Flexible medical container with selectively expandable compartments and method of making same

The subject of the invention is a flexible container for storage and administration and a method for producing a flexible container for storage and administration of medical solutions in a sterile environment. In particular, the invention relates to flexible medical containers intended for the storage and administration of intravenous solutions and having side walls that are stretched permanently to increase the capacity of the container.

Patients are given a variety of medical solutions intravenously from sterile containers, which may contain any type of medical fluid such as replacement body fluids, as well as drug-containing solutions. The common packaging for storing and administering these solutions contains flexible containers having a solution storage chamber. The outlet of the package is coupled to the chamber for administration and delivery of the solution to the patient through standard intravenous administration equipment.

Often, medical solutions are composed of a mixed combination of a liquid diluent, e.g., an aqueous solution of dextrose or NaCl, and a liquid drug. Preferably the drug and diluent are stored separately in the container under aseptic conditions and are not mixed together until used to prevent degradation of the final product. Packaging of the diluent and drug is often complicated by the nature of the drug, which may be in the form of a liquid, and is therefore susceptible to hydraulic pressure acting on the container as well as to degradation by light or oxygen.

Various drugs that become unstable in solution over time are usually stored separately in use in gas-tight vials, containers, etc. before use. Before administration to the patient, drugs stored in this manner must be mixed or diluted in physiological solutions or diluents that are also stored. separately. Although separate storage of the ingredients is suitable for maintaining the sterility and efficacy of the drugs, it is nevertheless troublesome and involves the risk of bacteriological contamination during handling, mixing and subsequent administration to the patient. Medical containers have therefore been developed that contain chambers for the storage of unstable drugs and chambers that contain liquid diluents. Just before intravenous administration to the patient, the ingredients are brought together so that the contents can be mixed aseptically.

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Multi-chamber containers that allow separate storage of diluents and drugs are known. Such containers are described, for example, in US Patent Nos. 4,608,043 (Larkin), 5,176,834 (Smith et al.) And 5,462,526 (Bamey et al.). US Patent Nos. 4,608,043, 5,176,834 and 5,462,526 are hereby cited in their entirety. The chambers of the containers described in the above patents are separated from each other by peelable or brittle welds. These welds are interrupted when the container is handled so that the contents of the chambers can be mixed together to form a solution that is administered to the patient through standard intravenous administration equipment.

Solution containers currently on the market are usually made of materials containing polyvinyl chloride. This material is usually quite dark, which makes it difficult to control the contents of a container made of such material. Consequently, it is quite difficult to check that the container is not leaking and is not contaminated with moisture. The control is additionally more difficult with multi-chamber containers, which require checking whether the drug and diluent have been mixed completely before administration to the patient. In addition, various hazardous chemicals are used in the production of polyvinyl chloride and this material needs to be disposed of in an environmentally safe way, because it produces toxic gas when burned. It also contains a toxic plasticizer that can be released into the environment when the container is in landfill. This plasticizer can also get into intravenously administered solutions, therefore polyvinyl chloride containers are not suitable for use with some types of medical fluids, especially liquid medications.

Flexible containers are usually made of a pair of opposing flat sheets that are joined together to form a body or jacket. Creating a body with specific dimensions ensures constant capacity. Usually containers are made to contain normalized volumes. This works well until you need to use a non-normalized volume. In this situation, one solution is to use only part of the solution stored in a larger container. However, such a solution is expensive, wasteful and dangerous. The user must also be very careful to use only the required or prescribed amount of fluid contained. In addition, the remaining solution may require special disposal.

The containers are also usually made up to a certain overall external dimension or in several common overall dimensions. This is usually because the overall size of the container determines its capacity, and currently the containers are delivered with a relatively small number of specific volumes. In addition, the production, handling and sterilization of such containers requires very complicated and expensive equipment that is partly adapted to the overall dimensions of the container. It is therefore desirable to develop a medical container that has normalized external overall dimensions and has an increased capacity relative to the normalized size. In addition, it is desirable that the medical container be manufactured using the same handling machines and equipment as those used for standardized containers.

Similar to single-chamber containers, multi-chamber containers are usually made with specific dimensions of the chambers. The diluent chamber is typically sized to store enough diluent to mix with the stored drug and form the correct solution. The dimensions of the diluent chamber are also based on the specific dose or amount of medical solution stored. The volume of the diluent chamber can also be limited by the overall external dimension of the container, which must be made to fit into the packaging and handling equipment. However, in some applications it may be desirable to increase the amount of diluent. Currently this is not possible or requires a second diluent container. Alternatively, some applications may require additional medication. It is therefore desirable to develop a multi-chamber medical container that has a normalized overall external dimension with normalized chamber capacities that can be permanently enlarged to increase the capacity of at least one of the chambers. In addition, it is desirable that the container be manufactured with a specific overall size and configuration to facilitate manufacture, sterilization and manipulation using the same devices and processes.

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A flexible storage and administration container according to the invention comprising a flexible front sheet having a first state defining a first surface area, a flexible rear sheet having a first state defining a first surface area equal to the surface area of ​​the flexible front sheet, the front and back sheets being disposed opposite each other along a common planes and welded together along a common peripheral edge creating a volume cover, defining the first capacity, characterized in that at least one of the sheets, front or rear, protrudes outwardly from a common plane permanently deformed to a second state in which the second surface area is larger than the first surface, creating a second capacity greater than the first capacity . Preferably, the flexible container has a front sheet and a back sheet permanently deformed to a second state and stand out from the common plane. Preferably, the second capacity is at least twice as large as the first capacity and is obtained by permanently deforming the front sheet and back sheet. The front sheet of the flexible container comprises a polypropylene-polyethylene copolymer mixed with an ethylene-butylene styrene elastomer, preferably in a weight ratio of 80% / 20%. The back sheet of the flexible container is a multilayer laminate comprising: an inner layer of polypropylene-polyethylene copolymer mixed with an elastomer containing ethylene-butylene styrene in a weight ratio of 80% / 20%.

Preferably, the container comprises at least one opening disposed between the front sheet and the back sheet defining the fluid connection path to the interior of the volume enclosure. The front and back sheets of the container are permanently deformed to a second state by introducing the pressurized fluid into the volume shield through said opening. Preferably, the fluid under pressure is gas, preferably air introduced into the volume shield at an inlet pressure of 103.4 to 172.4 kPa and maintained at an inlet pressure for 15-25 s. The inlet pressure is adjusted to approximately 137.9 kPa and maintained at this value for 15 seconds.

The compressed fluid usually permanently deforms the front and back sheets, thereby expanding the volume cover from the first capacity in the range 130-150 ml to the second capacity in the range 250-300 ml, specifically 280 ml ± 5 ml.

The flexible container may have a front sheet permanently deformed to a second state with a second surface area greater than 16% of the first surface area, and a rear sheet permanently deformed to a second state with a second surface area greater than the first surface area by up to 10%.

Preferably, the container further includes a second opening disposed between the front and back sheets and forming a fluid pathway into the volume enclosure.

