material, plain polypropylene, or the like.

Sacrificial ports 102 and 104 described in more detail in Figures 8a and 8b, with Figure 8a depicting diluent fill port 102 and powder fill port 104, respectively, in side view and with Figure 8b depicting the ports in 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 described as suspended above powder fill port 104.

Sacrificial ports 102 and 104 are a feature of the present invention and, as will be further described below, provide means for aseptically filling a single-compartment 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 thus the medical package to be supported and manipulated by automated robotic machinery.

As depicted in Figure 8a, sacrificial holes 102 and 104 each include vertically spaced flanges, a lower flange 103, and an upper flange 105. Each of the flanges is of a generally rectangular configuration (best seen in Figure 8b) with their long edges extending approximately 3mm, to 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 made approximately 1.5 mm thick, and are positioned in spaced, vertical relationship with each other and with the intersection of each rotating bore drum with its respective tapered flange (106 and 108). The lowermost flange103, in each hole, is positioned approximately 4 to 5 mm above

ES 2 215 830 T3 of the intersection of the rotating drum of the hole and the tapered flange of the hole, while the uppermost flange 105 is positioned so that its lower surface is approximately 4 mm above the upper surface of the lower flange 103, defining therefore a space of approximately 4 mm between the flanges and between the lower flange and the edge of the container.

In accordance with the practice of the principles of the invention, the generally tubular drum 107 of each sacrificial hole 102 and 104 has an outer diameter of approximately 12 mm and a length, or height depending on whether it is a hole that is filled with diluent 102 or a hole that fills with dust 104. In the case of the diluent port 102, in an exemplary embodiment, the rotating drum has a height of approximately 13mm, and in the case of the powder fill port 104, the rotating drum has a height of approximately 18mm. 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 the conventional plastic or glass drug vial. This configuration allows rotating sacrificial port filling drums to be accessed by the 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 10.4, thereby giving a cylindrical side wall thickness of approximately 0.8 mm. The top edge of each rotating drum has a chamfer provided at approximately a 45 ° angle towards the inside of the rotating drum.

A generally cylindrical cap (or plug) 109 is provided in each of the holes and is constructed with an outer diameter (10.5 mm) that is slightly larger than the inner diameter of each rotating hole filling drum (10, 4mm), so that when 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. The gasket is required to prevent particles from entering the container before filling and to prevent powdered medications or liquid diluents from escaping from the container that has been aseptically filled. As can be seen in Figure 8a, the lower edge 109a of the cap 109 is tapered at approximately a 45 angle, to engage the 45 ° chamfer of each rotary bore drum and aid in insertion.

In addition to the tabs 103 and 105 over the holes, a vertically spaced pair of tabs are also provided on the cap. In the exemplary embodiment of Figure 8a, a generally circumferential top flange 110 defines the top of the hood and has a thickness of approximately 1.0mm and a diameter of approximately 12.0mm to extend beyond the body of the cap. the cap by approximately 0.75 mm. The upper hanging flange thus allows a "lift" mechanism to engage the lower part of the upper flange 110 and provides means for vertically lifting the cap of its rotating drum from the respective hole. A lower flange 111 is provided in order to control the depth of insertion of the cap when the cap is inserted into the rotating bore drum or is seated again after a filling operation, for example. The lower flange 111 may be completely circumferential, or it may alternatively be made 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 vertically spaced from each other, along the body of the cap, to define a gap of approximately 3mm between them.

Accordingly, it will be appreciated that following insert 109 adds approximately 5 millimeters to the overall height of its respective sacrificial orifice. It will be noted that the diluent orifice 102 and the cap combination has a height of 18 millimeters, which is the same as the height of the medication port 104 without its cap being inserted. This particular feature allows the cap to be removed from the drug sacrificial port 104 and the container to fit under a conventional, rotary powder filling mechanism, while allowing the diluent compartment port to remain sealed. By holding 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 release a wheel of powder while being driven in line of a efficient way.

Turning now to Figure 8, permanent seals 110a, 110b, and 110c are then extended 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 from the filled container after the manufacturing process has been completed without danger of substantial weakening of the gasket. peripheral sealing of the container along the cut edge.

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

The seals, and the extensions of the seals, formed in the oversized portion of the container, define voids or channels 112a and 112b, in the container material intervening between the seals. Channel 112a allows communication between sacrificial orifice 102 and the interior of diluent compartment 18, while channel 1 12b allows communication between sacrificial orifice 104 and the medicament compartment17

ES 2 215 830 T3 opening 20. As will be further described below, channels 112a and 112b are closed by a rear permanent heat seal that joins the various spaced vertical sealing portions (110a-f) over the oversized portion of the container.

Packaging manufacturing apparatus

In accordance with the practice of the principles of the present invention, a method and apparatus for manufacturing the container 10 of Figure 8 will now be described in connection with the apparatus, both the apparatus and the method are adapted to be suitable for manufacture. of front and back foil medical packages comprising either single layer laminate films or multilayer laminate films. Additionally, it will be apparent from the following description that the number, shape, configuration and location of the various seals of the container 10 of Figure 8, can be easily changed or effectively 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 the various sealing gasket forming stations and the layout and configuration of the film tape supply rolls primarily from the container.

The bulk material for the front and rear 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 bulk film tape 122 and 124, which are mounted to the tape supply roll stations at the input end of the container making machine 120. Tape material from, for example, the front sheet supply roll 122 is threaded through an oscillating station 123, which functions to hold the tape material at adequate tension as the tape is drawn through the remaining stations 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, that is, including a single-layer front sheet 12, a transparent, high-barrier intermediate film (64 of Figure 4 or 71 of Figure 5), and a protective layer containing high barrier capacity aluminum foil (55 of Figure 3), the high barrier capacity covers for the drug compartment 20 are first cut for sizing, they are then placed on the area that will be the drug compartment, and then, they are sequentially attached to the front sheet of the container at the barrier film application stations 126 and 127 respectively. According to the invention, the transparent, high-barrier intermediate layer is first laminated onto the face sheet surface at the application station 126 and the protective layer containing the aluminum foil placed at the application station. application 127.