The flexible container for storing and administering medicaments and diluents of intravenous solutions according to the invention has a substantially transparent front sheet, composed of a flexible flat polymer film layer, with a first surface area and a back sheet, composed of a flexible flat laminate layer, with a second surface area, opposite the front surface sheet along a common plane and tightly attached to the front sheet along a common peripheral edge, forming a volume shield. The container also has a first tear weld between the opposite sides of the common peripheral edge and separately separating the front and rear sheets to form a first chamber for the first product, and a second tear weld that runs between the opposite sides of the first and second, a common peripheral edge and separably connecting the front and back sheet, forming a second chamber for the second product, and an outlet chamber, positioned in such a way that the second chamber is between the first chamber and the outlet chamber. The outlet chamber has an outlet opening in the common peripheral edge. At least a portion of the front sheet covering the first chamber in which the first surface area defines the first capacity extends outwardly from the common plane to deform to a permanent state having a second surface area defining a second capacity greater than the first capacity.

Preferably, the container further comprises a first sacrificial opening supported by a common peripheral edge and fluidly connected to the first chamber, and a second sacrificial opening supported by a common peripheral edge and fluidly connected to the second chamber.

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Preferably, the front sheet comprises a polypropylene-polyethylene copolymer mixed with a thermoplastic elastomer made of ethylene-butylene styrene, preferably in a weight ratio of approximately 80% / 20%, and is permanently stretched from a substantially flat surface. The back sheet contains an inner layer of polypropylene-polyethylene copolymer mixed with a thermoplastic elastomer made of ethylene-butylene styrene, facing the front sheet, an intermediate layer of aluminum foil, and an outer thermoplastic layer having a melting point higher than the melting point of the inner layer. Preferably, a substantially transparent, highly barrier, protective laminated film is welded to the front sheet so that the film covers the second chamber. Preferably, the container further comprises an opaque strongly barrier protective film detachably welded to the transparent laminated protective film, said opaque film having such dimensions that it covers the transparent protective film and the second chamber.

The method of manufacturing a flexible storage and administration container according to the invention, which uses a flexible container having a flexible flat front sheet with a first surface area opposite to a flexible flat back sheet with a first surface area along a common plane, the front sheet being sealed. to the flexible back sheet along the common peripheral edge, forming a volume cover having an opening, consists in that the volume cover expands permanently by stretching the front and / or back sheet, by expanding the first surface area of ​​the front or back sheet to a second larger surface area, thereby increasing the capacity of the volume cover. In the expansion step, the volume shield is inflated with compressed gas, keeping the back sheet and the common edge edge substantially in a common plane, permanently stretching a portion of the front sheet out of the common plane, or permanently stretching both the front sheet and the back sheet. Most often, the volume cover capacity after stretching is at least double the capacity before stretching.

The process of the invention preferably uses a front sheet made of a substantially transparent flexible flat polymer layer, and a back sheet made of a vapor-impermeable layer.

In one variant of the method according to the invention and in the expansion step, the volume shield is inflated with compressed gas, permanently stretching both the front sheet and the back sheet. The container is placed in a multi-part tool designed to receive a volume cover, the back sheet is facing the upper concave area of ​​the tool, and the front sheet is facing the lower concave area of ​​the tool, and the volume shield is inflated with compressed gas at an inlet pressure of 103.4 to 172.4 kPa by permanently extending the front and back sheets outward into the respective concave areas of the tool, the gas inlet pressure being maintained for 15 s. In addition, the permanently stretched volume shield is maintained in an inflated state.

In another embodiment of the method of the invention, the volume shield is inflated with compressed gas while maintaining the back sheet and the common peripheral edge in a substantially flat surface. The container is placed in a multi-part tool intended to receive the volume cover so that the back sheet of the container contacts the lower flat surface of the lower part of the tool, and the front sheet of the container is facing the opposite upper surface of the concave upper part of the tool, with the common circumferential edge of the container held down is at the lower flat surface of the tool by the flat edge of the upper concave surface of the upper part of the tool. In the inflating step, the pressurized gas is detachably connected to the opening, the gas having an inlet pressure of 103.4 to 172.4 kPa and the volume shield is inflated to a pressure sufficient to stretch the front sheet out into the concave surface of the tool, maintaining the gas inlet pressure by 15 p.

The preferred method variant uses a front sheet of substantially transparent sheet made of a flexible flat layer of polymer film, a back sheet of flexible and vapor-tight sheet made of flat multilayer laminate, a first sacrificial hole is made supported by a common peripheral edge and connected fluidly to the cover volume, a second sacrificial hole is made, supported

190 598 through a common peripheral edge and fluidly connected to the volume cover, the second sacrificial opening being spaced from the first sacrificial opening along the first side of the common peripheral edge, and an outlet opening fluidly attached to the volume enclosure is provided, the outlet opening being supported by lower side of the common peripheral edge. The volume shield is supported by gripping a common peripheral edge into a tool having a first concave area to receive at least a portion of the front sheet and an opposite second concave area to receive at least a portion of the rear sheet, wherein the first concave area has a volume greater than the second concave area, and then expands cover the volume with compressed gas by stretching the front sheet and back sheet to the corresponding concave tool areas, and pressurized gas is released from the inside of the volume enclosure, the front and back sheets being stretched permanently, increasing the capacity of the container. The front sheet is a polypropylene-polyethylene copolymer layer mixed with a thermoplastic elastomer made of ethylene-butylene styrene. The back sheet contains: an inner layer of polypropylene-polyethylene copolymer mixed with a thermoplastic elastomer made of ethylene-butylene styrene, which inner layer is located opposite the front sheet, an intermediate layer of aluminum foil, and an outer thermoplastic layer having a melting point higher than the inner layer. In addition, the permanently stretched volume cover is filled with gas, sacrificial holes are closed, and the outlet opening is closed keeping the container in an enlarged configuration.

Preferably, a transport carrier is additionally used, comprising a rail insert intended for receiving and supporting multiple containers, the rail insert being coupled to the containers through their respective sacrificial openings, multiple containers for the rail insert are loaded, the loaded rail insert is placed in the transport carrier, the transport carrier is sealed tight against environmental contamination, and the sealed transport carrier and loaded containers are sterilized by the use of a radiation beam. Each of the sacrificial holes is then removed, and welding is completed along the first side of the common peripheral edge on the inside of the sacrificial holes, thereby completing the container formation.

Preferably, in the step of expanding the volume cover, the front and back sheets are permanently extended, increasing the capacity of the container at least twice, and the volume cover is blown inside the tool to a pressure of 103.4 to 172.4 kPa. The compressed gas is preferably compressed air.

In another embodiment of the method, a front sheet of a flexible and substantially transparent flat polymer layer is provided, a back sheet of flexible and vapor-impermeable flat multilayer laminate is provided, the front and back sheets are heated in a first localized area to melt the front and back sheets together along the heated first localized area, thereby forming a first tear weld extending between the first side of the common peripheral edge and the opposite second side of the peripheral edge, wherein the first tear weld detachably connects the front and back sheets to form a first chamber having a first volume inside the diluent volume shield, followed by first sacrificial hole placed between the front sheet and back sheet and in fluid connection with the first chamber, and the first chamber is expanded from the first capacity to the second capacity by permanently stretching the front and back sheets of the first chamber. It is further preferred to heat the front and rear sheets in a second localized area to melt the front and rear sheets together along a heated second localized area, thereby creating a second tear weld between the first side and the opposite second side of the common peripheral edge, the second tear the weld separably connects the front and back sheets to form a second medicine chamber and an outlet chamber so that that the second chamber is located between the first chamber and the outlet chamber. In addition, a second sacrificial opening is made between the front sheet and the back sheet and in connection with the second chamber, and an outlet opening is provided between the front sheet and the back sheet and in connection with the outlet chamber. Preferably, a polypropylene 190 598 copolymer layer is used as the front sheet

- polyethylene mixed with a thermoplastic elastomer from ethylene-butylene styrene, and as a back sheet a multilayer laminate is used having: the inner layer of polypropylene-polyethylene copolymer mixed with a thermoplastic elastomer from ethylene-butylene styrene, which is opposite to the front sheet, an intermediate layer of aluminum foil and an outer thermoplastic layer having a melting point higher than the melting point of the inner layer. In the inflating stage, the volume shield in the tool is inflated to a pressure of 103.4 to 172.4 kPa for 10 to 25 s.

The subject of the invention in the embodiments is shown in the drawing, in which Figure 1 is a semi-schematic front view of an embodiment of the container according to the principles of the present invention; Fig. 2 is a semi-schematic cross-sectional view taken along line 2-2 of Fig. 1, showing the flexible flat sheets forming the container, the thickness of the layers in the sheets being enlarged for clarity of the drawing; Fig. 3 is a semi-schematic fragmentary cross-section along line 3-3 of Fig. 2, showing the configuration of flexible sheets in the first embodiment of the container according to the present invention; Fig. 4 is a semi-schematic partial cross-sectional view of the configuration of the flexible sheets in the first embodiment of the invention showing any transparent highly barrier intermediate film; Fig. 5 is a semi-schematic section along line 2-2 of Fig. 1 showing the first chamber permanently enlarged compared to Fig. 2; FIG. 6 is a semi-schematic front view of an embodiment of the container shown during manufacture according to the principles of the present invention; Figure 7 is a schematic top view of an example of a modular container manufacturing device according to the present invention; Figure 8 is an alternative embodiment of a flexible container according to the principles of the present invention; Figure 9 is a side view of the flexible container of Figure 8; Fig. 10 is a side view of the flexible container of Fig. 8 shown with permanently enlarged front and back sheets; Figure 11 is a perspective view of an embodiment of a tool for permanently stretching a front and rear flexible sheet of a container according to the principles of the present invention; Fig. 12 is a perspective view of the upper part of the tool of Fig. 11 showing the upper cavity; Figure 13 is a perspective view of an embodiment of a servomotor housing for use with the tool of Figure 11; FIG. 14 is a semi-schematic perspective view of a manipulation container according to the principles of the present invention comprising a rail insert and a heat sealed foil cover; Fig. 15 is a semi-schematic top view of the rail insert of Fig. 14 showing a plurality of flexible containers loaded in the rails; Fig. 16 is a semi-schematic side view of the loaded rail insert of Fig. 15 showing how flexible containers are held in rails through sacrificial holes; and fig. 17 is a side view of the flexible container of Fig. 8, shown with sacrificial openings removed and with a permanent weld made along the entire common peripheral edge.

Figs. 1 and 2 schematically show, respectively in front view and in cross section, a preferred embodiment of the flexible sterile container 10 according to a preferred embodiment of the present invention. The container 10 is made of a generally flat front sheet 12 and an opposing, substantially flat back sheet 14 (shown only in Figure 2). Front and rear sheets 12 and 14 can be made of one layer of flexible material or of multilayer laminates of flexible material, which will be described in detail below.

The sheets 12 and 14 forming the container 10 can be provided separately and placed opposite each other in a common plane 15 (Fig. 2). The sheets 12 and 14 are then permanently welded together along a common peripheral edge 16. Preferably, the welded common peripheral edge 16 extends around the entire circumference of the container 10 to form a cover around the space 17. Such circumferential welds may have different shapes and widths. A weld shaped according to the pattern as shown on top side 18 and bottom side 20 in Figure 1 can be used to form grip areas that allow medical personnel to manipulate the container 10 and allow the container to be attached, for example, to an intravenous administration rack. Alternatively, the front 12 and rear 14 sheets can be formed from a single sheet of film which is then folded and sealed

190 598 around the perimeter of the overlapping parts of the sheet. Regardless of the embodiment, the sheets welded together will be referred to as the coating or container body.

In an exemplary embodiment, the container 10 is divided into three separate chambers, a first or upper chamber 22, a second or middle chamber 23, and a lower or outlet chamber 24, each of which is sterile. The upper chambers 22 and the middle 23 are separated from each other by a first separable weld 25, while the middle chambers 23 and the bottom 24 are separated from each other by a second separable weld 26. Welds 25 and 26 extend between the first side 27 of container 10 and the opposite second side 28, from the common welded peripheral edge 16 on the first side 27 to the welded joint peripheral edge 16 on the other side on the side 28. Separable welds 25 and 26 connect the inner sides front 12 and back 14 sheets together in a defined weld area.

The peelable weld is a weld that is durable enough to allow normal container handling, but which will be torn to allow the front sheet to be separated from the back sheet in the weld area under the hydraulic pressure applied during container handling, thus mixing the contents of the container and dispensing . The peel seal is made by partially melting together the polymer material existing in the adjacent inner surfaces of the front and back sheets. The weld is obtained by welding, at which heat and pressure are applied to the local area with varying times, temperatures and pressures, which will be described in more detail below. In contrast, the weld along the common edge 16 is much stronger than the burst welds 25 and 26 and will not be interrupted by the hydraulic pressures produced to separate the burst welds. Each of the burst seals 25 and 26 is individually configured to be burst in such a way that it preferably allows first mixing of the liquid drug and liquid diluent, followed by dispensing of the mixed ingredients.

In a typical application of the container 10 according to the present invention, the upper chamber 22 is filled with liquid diluent and the central chamber 23 is filled with medicine, usually in liquid form. The lower chamber 24 acts as a safeguard for the outlet 30 and remains empty until the container is used. The orifice 30 extends downwardly and includes a main portion 38 and a nozzle 40 that is intended to be attached to a standard device for intravenous drug delivery. A cap (not shown) is provided to cover the nozzle and maintain its sterility. This hubcap is removed just before attaching the intravenous administration kit to the exit opening 30. A plurality of ribs 39 may be provided around the main portion 38 of the exit opening 30 to provide a surface that is easy to grasp and to facilitate connection to the intravenous administration kit.

The materials used to construct the front and back sheets of the container 10 are selected depending on the material stored therein. Preferably, at least one of the sheets is transparent to allow visual inspection of the container content and control during dispensing of the level of solution in the container. Suitable materials for making the transparent sheet are usually single-layer or multi-layer polymer laminates and polymeric films.

In particular, the materials that make up the front sheet 12 and back sheet 14 of the container 10, whether in the form of a single-layer or multi-layer polymeric film, are chosen for their transparency and transparency. Conventional materials based on polyvinyl chloride (PVC) used for the container usually have a rather dark appearance, which makes it difficult to properly observe the interior of the container and determine the levels of fluid contained in it or the presence of granular material. This is particularly dangerous when the medicine is administered intravenously. It is necessary for the nurse to be able to see at a glance that the medicine administered from the container does not contain granular material.