Similarly, the belt material that will form the backsheet of the container is threaded from its respective material belt supply roll 124 through a corresponding oscillating station 128, and is conveyed by vacuum feed wheels through a corresponding belt cleaning station 129.

As the continuous film of front and back sheet tape material leaves their respective make-up steps, the continuous films are fed into registration with each other and oriented so that the 80:20 surfaces of each continuous film meet. to the 80:20 surface of the other. After the tapes of the continuous film have been mated, the tape material is continuously guided and longitudinally moved through the gasket core 130 of the manufacturing apparatus 120. Sacrificial drug and diluent holes are located along the sandwich tape and positioned between the front and back foil film tapes, and several gaskets are sequentially formed on the tape sandwich material to join the tape together. tapes and substantially manufacturing the container within an intermediate stage suitable for aseptic filling.

In accordance with the practice of the principles of the invention, the core of the gasket of the manufacturing machine 130 comprises a multiplicity of gasket presses and orifice insertion stations, arranged in series along the travel path of the container film strip sandwich. The first such station is an adjustment hole loading station 131, in which an adjustment hole or outlet hole (30 of FIG. 8) is inserted into its proper position between the front and rear blades. A heat press, which includes a configured die, is compressed onto the tape material to create a seal between the exit port flange (34 of Figure 8) and the eventual bottom edge of the adjacent front and rear sheets. to the flange, at the adjusting hole gasket station 132. The fitting or outlet port 30 is composed 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 elastomer. Due to the similarities between the composition of the material of the adjustment hole 30 and the material of the surfaces that forms the inner seal of the front and rear sheet, it can be seen that the front and rear sheets can be sealed to the flange of the hole. adjustment 34 utilizing a substantially similar heat seal regimen, as used for the formation of permanent peripheral seals, described in more detail below.

ES 2 215 830 T3

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

Following the insertion of sacrificial holes 102 and 104, the front and back sheet film material is joined by a permanent peripheral thermal seal (16 of Figure 8) that extends through what will be the top, bottom, and a continuous side of the finished container. Along the opposite side of the container, the permanent heat seal 16 is provided parallel to, but spaced apart, the edge of the film strip sandwich band, and is formed in a discontinuous fashion along the desired edge of the container. finished (110a and 110b and 110c of Figure 8).

Following the formation of the perimeter seal at the perimeter seal station 136, the container material is conducted to an optional first drug sacrificial port seal station, 138. The front and back sheet material is sealed to the tapered flange 108 of the drug sacrificial orifice 104 by compression of the front and rear sheet material to the tapered orifice flange by a pair of concave conformable heated sealing dies. As was the case with the adjustment hole die, the heat seal die of the drug seal station 138 is adaptively configured such that when the two halves of the seal die are compressed together, they form a bag. generally elliptical having a configuration that is the mirror image of the tapered conically convex sealing surface of the drug orifice.

Next, the tape material is conducted to a second sacrificial orifice gasket station of the diluent compartment, optional 140, where the front and back sheet material of the container is compressed and heat sealed to the tapered flange. conically 106 from the sacrificial orifice of the drug compartment 102.

It will be appreciated that the order of sealing the sacrificial ports to the container is purely arbitrary and that the drug port sealing station 138 can be just easily followed by the diluent port seal station 140 as vice versa. Additionally, the sealing stations to seal the sacrificial holes to the container may precede the perimeter gasket station 136. Additionally, a further optional gasket station, peelable gasket forming station 142 which is described in FIG. 9, following the sacrificial hole insertion station 134 and preceding the perimeter gasket station 136, is optionally provided to form the peelable seals that cut and subdivide the container 10 into a plurality of compartments. Alternatively, the optional peelable gasket station 142 may be configured to proceed to the sacrificial hole insertion station 134, simply repositioning the peelable gasket station along the film tape path. As will also be apparent, that a multiplicity of peelable gasket stations can be provided, if the package is to be manufactured with multiple compartments.

It should be apparent to one skilled in the art that the sequential, but independent plurality of gasket stations may each be configured to operate automatically as the film strip is driven to their respective stations. Alternatively, the seal stations may be present on the container manufacturing machine, but rendered inactive, such that their particular seals are not formed over a specific production cycle.

Following the sacrificial orifice seals, the package tape material is conducted to an equalization zone sealing station 144, which applies a permanent heat seal to the package material that contacts and overlaps the discontinuous portion of the seal. of the permanent perimeter and extends to the edge of the film material of the container. The equalizing zone gasket regions (1 10d, 110e and 110f of Figure 8) are provided in the film region between the peripheral seal of the container and the edge of the tape to define a region of relatively low flexibility of material having a width sufficient to allow the retention groove (27 of FIG. 1) and the retaining tab (28 of FIG. 1) is stripped of the relatively rigid material of the seals of the equalization zone. Additionally, the equalizing zone gaskets function to add width to the peripheral gaskets (110a, 110b, and 110c), so that the perimeter gaskets in this region are formed with a suitable width to allow this region of the container (including the sacrificial holes) is cut from the container after the manufacturing and filling processes have been completed, without substantially weakening the peripheral seal of the container along the cut edge and without compromising the integrity of the filled container.

As can be seen from Figure 8, the sealing gaskets of the equalization zone 110d, 110e and 110f define voids or channels 112a and 112b in the material of the container that intervenes between the seals. The channel 112a therefore allows communication between the sacrificial orifice 102 and the interior of the diluent compartment 18,

ES 2 215 830 T3 while channel 112b allows communication between sacrificial orifice 104 and drug compartment 20, thus allowing both compartments to be accessed through their respective sacrificial orifices. As will be further described below, channels 112a and 112b are closed by a rear permanent heat seal that joins the equalization zone seal portions (110a-f) in these regions of the container.

After the heat seal process steps, the container is guided through a hanger drill station 146, which forms a hanger recess from the top center of the container. Following stations 147 and 148 the packages are separated by cutting the tape of material, first, at the end of the hole where the package is discharged from the manufacturing machine 120 and construction of the package is substantially completed.

As will be apparent to one of ordinary skill in the art, the number and configuration of the compartments that comprise the package is determined solely by the number and location of the various heat 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 are positioned along their respective material belt edges. It will be understood that the modular manufacturing process in accordance with the present invention can be adapted to the manufacture of medical packages having single primary compartment packages, or multi-compartment packages having any number of compartments, simply by providing the seals. additional peelers and additional sacrificial holes with which to fill the compartments. For each configuration of compartments and sacrificial orifices, the equalizing zone gasket press at the equalizing zone gasket station 144 can be appropriately reconfigured by removing one press face and replacing another, which is configured to provide one, three or the like channels or openings for connecting a plurality of sacrificial ports to a plurality of compartments.

Similarly, it will be apparent to a skilled artisan that the composition of the front and rear sheets of the package can be changed by suitable replacement of the front and rear film supply tape rolls with other suitable materials. In particular, both the front and back foil supply rolls can be a single layer 80:20 film such 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 sheet barrier application station can both be rendered inoperative, as well as the peelable gasket forming station, thereby configuring the sealing machine. manufacture of the container to provide a single compartment container which is completely transparent, and which may comprise a multiplicity of outlet ports, such as separate middle holes and adjustment holes.

Accordingly, the container manufacturing machine according to the present invention is observed to be suitable for the manufacture of a wide variety of medical containers, having a varied range of sizes, and a variety of seal configurations and locations. hole. All packages thus manufactured will be observed 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.

Formation of the gasket

The peelable gaskets formed during the manufacturing process described above are straight line gaskets having a thin, rectangular configuration. Although they appear similar to conventional straight line gaskets, the peelable gaskets of this embodiment are improved in that they show a more predictable rupture characteristic across production batches, i.e., they show a uniform strength characteristic. to handling pressure.

Without being bound by theory, it is believed that the peel ability of the gaskets is achieved by limiting the time, pressure and temperature necessary to melt the interface between the inner layers of the front and back sheets that have a melting temperature lower than the of the intermediate and outer layers of the backsheet. The depth of structural alteration in the inner layers in the fusion zone is limited, thus imparting peelable character to the gasket, while providing sufficient strength to prevent fracture in normal container handling.

Preferably, the activation force for the package of the present invention is closely controlled to provide package integrity under extreme handling conditions, which is still easy for all users to activate. This stress or activation force is characterized by a burst pressure that is preferably about 0.028 ± 0.007 MPa (4 ± 1 pounds per square inch).

In order to achieve such a uniformity in the burst pressure of a generally rectangular gasket, it has been determined that the critical parameter that must be controlled is temperature. Uniform burst pressure response can be achieved by controlling the gasket temperature to within ± 1 ° C (2 ° F). Commercially available production heat seal apparatus are not capable of controlling variability in heat seal temperature at this desired range. However, the heat sealing time is capable of being controlled very precisely. Therefore, time is chosen as

ES 2 215 830 T3 the control parameter y is adjusted to compensate for the variation in the temperature of the thermal seal. The gasket head time and pressure are monitored to ensure they are within acceptable ranges as described above, and the heat seal time is adjusted accordingly. Although the contact pressure is preferably in the range of about 1.59 MPa (230 psi) to about 2.35 MPa (340 psi), it will be recognized by one of skill in the art that the figure below is in the range 1.59 MPa o (approximately 230 psi) is intended for convenience in setting the parameters of a production heat seal machine. As long as the pressure exerted by the heat seal bars on the container material is sufficient to force the sealing layers of the material into contact over the desired gasket surface area, the peelable gasket will form given a temperature and adequate time. Indeed, it has been experimentally determined that variations in temperature and time of the thermal seal beyond those contemplated by the present invention result in seals that not only fail to display the desired uniform strength characteristic, but also they also fail to rupture completely along the length of the gasket. Incomplete rupture of the seal often results in residual diluent, for example, remaining entrapped at 90 ° vertices, where the peelable seals contact the permanent peripheral seals of the container. Accordingly, the diluent / drug mixing ratio cannot be designated, and the drug delivery may be at a higher concentration than desired.

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

Higher temperatures and associated pressures and times are used to provide the permanent, peripheral thermal seals and the outlet port seal, which produce structural altering effects in a greater proportion, or depth of layers. sealing. Such gaskets can be formed by heat sealing at a temperature of 143 ° C (290 ° F), and a pressure of up to 1.38 MPa (200 psi) for approximately two seconds. Those skilled in the art will recognize that various techniques for forming both permanent and peelable seals can be used in the construction of the container of the present invention. In particular, it will be apparent that controlling the gasket temperature to a higher degree (within about ± 1 ° C or 2 ° F) will allow the formation of peelable gaskets having a uniform burst pressure. Additionally, time is chosen as the control parameter for gasket formation since it is capable of being precisely controlled. Precision control of temperature, pressure, or both would give the same result.

Furthermore, those skilled in the art will recognize that the sequence for the construction of the container 10 of the present invention is arbitrary and has been defined to suit a particular production process and a particular embodiment of the final container. Various alterations in the order of the formation steps, as well as the placement 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 package is taken to the manufacturing step exemplified in Figure 8, the package is now in a condition for aseptic filling with a drug, a diluent, or both or any desired combination of the above. In an exemplary filling process, the particular embodiment of the container to be filled, in accordance with the invention, is one that incorporates either a single-layer or multi-layer laminating front sheet film or a film of aluminum foil laminate backsheet and has been formed to comprise a diluent compartment 18 and a drug compartment 20, both of which have unsealed peripheral edges for filling through the sacrificial holes provided respectively 102 and 104. This embodiment of the container is in the manufacturing stage as described in figure 8. The manufacture of the primary container, which includes the provision of an exit port and sacrificial ports, is achieved by the method and apparatus previously described.