Fig. 3 schematically shows a fragmentary cross-section of an embodiment of the container 10. As shown, the front sheet 12 is made of a transparent single-layer film 44 of thermoplastic polymer. The transparent film 44 may be made of a flat layer or sheet of a mix of about 80 wt. polypropy 190 598 flax-polyethylene copolymer from Oil and Chemical Company of Deerpark, Texas with the trade designation Z9450 and about 20 wt. a thermoplastic elastomer made of ethylene-butylene styrene, available from Shell Chemical Corporation under the trade name KRATON® and with the trade designation G1652. The G1652 thermoplastic elastomer is a two-phase polymer with polystyrene domains (end blocks) and a rubber-like polyethylene-butylene matrix and is usually supplied in crushed form. In practice, this film is produced by mixing Z9450 copolymer resin granules and G1652 thermoplastic elastomer in crushed form in a 80% / 20% weight ratio in a high shear mixer and melting and re-granulating the mixture. Mixing crushed G1652 material in a high shear device can cause a rise in temperature, so care must be taken not to allow the temperature to exceed about 500 ° F (260 ° C). Then, transparent film 44 is made from the granules of the mixture in an industrial extrusion device.

The transparent polymer film 44 forming the front sheet 12 can be made with different thicknesses depending on the intended use of the container and the durability required for that specific purpose. Suitable thicknesses of the material forming the front sheet 12 may be in the range of 0.08-0.24 mm (3-15 thousandths of an inch), but in the embodiment of the container the transparent polymeric film 44 forming the front sheet 12 is preferably about 0.32 thick mm (12 thousandths of an inch).

Although the composite material chosen to form the transparent polymer film 44 (which may alternatively be called 80:20 film) was chosen for its transparency and transparency, the film 44 is also particularly well suited for forming both peel and permanent welds, such as a permanent weld along the common peripheral edge 16 of the container 10. As described in detail below, the 80:20 film of the invention allows both a low-temperature peel welding process and a high-temperature permanent weld formation process without affecting the integrity of the material or its ability to form an effective peel or permanent weld.

For medical solutions containing certain combinations of diluents and drugs, the back sheet 14 can be made with the same single-layer composition and configuration as the front sheet 12. Alternatively, multilayer films that contain moisture and light impermeable layers and are therefore able to extend the time storage of a filled container are the preferred films for the construction of the back sheet. As shown, a three-layer laminated back sheet 14 can be used. Preferably, the laminated back sheet 14 is a flexible flat sheet that is impermeable to water vapor and light. This configuration allows the efficiency and activity of the solution to be maintained in a single-chamber container and two-component drugs (unmixed drug and liquid diluent) in the case of multi-chamber containers, and thus prolongs the storage of the filled container.

In the embodiment shown, the rear sheet 14 comprises an inner sealing layer 46 on its inwardly facing surface. This inner sealing layer 46 can be made of a 80% / 20% w / w mix. polypropylene-polyethylene and thermoplastic elastomer made of ethylene-butylene styrene, the mixture having a thickness of 0.08-0.16 mm (3-6 thousandths of an inch) (80:20 foil). Preferably, the inner seal layer 46 (80:20 foil layer) may be approximately 0.16 mm (6 thousandths of a in) thick with bonding by means of a transparent inner adhesive 48 with an intermediate layer 50. Preferably, the intermediate layer 50 may be a barrier layer of aluminum foil thicknesses of about 18-32.5 pm (0.7-1.3 thousandths of an inch), more preferably about 25 pm (1.0 thousandths of an inch). An outer layer 54 is provided on the outwardly facing surface of the back sheet 14 and is bonded to the aluminum foil barrier layer 50 by means of a suitable transparent adhesive 52.

The inner adhesive layer 48 may include a modified aliphatic polyester polyurethane adhesive available from Liofol Company of Cary, North Carolina, with the trade designation TYCEL 7909. The outer adhesive layer 52 may be a modified aromatic polyester polyurethane adhesive, also available from Liofol Company of

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Cary, North Carolina, with the trade designation TYCEL 7900. An aliphatic adhesive containing the inner adhesive layer 48 may also be used for the outer adhesive layer 52, although the reverse is not the case. Aromatic glue, although it provides a stronger bond than the aliphatic version, can introduce very unwanted aromatic compounds either into the liquid diluent or into the liquid drug through the 80:20 film layer. Aromatic glue, if used, is only used when the aluminum foil layer 50 is placed as a barrier between it and the volume 17 inside the container 10.

The aluminum foil layer 50 is suitably constructed of commercially available 25 μιη (1.0 thousandth of an inch) thick aluminum foil, such as ALCAN 1145 from the Alcan Rolled Products Company, Louisville, Kentucky. When the aluminum foil layer 50 remains exposed as the outer layer of the rear sheet 14, the welding process used to form both the weld along the common peripheral edge 16 and the transverse peel welds 25 and 26 may damage the foil layer 50 and destroy its integrity and ability to form a barrier. To avoid this damage, a heat resistant outer layer 54 is used. Preferably, this outer layer 54 is made of a polymer with a relatively high melting point, which acts as a protective layer on the aluminum foil and prevents contact between the intermediate layer 50 of the foil and the hot plates of the welding device. In addition, the high temperature resistant layer 54 acts as a heat transfer layer because this material does not melt and does not stick to the welding plates at temperatures used in the welding processes. Pressure and temperature can therefore be applied to the outside of the container without the need for special coatings. Preferably, the outer layer 54 may have a higher melting point than the inner layer 46 of the weld.

The high temperature resistant outer layer 54 is preferably made of polyethylene terephthalate (designated here as PET) from Rhone-Poulenc under the trade designation TERPHANE 10.21, which layer has a thickness in the range of 10-1.5 pm (0.4-0 , 06 thousandths of an inch). In the embodiment shown, the thickness of the film layers 14 of the multilayer laminate is preferably 13 pm (0.48 thousandths of an inch) for the outer polyester layer 54 resistant to high temperature, about 25 pm (1.0 thousandths of an inch) for the barrier layer 50 of foil aluminum and about 150 pm (6.0 thousandths of an inch) in the case of foil 46 with an internal 80:20 welded layer.

It has been found that preferred materials selected for the front 12 and rear 14 sheets, and which provide optimal properties of the peel seals 25 and 26, include an inwardly welded layer on each sheet containing an 80:20 film. Alternatively, the inwardly sealed layers of the front and back sheets may contain blends of polypropylene-polyethylene copolymer and thermoplastic styrene-ethylene elastomer at different percentages of these components; The relative percentages used will depend on the properties of the various welds considered for use in conjunction with the medical container and the temperature and pressure of the welding processes. Other types of flexible films that may be useful in making the front and back sheets of the container shell 10 of the present invention, as well as inwardly sealed layers on both sheets, are described in US Patent Nos. 4,803 102, 4,910,085, 5,176 634 and 5 462 526, to which this description is cited in its entirety.

In some applications, especially for multi-chamber containers, such as the container shown in Figs. 1-2, additional protection may be desirable. This may be especially true where the drug is exposed to steam contamination or degradation caused by visible spectrum or ultraviolet radiation, and therefore requires additional protection on the part of the front sheet 12 covering the intermediate chamber 23 (with the drug). However, such additional protection may be used on any number of compartments or even on the entire front sheet 12. This additional protection may be provided to prevent moisture, oxygen and / or light from entering the part of the front sheet 12 containing the second or intermediate chamber 23 and to protect 190 598 before decomposition. Such additional protection allows the container 10 to be stored for a significant amount of time without losing the effectiveness of the drug.

As shown especially in Figs. 2 and 3, an opaque film 55 with strong barrier properties has been used to cover the intermediate chamber 23. This opaque film 55 is a barrier to the penetration of water vapor and free oxygen into the drug chamber and in the embodiment is a multilayer laminated structure, which contains a layer of aluminum foil with strong barrier properties. The use of an opaque aluminum foil in the laminate helps to protect the drug contained in the intermediate chamber 23 from degradation due to exposure to invisible light and ultraviolet radiation. In the embodiment shown, the opaque aluminum foil including both the protective film 55 and the back sheet 14 surrounds the intermediate chamber 23 and prevents ultraviolet radiation from penetrating into the intermediate chamber 23 from each direction. The highly barrier protective film 55 may be a multi-layer laminate with an inner sealing layer 55 on its inwardly facing surface. In an exemplary embodiment, the heat seal layer 56 is a soft coextruded resin coated containing modified ethylene vinyl acetate polymer available from Dupont Chemical Company under the trade designation APPEEL 1181 with a thickness of 5-10 pm (0.2-0.4 thousandths of an inch). A layer of aluminum foil such as ALCAN 1145 with a thickness of 17.5-32.5 pm (0.71.3 thousandths of an inch), and preferably about 25 pm (1.0 thousandths of an inch) is bonded to the inner welded layer 56 by means of a suitable transparent glue 57. The outer heat dissipation layer 60, which is a polyethylene terephthalate (PET) film such as TERPHANE 10.21, approximately 12 pm (0.48 thousandths in) thick forms the outwardly facing surface of the highly barrier protective film 55. The heat dissipation layer 60 is bonded to the aluminum foil layer 58 by means of a suitable transparent adhesive 59. The adhesive layers 57 and 59 in the embodiment shown comprise a modified aliphatic polyester-polyurethane adhesive available from Liofol Company with the trade designation TYCEL 7909. Alternatively, the external transparent adhesive 59 may be a modified aromatic polyester-polyurethane adhesive, also available from the Liofol Company, under the trade designation TYCEL 7900. Due to the dangers of aromatic compounds penetrating either into the liquid diluent or into the liquid drug, the aromatic adhesive is only used on the outside of the aluminum foil layer 58. The inner adhesive layer 57 will preferably contain an aliphatic adhesive.

Since the inner heat seal layer 56 of the highly barrier protective film 55 may be a coextruded resin coated, it is capable of forming a peelable seal in a wide range of temperatures when applied to a wide variety of materials. Materials with which such co-extruded coated resin can form a peel seal include acrylonitrile butadiene styrene (ABS), high density polyethylene (HDPE), high impact polystyrene (HIPS), polypropylene (PP), polystyrene (PS), polyvinyl chloride vinyl (PVC) and 80:20 film that forms the front sheet 12 of the container. The highly barrier protective film 55 may therefore be releasably (tearably or separable) attached to the outer surface of the front sheet 12 covering the intermediate or drug chamber 23.

Preferably, the highly barrier protective film 55 is removed (torn off or separated) from the container 10 prior to use to allow visual inspection of the state of the drug in the drug chamber 23. In the exemplary embodiment, as best shown in Figure 1, the protective film 55 includes a projection 62 that can be gripped to tear the protective film 55 from the transparent front sheet 12. As a result, the contents of the drug chamber 23 are exposed to facilitate visual inspection .

The strongly barrier protective layer 55 may be welded and glued only to a part of the front sheet 12. Preferably, those parts of the highly barrier protective film 55 that are not welded to the underlying material of the front sheet 12 form a regular field or pattern of substantially circular raised recesses 51, which are the tangible residue of a welding rod in which a rectangular hole field is cut out. When this welding rod is pressed against the surface of the highly barrier protective film 55, welding is provided only in the areas of the contact surface of the welding rod and not in areas where mate16

190 598 rod bodies were removed (holes). Because pressure is applied during this process with heat, the highly barrier protective film 55 is subjected to inverse pressure from the welding head, resulting in a textured raised surface with cavities. The recesses 51 allow suitable sealing of the strongly barrier protective film 55 to the underlying material (front sheet) of the medical container, but at the same time ensure easy removal of the film 55 without applying excessive force.

If the entire protective layer 55 were sealed on the front sheet 12, then a relatively strong bond would be formed and a greater force than desired would be required to completely break it. By reducing the weld surface area, less force (proportional to the weld surface area) is needed to remove the opaque barrier that is being torn off. From the above description, it follows that the value of the force needed to remove the torn aluminum web is inversely proportional to the number of pits (51 of Fig. 1) formed in the film 55. Depending on the purpose of the medical container, it is easy to construct a harder or more easily removed highly barrier protective layer, only by increasing or decreasing the number of cavities made in this layer during the welding process. It should be noted, however, that the highly barrier film 55 has its entire circumference, except for projection 62, welded to the container material underneath. The formation of a complete peripheral weld around the highly barrier film 55 ensures that the barrier properties of the film apply throughout the drug chamber 23.

In practical use, the filled container 10 may be stored for some time prior to final use. Typically, before dispensing, the pharmacist or other user removes the strongly barrier film layer 55 from the front sheet 12 of the container 10 to visually control the integrity of the contents. If the container 10 is not used within this time, it is returned to the warehouse and put away until it is needed again. Removal of the tear-off strongly barrier film 55 leaves the contents of the container or, in particular, the drugs in the intermediate chamber 23 in a state prone to degradation under the influence of moisture, light and transmitted oxygen. It is desirable that the filled containers of the invention may be stored for up to 30 days prior to use without causing severe decomposition of the medical solution or drug due to moisture and free oxygen after the strongly barrier protective film has been removed from the drug chamber.

As shown in Figure 4, the transparent highly barrier film 64 of the intermediate laminate is optionally sandwiched between the highly barrier aluminum foil of the protective film 55 and the 80:20 material of the front sheet 12 of the container. Preferably, this intermediate laminated film 64 is placed on a portion of the front sheet 12 covering the intermediate chamber 23. In this configuration, the transparent highly barrier intermediate film 64 covers and protects the contents of the intermediate chamber 23 when the highly barrier protective film 55 is removed from the container 10. The transparent highly barrier intermediate film 64 has barrier properties that protect medical solutions and drugs against at least water vapor penetration and oxygen for a considerable time, which depending on the specific activity of the drug can last up to 30 days. In other words, the opaque strongly barrier protective film 55 in combination with the transparent highly barrier intermediate film 64 can be used to form a highly barrier protective coating on the intermediate chamber 23.

The definition of the protective cover as a highly barrier cover is associated with the degree of impermeability of this protective cover to various permeating gases. Polymers are classified according to the degree of containment of penetrating gases, e.g. oxygen or steam. These categories range from strong barrier activity (low permeability) to weak barrier activity (high permeability). The category in which the polymer is included may vary depending on the permeating gas. The concept of strong barrier used here with respect to water vapor transmission means a film with a permeability of less than 0.06 g / pm / m^_/ 24 h / at 30 ° C, 1θ0% relative humidity. As used here, the concept of strong barrier use in oxygen permeation means a film whose permeability is less than about 1 cm³/ pm / m724 h / at at 25 ° C, 100% relative humidity.