In order for an aseptic filling process to be 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 complex and rather expensive equipment and processes required for material sterilization. A particular unwanted feature of the sterilization procedure is that the package must be transported to the sterilization facility for processing, whereby 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 in order to prevent contamination of the aseptic zone by the container. Once introduced into the aseptic zone, the container must 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 package, a plurality of empty packages are loaded into a handling package which is then sealed to protect the bags contained within from environmental contamination.

Turning now to Figure 10, a handling container, generally indicated 150, and referred to herein as a "carrier," functions as a movable sterile containment isolator for sterilization, transport, and introduction into

ES 2 215 830 T3 the empty aseptic area containers in a systematic way. Carrier 150 comprises three components; a generally rectangular container tray 152, a sealable film lid 154, and a rail cartridge 162 to support a multiplicity of packages within the tray and which will be described in more detail below in connection with Figures 11a and 11b.

The generally rectangular container tray 152 is comprised of a thermoformed polystyrene material chosen to be capable of withstanding multiple sterilization cycles without significant degradation. Tray 152 is generally configured in the shape of a basin with its upper peripheral edge folded outward to form a flat, horizontally oriented peripheral lid 156 that extends beyond the sides of tray 152 for a distance between approximately 6.3 mm. (1/4 inch) to approximately 25.4 mm (1 inch). Preferably, the lid 156 extends approximately 19mm (3/4 inches) beyond the sides of the tray, but any extension that provides rigidity to the tray 152 and a sufficient surface to support a gasket 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 down the sides of the tray and thus form two opposing recesses into which the ends of the rail cartridge 163 can be inserted. The rail cartridge 162 rests on the bottom surfaces of the bags 158 and 160 and is thus suspended above the bottom of the tray 152 at a height sufficient to allow the packages disposed on the rail cartridge to hang freely within the interior volume of the rail. the tray. Accordingly, the bags 158 and 160, in combination with the rail cartridge 162 function to maintain a multiplicity of packages in a specific orientation during transport, storage, and UV sterilization.

Once the lane cartridge 162 has been loaded with packages and is inserted into the bags 158 and 160, the tray 152 is sealed from the environment by heat sealing the plastic film lid 154 to the tray flange. 156 in a different orientation. For illustrative purposes in Figure 10, the film cap 154 ​​is described half through the sealing process, with a portion of the cap raised upward to show the rail cartridge 162 nested within the tray 152. The film cap 154 it is positioned over flange 156 so that there is no "overlap" of film cover material on the edge of the tray flange around the perimeter of the tray. In an exemplary embodiment, the plastic film cap 154 ​​is constituted by having dimensions that allow the film cap to be placed on the tray flange, such that the edge of the film cap is inserted from the edge. of the tray flange around the entire periphery of the flange. Additionally, the film cap heat seal is applied to extend beyond the edge of the film cap 154, to ensure that no part of the unsealed film cap edge would create a loose edge "tab". The orientation of the film cap, placement and being able to avoid loose edges is particularly important for the surface ultraviolet (UV) decontamination process performed on the carrier 150 when the carrier is introduced into the aseptic zone. Cracks caused by the edges and / or tabs of the loose film cover can cause a local shadowing, when exposed to U radiation, the shading effect of which can cause the UV decontamination process to fail.

Once the film cap 154 ​​has been heat sealed to the tray flange 156, the carrier 150 defines a hermetically sealed environment that functions to isolate its contents from external contamination. Carrier 150 is subsequently placed in a polybag envelope (not shown) that acts as a "dust cover", and identified with an adhesive label that is placed over the overlap.

Turning now to Figures 11a and 11b, the support rail cartridge 162 is described in its component form, ready for assembly in Figure 11a and in a fully assembled condition in Figure 11b. Carrier rail cartridge 162 suitably comprises a plurality of injection molded polystyrene T-beams 163a, b, c, d, e, and f arranged at spaced intervals to form longitudinally extending notches 164a, b, c, and d between them. . The polystyrene T-bars 163a-f are oriented with the legs of the T-face facing upward (from the perspective of Figures 1 1a and 1 1b) and include snap or snap pins 165, adapted to join with the corresponding receptacles 166 on one or more spacer plates 167. Spacer plates 167, like T rails 163a-f, are made 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 carrier rail cartridge 162 are provided to separate and maintain the rails at predetermined distances between T163a-f. The spacer plates may include recesses 168 arranged to provide hand grips so that the end carrier rail cartridge assembly can be easily grasped, lifted, and moved. Alternatively, a thin, flexible plastic crank may be attached to the extended spacer plates 167, or certain other well known means may be provided whereby the carrier rail cartridge can be grasped and manipulated.

Once the carrier rail cartridge has been assembled, the manufactured packages can be loaded onto the cartridge in accordance with the invention, in a manner described in Figures 12a and 12b. In Figure 12a, which is a plan view of finished packages of a loaded carrier rail cartridge 10, such as those described in Figure 8, are loaded onto the carrier rail cartridge 162 by inserting their sacrificial holes (102, 104 ) in the notches 164a-d formed between the T-rails of the cartridge 163a-f, in the manner described in Figure 12b. The flange edges of the T-rails 163a-f are spaced a sufficient distance (approximately 13.0 mm), so that the rotating central filling drum 107 of each sacrificial hole is able to fit between them, and they are fixed to engage in the sacrificial holes between the hole circumferential flanges (103 and 105 of

ES 2 215 830 T3 figure 8), so that each container 10 is grasped by the flanges of the T-rail below its flange of the uppermost circumferential sacrificial hole 105.

In the exemplary embodiment of the carrier rail cartridge described in Figures 12a and 12b, four notches 164a, b, c and d are provided to receive the packages, with the packages loaded onto the rail cartridge 162 in alternate left and right orientations. . The sacrificial holes 102 and 104 of each container are inserted into two of the notches 164a-f. As described in figure 12b, a first container 10 'is loaded in the second and fourth notches (164b and 164d) and is oriented in a first horizontal direction, such that its hanging end is oriented to the right, (from the perspective of Figure 12b), and this adjustment hole is oriented to the left. The second container 10 (the front container in the perspective view of FIG. 12b) is loaded onto the rail cartridge 162 with its sacrificial ports 102 and 104 inserted in the first and third notches of the cartridges 164a and 164c. The second container 10 is loaded in a second horizontal direction 10 with its adjustment 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 on the right side when viewed from the perspective of Figure 12b. Additional packages are loaded onto the carrier rail cartridge 162 in the same way, with the horizontal orientation of the package alternating left and right; the sacrificial holes of the right-facing containers loaded into the first and third notches, as described above, until the carrier rail cartridge 162 is completely filled.