The transparent highly barrier intermediate film 64 can be a three-layer structure of a highly barrier laminate that has a high resistance to free penetration

190 598 oxygen and water vapor so as to protect the contents of the drug chamber and increase the storage time of the container with two components. In the embodiment shown, the intermediate layer 64 of the laminate film comprises an outer layer 66 of polyethylene terephthalate with embedded silica (also SiO-coated polyester)_x or SiO coated PET_x) from Mitsubishi Kasei with the trade designation TECH BARRIER H. Layer 56 of the highly barrier sealant sealant 55 is placed in contact with the outer layer 66 of intermediate laminate foil 64. Intermediate layer 68 containing coated silica (SiO_x) a polyvinyl alcohol (PVA) film from the Mitsubishi Kasei company with the trade mark TECH BARRIER S is bonded to the outer layer 66. On its inward surface the transparent strongly barrier intermediate film 64 has an inner welded layer 69 formed from a polypropylene-polyethylene copolymer. This copolymer can be mixed with a thermoplastic elastomer made of ethylene-butylene styrene in various proportions, but a 100% polypropylene-polyethylene copolymer layer is preferred. The individual layers of intermediate laminated film 64 are glued together. For clarity, these glue layers are not shown, but they contain a modified aliphatic polyester-polyurethane laminate available from Liofol Company under the trade designation TVCEL 7909. The inner welded layer 69 is attached to the outer surface of the front sheet 12 by suitable permanent welding or ultrasonic welding, by pressure-bonding, etc. The transparent strongly barrier intermediate laminated film 64 has both horizontal and vertical dimensions such that it covers the entire surface area of ​​the drug chamber and in addition, it was sufficient to cover the peel and permanent welds made at the drug chamber.

Similar to the flexible thermoplastic materials that make up the front sheet 12, the three-layer laminated structure of intermediate layer 64 is substantially optically transparent and transparent to allow control of the contents of the drug chamber 23. Unlike polyvinyl chloride (PVC) and other similar materials, which are quite cloudy (translucent), the intermediate layer 64 according to the present invention is transparent while maintaining significant protection against degradation due to moisture and free oxygen.

In particular, the barrier properties of the transparent, highly barrier intermediate laminated film 64 are much stronger than for conventional films such as low density polyethylene (LDPE), medium density polyethylene (MDPE), linear low density polyethylene (LDPE), ethylene copolymers - vinyl acetate (EVA) or a mixture of these polymers, in areas important for the operation of the container, e.g. in terms of moisture and oxygen permeability. The oxygen permeability through intermediate layer 64 is approximately 0.2 cm³/ Pm / m²/ 24 h / at. However, oxygen permeability through EVA, LDPE and MDPE copolymers is approximately 50 (EVA 5%), 166 (LDPE) and 170 (MDPE) cm respectively³/ Pm / m²/ 24 h / at. Oxygen permeability through LLDPE is approximately the same or slightly higher than through LDPE. Thus, the oxygen permeability of the transparent high barrier intermediate layer 64 is whole orders of magnitude less than the oxygen permeability of polymers typically used to build medical containers for two components. In other words, the barrier properties of the highly barrier intermediate layer 64 are several orders of magnitude better than the barrier properties of polymers typically used to build such containers.

Due to the barrier properties of the intermediate laminated film, the peel-off protective film containing aluminum foil can be removed by a pharmacist to visually inspect the contents of the container prior to dispensing, and then the container can be stored for a reasonable additional time without the risk of drug degradation under the influence of oxygen or moisture. After removing the protective film layer, it is desirable that the container be stored for about 30 days. After removing the aluminum foil layer, the exact storage time of the container that contains the transparent, highly barrier laminated film 64 depends necessarily on the sensitivity of the drug contained in the intermediate chamber 23 to moisture or oxygen. Drugs with relatively low moisture sensitivity can remain effective for a period of significantly longer than 30 days by being protected by a transparent highly barrier laminated film 64. In addition, drugs with very high moisture sensitivity, i.e.

190 598 re normally start to lose their effectiveness after exposure to steam by removing the aluminum foil layer, they can be stored for up to two weeks without losing their effectiveness due to moisture barrier properties of the transparent strongly barrier film covering the intermediate chamber 23.

Although the intermediate film 64 has been described in the embodiment as being attached to the outer surface of the drug room, it is obvious to those skilled in the art that the intermediate layer may be sized to cover both the intermediate chamber and the first chamber. Intermediate film 64 can also be used to cover the entire front sheet 12. The method of attaching the intermediate layer 64 to the outer surface of the container can also be changed without departing from the spirit or scope of the invention. The intermediate layer 64 can be permanently attached to the outer surface of the container by means of a suitable adhesive, as well as by permanent welding or ultrasonic welding. Alternatively, intermediate film 64 can be detachably placed on the surface of the container by adjusting the temperature and pressure during welding to obtain a peel welding. In this case, the film 64 can be peeled off the container 10, as in the case of the opaque strongly barrier laminated film 55.

It should be noted that in the embodiment the drug is described as being in the form of a liquid. The drug may also be in the form of a colloid, crystalloid, liquid concentrate, emulsion, etc. In addition, the drug may be in the form of a dry powder, as in the case of antibiotic compositions or anti-drug compositions, with non-limiting examples being: cefizolin, cefuroxime, cefotaxime, cefoxitin , ampicillin, nafcillin, erythromycin, ceftriaxone, metoclopramide and ticar / clav. Intermediate chamber 23 does not need to be filled with medicine. Other medical compositions such as lyophilized blood fractions, blood factor VIII, factor IX, prothrombin complex etc. can be dispensed particularly advantageously from the container according to the invention. Although a container according to the invention with multiple chambers and in particular with a single drug chamber and a diluent chamber according to the invention has been described single-chamber containers may be used, as will be described in detail below. In addition, containers that have a plurality of chambers filled with different diluents and various drugs can also be provided according to the present invention.

Although preferred materials for the transparent, highly barrier intermediate film 64 will include both an oxygen barrier layer and a moisture barrier layer, other materials may be used to provide a drug chamber covering suitable for a variety of specific applications. For example, one of the highly barrier layers may be omitted to provide a highly barrier intermediate film that contains only a moisture barrier layer or only an oxygen barrier layer. In addition, the highly barrier intermediate film 64 may include a moisture barrier layer as described above in conjunction with a detachable weld layer that is made of a high melting material that also has some oxygen barrier properties.

Preferably, the flexible container 10 can be made with a specific overall dimension or with several dimensions. This reduces the need for multiple machines or alternatively many machine settings. As discussed previously, the single overall dimension of the container, such as the dimensions of the rectangle around the common edge edge 16, facilitates the handling of the container as well as the administration of the medical solutions contained. In particular, this allows manufacturing, handling, sterilization and labeling of containers 10 with similar or identical machines and procedures, and eliminates the need for various tooling and machine runs. However, limiting the overall size of the container 10 limits the amount of medical solution that each chamber can hold.

In order to increase the capacity of the container 10 and in accordance with the principles of the present invention, at least one of the sheets 12 and 14 is elongated or otherwise permanently stretched. Increasing the capacity of the container 10 makes it possible to make a single container model for storing and administering a much larger number of different combinations of medical solutions and drugs. Since the enlarged containers are unchanged compared to conventional containers, there is no need to change the tooling to produce these bags with special dimensions. This is especially beneficial where

190 598 smaller quantities of containers may be needed, which otherwise could not be produced for cost reasons. Figure 5 shows a conventional or standard sized container 10 in which both the front sheet 12 and the back sheet 14 are stretched stably to increase the capacity of the first chamber 22. In particular, the front sheet 12 and the back sheet 14 contain a corresponding surface area 70. These respective surface areas 10 are opposite each other with a common plane 71, which is generally formed along a common peripheral edge 16. The front sheet 12 and rear sheet 14 have been enlarged by permanently stretching the respective surface areas 70.

In the embodiment shown, only the first chamber 22 has been enlarged. This configuration can be particularly useful when an amount of diluent larger than normal for use with a normal amount of drug is needed. The front sheet 12 is stretched more than the back sheet 14. This is especially true where the back sheet 14 contains an aluminum layer or other less stretchable layer.

Production and assembly of the container

Based on Fig. 6, a method for producing and assembling the flexible container 10 will now be described in accordance with the practice of the invention. The front sheet 12 and back sheet 14 are placed facing each other. The inwardly facing layer of the front sheet 12 includes an 80:20 film which is in contact with the inwardly facing 80:20 layer of the rear sheet 14. Other inwardly directed films may be used that do not fall outside the scope of the present invention.

The composition of the front and rear sheets 12 and 14 of the container 10 allows a weld to be made along the common peripheral edge 16 and peelable welds 25 and 26. Hot rods or dies with different temperatures, pressures and application times are used to bring inwardly returned parts of the materials and laminates used to temperatures close to or above their melting points, to allow material migration through the contact surface to thereby create a bond with the desired strength and properties.

The procedure for producing the container 10 is described either in the case of a single-layer film or in the case of a laminated multilayer film, forming a front sheet 12 and a laminate with aluminum foil, forming a back sheet 14. This procedure involves cutting the front and back sheets of the container to the desired vertical dimensions of the container, but with horizontal excess.

If the container 10 is built with a single-layer front sheet 12, the highly barrier protective layer 55 comprising the aluminum foil (of Fig. 3) and the transparent highly barrier intermediate layer (64 of Fig. 4) containing the strong barrier covers of the second chamber 23 are cut to size, placed on an area that will become an intermediate or drug chamber and then attached to the container's front sheet 12. According to the invention, the transparent highly barrier intermediate layer 64 is first laminated on the surface of the front sheet 12, followed by a protective layer 55 comprising aluminum foil.

In particular, the transparent strongly barrier intermediate layer 64 is placed on the second chamber 23 and held in place by means of a pair of rods or similar devices during its lamination on the surface of the front sheet 12. Part of the layer 64 in contact with the rods is therefore inaccessible for example to the welding head due to which a small part of the film is not welded on the surface of the front sheet. The residue from the use of rods for attaching the transparent highly barrier intermediate layer is the non-welded surface that marks the rod. The contact surface of the rod is usually circular, whereby there are two circular non-welded areas 41, which remain visible due to the inverse impression caused by the pressure applied during the welding process. After lamination of intermediate layer 64, an aluminum foil layer 55 is applied to its surface using a welding matrix having a certain pattern as described above.

After attaching the aluminum foil layer 55 and the transparent highly barrier layer, the front sheet 12 and back sheet 14 can be brought together and permanently welded along

190 598 of the outer peripheral edge 16. The outlet 30 may include a flange 34 which is inserted into its desired end position between the front and rear sheets 12, 14 and is fluidly connected to the outlet chamber 24. The outlet 30 may be injection molded and may be foldable. with 40% FINA Z9450 polyethylene-polypropylene and 60% thermoplastic styrene-styrene Kraton ™ G1662 thermoplastic elastomer. After introducing the outlet opening 30 along the common peripheral edge 16, a heated matrix is ​​used to form a permanent weld between the outlet flanges 34 and the bottom side 20 of the front and rear sheets 12, 14 at the flange 34.

Then, tear welds 25 and 26 and any additional tear weld separating the chambers and container 10 are made, using e.g. double hot rods, including the front rod in a position compatible with the rear rod, gripping the front and rear sheets 12, 14 between them to form welds 25 and 26. For example, the front bar may be in contact with the previously combined strongly barrier protective film 55, intermediate films 64, and front sheet 12. This front stick has a temperature kept in the range of 245-265 ° F (118-129 ° C). The rear bar that contacts the back sheet 14 is maintained at substantially the same temperature as the front bar (in the range of 245-265 ° F (118-129 ° C)) and may optionally include a thin rubber coating to ensure uniform pressure application. These double rods are pressed to contact the front and back sheets with a pressure in the range of 230-340 psi (1.6-2.3 MPa), this temperature and pressure being maintained for about 1.5-2.5 s. Tear welds 25 and 26 can also be made individually with a single set of two rods or simultaneously with a double set of two rods. Any additional tear welds can easily be made with a triple set of two rods.

After the tear welds 25 and 26 are formed, the front sheets 12 and rear 14 are brought into contact with each other and permanently welded along the perimeter along a common peripheral edge 16. This permanent weld is spaced from the oversized edge of the first side 27 of the container and forms holes between front sheet 12 and back sheet 14. In other words, this permanent weld is continuous along the vertical upper side 18, the second side 28 and the vertical lower side 20, and intermittent along the first side to allow access to the first and second chambers 22 and 23. This permanent weld has no effect on the fluid connection outlet opening 30 with outlet chamber 24.

The first sacrificial opening 72 can be inserted between the front and rear sheets 12, 14 and fluidly connected to the first chamber 22. In a similar configuration, the second sacrificial opening 74 can be inserted between the front and rear sheets 12, 14 and fluidly connected to the second chamber 22. Preferably each of these sacrificial holes 72 is positioned and supported along a common peripheral edge 16 of the first side 27 within the slots in a permanent weld. Sacrificial holes may be supported by a common peripheral edge 16 in a configuration similar to outlet 30. Each sacrificial hole 72 and 74 includes tapered mounting flanges 73 that are positioned and welded between the front and rear sheets 12, 14 along the common peripheral edge 16 of the first side 27. Sacrificial holes 72 and 74 may be injection molded. Preferably, sacrificial holes 72 and 74 are made of cheap thermoplastic material because they will be removed and discarded in the last stage of the process. In particular, sacrificial holes 72 and 74 may be made of re-ground 80:20 foil material, ordinary polypropylene or other similar material.

Sacrificial holes 72 and 74 are an important feature of the present invention and are means for aseptic filling of a single-chamber container with a medical solution or a multi-chamber container with liquid diluents in the first chamber 22 and the drug etc. in the second chamber 23. In addition, sacrificial holes 72 and 74 have a design that allows the holes these and thus the flexible medical container 10 were supported and manipulated by automated robots.