Turning now to Figure 12a, it will be understood that the particular design of the tabs of the sacrificial ports 102 and 104, in cooperation with the carrier rail cartridge 162, functions to maximize the packaging density of the packages within the container tray 152. As can be seen in Figure 12a, the tabs of the sacrificial hole project only along the longitudinal direction of each container, and not along its width or thickness dimension. Consequently, as the carrier rail cartridge fills, the thickness of any particular container is defined by the width of the carrier rail cartridge, only the rotating drums for filling the sacrificial holes of the carrier contact each other. alternate containers. Alternating the horizontal orientation of the consecutive packages, as well as alternating their notch offset position, also contributes to the improvement of the packaging density of the packages in a fully loaded rail cartridge. As can be seen from Figure 12a, by providing a second set of notches, the packaging density of the container is allowed to be substantially double, unlike a carrier rail cartridge system with only a single pair of notches.

It will be apparent to one skilled in the art that the packages are loaded onto the carrier rail cartridge and are held within in a systematically aligned orientation, such that the alternate package is 180 ° opposite the previous package as well as being laterally offset from the previous package. prepackaged through the notch space of the cartridge. It will be understood that this alternate container orientation maximizes the packing density of the containers along the length of the cartridge as well as defining the specific orientations and locations of a multiplicity of containers with respect to the cartridge rails, to facilitate the adaptation of the set of cartridges to an automatic loading and unloading system. The carrier rail cartridge and container loading sequence allows the cartridge to be temporarily "stored" or mounted to capture and position robotic machinery. Additionally, recesses (or thumb holes) 168 in the spacing plates 167, allow an operator to easily insert and remove a fully loaded cartridge from the carrier tray without improperly tilting the cartridge, thereby minimizing the possibility of containers falling off the lane.

After loading, the carrier rail cartridge is positioned within tray 152 with the ends of the T-rails 163a-f nested in bags 158 and 160 formed at the ends of the tray. Bags 158 and 160 support the carrier rail cartridge 162 within the interior volume of the tray and provide additional lateral support that prevents the cartridge from skewing during shipping, sterilization, and storage.

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

Container filling process

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

Primary bag filling will take advantage of manufacturing technology created in connection with integrated circuit manufacturing that is increasingly common in the medical industry. This technology generally involves a move away from filling conventional containers in class 100 aseptic environments, to filling containers within an "isolating" 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, in essence, in a "mini environment" that encloses the immediate machinery and the container filling operation within a controlling space. The worker is separated from this space and adapts to the materials inside through holes for gloves and / or “semi23

ES 2 215 830 T3 garments ”. By separating the worker from the environment, it is possible to create and maintain a small sterile environment, since the worker is typically the main source of biological contaminants.

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

Turning now to Figures 13 and 14, and having particular reference to Figure 13, before the carriers are introduced into the fill line, the polybag overlap is removed from each loaded carrier under unidirectional HEPA filtered air with the in order to maintain a low level of particulate matter and bio-contaminants on the outer surface of the carriers. After removal of the polybag overlap, each carrier is individually tested for tight integrity by pressure drop, again under unidirectional HEPA filtered air.

Turning now to Figure 14, in combination with Figure 13, assuming that each integrity of the carrier has been maintained throughout transport and E-beam sterilization, the carrier is introduced into the fill line, generally indicated with 170, passing through a UV decontamination tunnel 172, within which the exterior of the carrier is surface decontaminated by UV radiation before the packages are removed from the carrier for filling. The carrier is inserted into the inlet end of the UV tunnel 172, where UV-emitting lights surround the carrier and radiate the entire exterior surface to control potential contaminants that are introduced into subsequent fill line insulators.

After the UV cycle is complete, the carrier is transferred, through a chamber transfer port into a carrier inlet chamber (not shown) in which the carrier film cap and the cartridge of the carrier are opened. lane, including containers, is removed from the carrier. Containers are removed from the cartridge rails and placed on the tracks from which they are driven on a pick-and-place swing arm 177 for transfer into a first fill isolator 174, which in the exemplary embodiment of the invention is a controlled environment for filling containers, for example with powdered medicines. Although the foregoing transfers may be achieved through the use of automatic equipment, the transfer is typically performed manually, reaching into the wearer's entry station through "glove holes" or alternatively through the arms of a "semi- Garment ”and handling the holder, cap and cartridge. At this time, the empty rail cartridge and carrier are transferred back into the UV chamber and the transfer door is closed prior to removal of the cartridge and carrier from the UV chamber 172.

Pick-and-place arm 177 rotates a container to a position for loading on a continuous conveyor belt mechanism, by means of which the containers are fed into the powder fill isolator.

174 and subsequently led through the operational stages of the powder filling process. A portion of the continuous conveyor belt mechanism 176 is depicted in Figure 15a and generally comprises a flat web of 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 a stepped motor, which causes the conveyor belt 176 to be driven, in predetermined spaced stages through the isolator. The conveyor belt 176 includes a series of spaced notches 175 that are cut into the belt material in a direction orthogonal to the direction of travel of the belt. Each of the notches 175 has a width of approximately 12.4 mm, to accommodate the rotary filling drum of one of the sacrificial holes in the container. Therefore, the notches

175 they are configured wide enough to receive the rotating filling drum, but are also narrow enough to engage the lower surface of the lowermost flange of the sacrificial holes (103 of Figure 8a).

A hole 173 is arranged in the middle of a pair of notches, and is provided all the way through the material of the conveyor belt 176. Each hole 173 has a diameter of approximately 1 1.0 mm and functions to provide a convenient receptacle. to receive a sacrificial port cap (109 of FIG. 8a), when a cap has been removed from a sacrificial port for filling. Although the hole 173 is described in the exemplary embodiment of Figure 15a, positioned equidistant between two notches 175, it will be apparent that the placement of the hole (or cap receptacle) 173 can be provided anywhere in proximity to the notches. 175. If, for example, robotic pickup and placement equipment 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 notches 175 so that the position of the receptacle cap 173 may be programmed into the robotic equipment.

Turning now to Figure 14, the packages can be removed from the rail cartridge and loaded onto the web.

ES 2 215 830 T3 conveyor 176 manually; an operator who reaches the isolator by means of a semi-garment or flexible arm covers, accesses the packaging holes, or alternatively, the containers can be loaded onto the conveyor belt 176 by an oscillating arm, automatic pick-up and placement 177 which grabs each container and rotates it through approximately 90 ° to join the tabs of the sacrificial orifice with the transport band recesses.

Initially, the conveyor belt 176 leads each container to a tare weight scale 178 (shown in Figure 14) in which the tare weight of each container is determined in order to provide a reference empty weight against the that a correlation of subsequent control weights is made. The empty container can be removed from the conveyor belt 176 and placed on the tare weight scale either by hand or by means of an automated robotic pick-and-place arm 179. The container is then re-inserted at conveyor belt and is led to an aseptic rotary powder filling device in line 180. In powder filling device 180, a robotic arm 181 swings through an arc to engage the cap over the sacrificial port of the drug compartment (104 of FIG. 8). The cap is removed by clamping 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 FIG. 15a) located between the sacrificial port notches on the conveyor belt. The cap of the sacrificial port of the drug compartment is now in a known location relative to the sacrificial port of the drug compartment, so that robotic machinery can now easily retrieve the cap for reinsertion into the sacrificial port of the drug compartment as will be described. additionally below. Following removal of the cap, the drug compartment is opened (unblocked) with a jet of 0.2 micron filtered air or nitrogen, introduced through the rotating drum for filling the sacrificial orifice of the drug compartment.

Turning now to Figure 15b, the transport band then leads 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 into the medicine compartment through the open hole. Dosing wheel 182 is oriented in a direction orthogonal to the direction of travel of conveyor belt 176 and containers 10 hung therefrom. Therefore, the reason for the holes in the drug compartment to be larger than the holes in the diluent compartment is now apparent. In order for any powder charge contained in the dosing wheel to be introduced into the medication compartment without undue spillage, the orifice of the medication compartment is sized to place its open throat in proximity to the dosing wheel at a distance of approximately 1.0 millimeters. In order for the diluent compartment orifice, including the cap still attached, to release the bottom of the ossification wheel after ossification is complete and as the container is driven to the next station, the full height of the combination of the cap and diluent compartment hole must not be greater than the height of the medicine compartment hole with the cap removed, i.e. no greater than a gap between the conveyor belt 176 and the metering wheel 182.

An alternative configuration can be devised with respect to the orientation of the containers and the dosing wheel. For example, instead of moving in line, along their long axis, the containers could be inserted into the face of the dosing wheel, so that only the sacrificial orifice of the drug compartment passes under the bottom of the arch of the dispenser. dosing wheel. This particular orientation would allow the diluent orifice to avoid the narrow space between the conveyor belt and the bottom of the dosing wheel arch and therefore avoids the need to provide sacrificial orifices of separate heights.

Referring now to Figures 13 and 14, after filling with powder, 0.2 micron filtered air or nitrogen gas is introduced into the headspace of the drug compartment and the transport band 176 conducts the compartment to a station. heat seal 184. Although both nitrogen gas and 0.2 micron filtered air are within the contemplation of the present invention, it will be understood that the choice between these two gases, or other filtered sterilized gases (inert or otherwise), will 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 will preferably be filled with filtered sterile nitrogen, or a similar insert gas. At heat seal station 184, opposing heads of heat seal are brought together to either side of the container, thereby closing the channel (112b of Figure 8) between the sacrificial orifice and the drug compartment. The heat seal, thus formed, effectively continues the permanent seals between the oversized edge seals 110e and 110f depicted in Figure 8, thereby sealing the drug compartment.

Next, the cap is reinserted into the sacrificial hole of the drug compartment, and the powder fill container is conducted to a 186 total weight scale where its total weight is taken to verify that the proper amount of powder drug has been taken. distributed in each container. The total weight, determined at station 186 is correlated to the weight of the vacuum package as determined at tare weighing station 178. If the total weight scale 186 determines that an inappropriate 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 checkweigher determines that the amount of powdered drug in the drug compartment is correct, the container is deemed to have been filled correctly and is driven to the next station, or stations, if further processing is desired.

ES 2 215 830 T3

In accordance with the practice of the principles of the invention, additional compartments of a container can be filled by additional drugs or diluents (successive refilling) in a subsequent isolator unit, or multiple successive isolator units. Although the first filling step was described in connection with the introduction of a powdered drug into the drug compartment; It will be understood that this was done in the context of a multi-compartment medical package having separate compartments for a powdered 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, either a powdered drug, in the manner described above, or a diluent or liquid drug 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 inserted into a second isolating liquid fill unit 190 for aseptic filling with a diluent.

In particular, upon completion of the powder fill process, and as indicated in the exemplary process flow diagram of Figure 14, the partially filled container is moved from the powder fill isolator 174 to the liquid fill isolator. 190 through a transfer tunnel 192 that is connected between the two isolator units. After the powder filling procedure described above, the container is removed from the conveyor belt 176 of the powder fill isolator 174, and is placed on a transfer belt 194 that passes through the transfer tunnel 192 and joins the two isolating units. It will be understood by one of ordinary skill in the art that transfer tunnel 192 and transfer belt 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 multiplicity of isolators can be joined together by transfer tunnels to add additional filling steps, with perhaps a multiplicity of ingredients to the process. The modular nature of the package construction process, whereby single-compartment or multi-compartment packages can be manufactured, is easily coupled with the modular nature of the filling process. Since as many fill isolates as are needed to fill the desired number of compartments, they can easily be linked together with transfer tunnels to thus carry out a full flexibility fill and manufacturing 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 are placed back onto a continuous loop conveyor 196 which leads the container through the stages of the liquid filling process.

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

After the diluent dispensing step, the container is led to a diluent compartment heat seal station 200, where the diluent compartment headspace is first adjusted with nitrogen or 0 filtered air. 2 microns. The heat seal station 200 comprises a thick heat seal plate opposite a bearing plate which is proximally closed on the container to seal the channel (112a of Figure 8) between the diluent compartment and its sacrificial orifice. In effect, the diluent compartment heat seal continues the permanent peripheral seal between regions 110d and 100e of FIG. 8, thus completing the out-of-package seal now completed from the sacrificial band.

The filled container now exits the liquid fill isolator 190 via an exit tunnel 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 leveled to its final dimensions by removal of the portion of the oversized edge of the container that includes the sacrificial holes. As an optional part of the matching process, the peripheral seal along the side of the container to be matched can be reinforced thereby securing the drug seal and diluent compartments on all sides of the container. The manufacturing and filling of the container is now complete and the finished and filled container is folded along the seal between the diluent and drug compartments, wrapped and packed in shipping containers.

The production process for the manufacture and filling of the container is therefore only contemplated as an individual sterilization procedure that follows the manufacture of the primary container. In accordance with the practice of

ES 2 215 830 T3 principles of the invention, the construction of the container and the use of the sacrificial orifices that communicate with the diluent and medicine compartments, allowing the diluent and medicine compartments to be aseptically filled later, and sealed without the need for any of the sterilization procedures. Indeed, since the container of the present invention is not capable of terminal steam sterilization, due to the high moisture sensitivity of powder drugs and the moisture barrier properties of the drug compartment cover, The aseptic filling methods, described above, are a necessary accessory for the manufacture of a sterile final product. Manufacture and filling of the container in accordance with the practice of the invention therefore allows the container 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 eliminated, medical packages can be manufactured to include high barrier capacity laminates, thus providing medical packages that are particularly well suited for long-term storage, and that can be efficiently manufactured with low manufacturing cost.

Additionally, it will be understood by those skilled in the art that the construction and use of the sacrificial orifices that communicate with the diluent and drug compartments provide means for conducting, retaining, positioning, and manipulating the container throughout the filling process. The size of the sacrificial orifice openings is tailored to the container which must be compatible with the technology of conventional drug vial filling equipment.

The sacrificial orifices are designed with tabs so that the container is able to hang on a coordination mechanism, and two tabs are provided over each hole, so that the container can be "handled" by a robotic pick-up and placement equipment until control weighting stations offline or transferred between isolators. Additionally, it will be appreciated that utilizing the sacrificial orifices, in connection with the manufacturing and filling processes of the medical package, 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 container 10 and the mixing system will be received by healthcare personnel, typically 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 12 over the protective layer containing aluminum foil 55 and peeling the protective layer from the container until inspection is allowed. visual of the intermediate compartment 20 containing the powdered medicine. If the medication appears dry and in normal condition, the solution can be mixed as shown in figure 17 by manipulating the container to compress the front and rear sheets in the upper diluent compartment area 18. Mechanical pressure from hydraulic forces created by Handling the container breaks the peelable seal between the diluent and drug compartments (shown in the broken condition as 24 '). In addition to the shake handling, mixing of the liquid diluent and the powdered drug is caused. Verification that complete mixing is obtained occurs by visually viewing the mixed solution through the clear, transparent front sheet. After mixing is complete, the peelable seal between the drug compartment and the safety compartment is broken as shown in Figure 18, again compressing the front and rear sheets of the container creating hydraulic pressure in the container to break the gasket (shown in the broken 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 prevents the delivery of the 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 delivery of the medication to the patient. For packages that include a liquid diluent and powdered drug, the breakdown of the first peelable seal between the diluent compartment 18 and the drug compartment 20 is ensured essentially prior to the breakdown of the second seal between the compartment of the medication 20 and the lower safety compartment 22, since the hydraulic forces created in the diluent by handling the container cannot be transmitted through the powder in the medicine compartment until the first seal has been broken and mixing of the diluent and powder has started. For these cases, where liquid medicine can be used, the relative size difference between the diluent compartment and the medicine compartment and the placement of the smallest medicine compartment intermediate between the larger diluent compartment and the bottom or safety compartment , ensures the development of hydraulic forces that will break the first seal between the diluent and drug compartments before the rupture of the second seal leads to the safety compartment with only minimal care.

In the exemplary embodiments of the container, shown in Figures 16, 17 and 18, the peelable seals are described as having a conventional, rectangular configuration such as the seals described in US Patent No. 5,176. .634 to Smith et al. In accordance with the practice of the principles of the invention, the gaskets, although configured in a conventional manner, are formed in the manner described above to provide a predictable, uniform response with respect to handling pressure and peel open to a applied force of approximately 0.028 ± 0.007 MPa (4.0 ± 1.0 psi). In a further embodiment of the invention, curvilinear peelable seals are provided which function to

ES 2 215 830 T3 the peel open fully, along their lengths, under hydraulic pressure, and which are formed in substantially the same manner as the uniform peelable seals 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 seal configuration is intended to address the two conflicting performance requirements imposed on peelable or frangible seals used in connection with a binary medical container. The first performance requirement for a peelable or frangible 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 unexpected rupture of the gasket. shutter during normal handling. The second performance requirement is that the gasket peel can be separated substantially completely during user activation, thus 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 that the gasket, either peelable or frangible, will be incompletely peeled during activation. This can allow significant amounts of either mixed or liquid diluent medication to remain trapped against the unopened seal line portions.

Additionally, it has been noted that for conventional straight peelable gaskets, as the force required for user activation increases, so does the probability of incomplete gasket opening.

The operational use of a binary medical container requires the peelable gaskets to survive various impacts over the life of the product. Most of these impacts will tend to occur while the product is folded along a seal line, thus the peelable gaskets are well protected. However, significant impact events can occur after the product has unfolded and, during this period, peelable gaskets are susceptible to unanticipated activation with consequent activation of the product. In order to reduce the risk of unanticipated activation, an effective binary medical package should be manufactured with peelable seals strong enough to withstand most unexpected impacts, while still yielding fully to intended handling pressures.

Accordingly, the curvilinear peelable gasket 86 solves the two conflicting performance requirements with a configuration that is symmetrical to the configuration made by a conventional straight peelable gasket as it begins to peel. As described above in connection with Figures 1 and 2, as shown in Figure 19, the peelable seals extend in the container horizontally, and have a length 88 sufficient to connect between the permanent seals 16 on the sides of the bag, thus dividing the package into compartments. Each seal 86 comprises a first, generally rectangular portion 90 that defines the minimum width of the peelable seal 86 at its intersection with the permanent seals 16 on the sides of the container. The dimension of the conventional portion 90 in the height direction (the small dimension) is about 2.54 to 6.35 mm (1/10 to 1/4 inch) and preferably 3.175 mm (1/8 inch). . The rectangular portion 90 is then configured as a conventional rectangular (straight) gasket. The peelable gasket 86 further includes a second curvilinear portion 92 comprising a curved section that mounts on top of the rectangular portion 90, with the bead 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 will provide the gasket opening pressure source. The convex edge of the arch 94 is generally radial and has a maximum bead depth that is at least about half the width of the rectangular portion 90 of the gasket 86. The specific configuration, radius of curvature and depth of the bead of the curvilinear section 92 will, of course, vary with the length of the gasket, and the particular application to which the binary container is placed, including the anticipated resistance to any impact. unexpected. However, specific gasket configurations can be adequately calculated, by a person skilled in the art, using beam theory and the desired opening pressure for the gasket properly determined.

In operation, the convex leading edge 94 of the peelable seal 86 exhibits a characteristic of resistance of the compound to the hydraulic pressure of the diluent, or mixed drug, when a respective compartment is compressed. As described in FIG. 20, the peel characteristics of conventional peelable gaskets show a curved front peel, when the gasket is examined after it has only partially peeled open. This curved front peel indicates that the hydraulic pressure, which forms the gasket opening, is the largest approximately in the center of the gasket, and decreases uniformly, but according to an outward power law. edges of the gasket. A conventional partially peeled open gasket would therefore have a concave gap pattern, with the deepest portion of the concavity being approximately in the center of the gasket. Thus, you can easily see that conventional gaskets will naturally tend to open as soon as possible 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 permanent edge gasket.

In accordance with the practice of the principles of the invention, the curvilinear peelable gasket 86 of FIG. 10 provides a convex edge 94 having a configuration that is image mirroring of features.

ES 2 215 830 T3 of the concave peel for a conventional gasket. As described in figure 21, the strength characteristic of the curvilinear gasket will match the curvilinear pressure gradient of the diluent or mixed measurement that is trying to peel the gasket opening. The strength characteristic of the curvilinear gasket 86 is the strongest in the center, where the pressure is greatest, and the non-linear mode is reduced according to the falling pressure, towards the edges of the gasket. In this way, the gasket is caused to peel open evenly along its entire length.

Although the curvilinear peelable gasket 86 has been described as providing a non-linear resistance characteristic to hydraulic pressure by having a curvilinear width, it will be apparent to those skilled in the art that non-linear resistance characteristics can be provided by other means. For example, you can obtain a curvilinear strength characteristic in a rectangular shaped straight peelable gasket by varying the temperature or pressure of a heat seal bar when the gasket is formed. The temperature of the heat seal can cause it to become hotter in the center and cause a non-linear descent towards the ends of the gasket, thereby providing a peelable gasket that is strongest in the center, by virtue of the gasket that is more permanent. Alternatively, a curved sealing bar can be used to provide the same effect, the sealing bar being constructed to have a convex contact face that is pressed against the binary medical container during the peelable seal manufacturing process. Although such a peelable gasket may exhibit a conventional linear configuration, its central portion would be crushed much more tightly during the sealing process. The application of pressure would result in the central portion of the gasket being the strongest, with the gasket strength decreasing in a non-linear (curved) way towards the ends. All that is required is that the peelable gasket have a non-linear resistance characteristic that substantially matches the non-linear pressure characteristics of the diluent, or mixed medication, when the respective compartment is compressed.

Additionally, the thorough mixing of the diluent and the drug, and the complete delivery of the mixed solution through the outlet port to a standard IV delivery device is enhanced by the non-linear peel characteristics of the gaskets of the present invention. . As described above, the non-linear resistance of the peelable gasket with respect to hydraulic pressure ensures that the gasket opens substantially along its entire length and thus ensures that substantially all of the liquid diluent is able to enter the drug compartment and mix with the drug contained within. After mixing, the non-linear peel characteristic of the second gasket ensures that the gasket is peeled open substantially completely along its length, allowing the mixed solution access to the outlet port and system. supply IV.

Those skilled in the art will recognize that the primary description of embodiments comprising a liquid diluent and an individual powdered medicament does not limit the scope of the invention. The use of liquid drugs in the intermediate compartment or a plurality of compartments for powder and liquid drugs, which are to be mixed with the diluent, can be employed using the present invention. The multiple sacrificial ports and communication channels between the sacrificial ports and the respective compartment can be readily provided in accordance with the practice of the principles of the invention. Furthermore, depending on the susceptibility of some components that comprise the contents of the multiple compartments to contamination from moisture or free oxygen, these compartments may be protected by the additional applications of a clear high barrier laminate containing transparent SiOx on the surface. front sheet of the package in these compartment regions. Such high barrier laminates may be provided with or without being combined with an aluminum foil containing peelable cover of high barrier laminate.

The above descriptions of exemplary sterile flexible packaging embodiments are for illustrative purposes. Due to the variations that will be apparent to those skilled in the art, the present invention is not intended to be 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.