As shown, each sacrificial opening 72 and 74 includes a lower flange 78 and spaced apart upper flange 80. Each of the flanges 78 and 80 may be substantially rectangular or otherwise shaped to facilitate handling. In particular, each of the flanges 78 and 80 may be configured to be operated by means of a support and handling device. An internal opening extending through each of the sacred openings 72 and 74 provides connection to each of the respective chambers 22 and 23.

A substantially cylindrical hubcap or plug 82 is provided for each of sacrificial holes 72 and 74. Caps 82 may be made with an external average that is slightly larger than the inner hole of each of sacrificial holes 72 and 74, so that when cap 82 is inserted, the surface couplings between the outer diameter of the hubcap and the inner diameter of the hole ensure a hermetic seal. This friction seal is required so that particles of solid material cannot get inside the container 10 before filling and to prevent powdered drugs or liquid diluents from escaping from the interior after aseptic filling of the container. Preferably, each of the hubcaps 82 may have a sloping bottom edge so that it engages with a similar slant at each of the respective sacrificial holes 72 and 74.

In addition to the flanges 78 and 80, these holes have a pair of vertically spaced flanges provided on the cap 82. In the embodiment shown, essentially the peripheral upper flange 84 forms the top of the cap 82. This upper flange enables the lifting mechanism to engage under the upper flange 110 and forms an element for vertical lifting of the hubcap from the respective sleeve bushing 72 and 74. A lower flange 86 may also be provided around the hubcap 82. This lower flange 86 limits the depth of entry of hubcap 82 when inserting the bore 72 and 74 into the sleeve, or when re-seating after the filling operation. The lower flange 86 can be completely circumferential, or alternatively it can be made as a partial flange simply forming a lateral extension of the hubcap body 82. The upper and lower flanges 84 and 86 are spaced apart along the cap body 82.

These manufacturing steps form the described flexible container 10 with a conventional configuration with non-enlarged chambers 22 and 23. As discussed previously, the first chamber 22 can be enlarged to increase the available space for storage of the diluent. In a similar manner, the second and outlet chambers 23 and 24 can also be enlarged. This may consist of permanently stretching the front sheet 12 and / or back sheet 14 by inflating the respective chamber 22, 23 and 24 with compressed gas, as will be described in more detail below.

The device for making the container

According to the practical implementation of the principles of the present invention, the procedure and device for producing the container 10 of Fig. 6 will now be described with reference to Fig. 7. As follows from the description of the device for producing the container below, both the device and the procedure are adapted for producing medical containers, in which the front and back sheets comprise either a single-layer film or a multi-layer laminated film. Furthermore, the following description will show that the number, shape, configuration and positioning of the various welds of the container 10 of Fig. 6 can be easily changed or even omitted due to the modular design of the device components.

Figure 7 is a semi-schematic top view of an embodiment of the container manufacturing machine 88 of the present invention showing the structure and location of various weld forming stations and the structure and configuration of the spools providing film webs to the container.

The material for the front and back sheets (12 and 14 of Fig. 2, for example) of the container is delivered to the machine 88 producing containers in the form of spools 90 and 92 with a film web that are mounted at the supply spool stations at the entry end of the machine 88 for manufacturing containers. Material web e.g. from the front sheet spool 90, it is threaded through a guide station 94, which is intended to keep the web of material under the correct tension when the web is pulled through the remaining machine stations 88.

After the guide station 94, the web of material is transported through the vacuum feed wheels through the first web cleaning station 96, and then through a series of optional barrier film 98 and 100 stations, arranged in series along the web path. If the container 10 is constructed in the manner previously described, i.e. it comprises a single-layer front sheet 12 which is highly transparent

190 598 a narrow intermediate film (64 of Fig. 4) and a highly barrier protective layer 55 containing aluminum foil, the strong barrier covers for the second chamber 23 are first cut to size, then placed on a part of the surface area 70, which will become the second chamber, and then successively attached to the front sheet 12 of the container 10 at the barrier 98 and 100 application stations respectively. According to the invention, the transparent highly barrier intermediate layer is first laminated on the surface 70 of the front sheet 12 at the application station 98, and the protective layer 55 containing the aluminum foil is applied at the station 100.

In a similar manner, the web of material that forms the back sheet of the container is threaded from the respective spool 92 with the web through the respective guide station 102 and is transported through the vacuum feed wheels through the respective web cleaning station 104.

When the continuous films of the front and back sheet web materials 90 and 92 leave their respective preparation steps, they are guided in such a way that the 80:20 surfaces of each continuous flat film are facing the 80:20 flat surface of the second film. After bringing the continuous film webs 90 and 92 to a compatible position, the web material is continuously displaced longitudinally through the welding core 106 of the device 88. Sacrificial holes 72 and 74 first for diluent and second for drug are placed along the applied webs and between the webs of the front and back sheets, and then different welds are sequentially formed on the material of the applied webs so as to connect the webs together and essentially form a container 10 to the intermediate stage, when it is suitable for expansion and aseptic filling, as best shown in Fig. 6.

According to the practical implementation of the principles of the invention, the welding machine core 106 comprises a plurality of welding presses and hole insertion stations arranged in series along the path of movement of the adjacent container webs of foil. The first such station is the opening insertion station 108 in which the outlet opening 30 is brought into its correct position between the front sheet 12 and the rear sheet 14. The heated press containing the shaped die is clamped onto the web material to form a weld between the outlet opening flange 34 and the bottom end edge of the front and rear sheets at the collar at the opening welding station 110.

The outlet opening 30 is made of plastic by injection of a composition composed of 40% FINA Z9450 polypropylene copolymer and 60% thermoplastic styrene styrene ethylene butylene shell Kraton G1652. Due to the similarities between the composition of the hole material 30 and the material of the inner weld forming surfaces belonging to the front and back sheets, it can be seen that the front and back sheets can be welded to the hole flange 34 using a substantially similar welding regime as that used in the manufacture of a permanent peripheral weld , which will be described in more detail below.

After introducing the opening 30 and welding it to the container material, the adjacent foil webs are moved to the sacrificial opening introduction station 112, where the sacrificial holes (72 and 74, Fig. 6) are inserted between the front and back sheets at locations along the first side of the container and connected to the places that will become the first and second chambers 22, 23. These sacrificial holes 72 and 74 are preferably injection molded from a material composed of 100% polypropylene, but can also be made of a material with a composition similar to the material of the outlet 30. In a manner similar to the outlet 30, the front and back sheets are welded to sacrificial holes 72 and 74 along tapered flanges 76, which are provided for this purpose.

After introducing sacrificial holes 72 and 74, the film material of the front and back sheets are joined together by a permanent weld along a portion of the common peripheral edge 16 that extends through the place that will become the top 18, bottom 20 and one continuous side 28 of the finished container. Along the opposite side 27 of the container 10, a permanent weld is made parallel to the peripheral edge 16 of the adjacent foil webs, but at a distance from that edge, and is made intermittently along the desired edge of the finished container slightly inward from the common peripheral edge 16.

190 598

-:23

After formation of the peripheral weld at station 114, the container material is moved to the first optional sacrificial welding station 116 of the drug well. The material of the front and back sheets is heat sealed to the tapered collar 76 of the second sacrificial opening 74 by pressing the material of the front and back sheets against this tapered collar of the hole through a pair of concave conformal heated welding dies. As was the case with the first hole matrix, the heated welding matrix of the second welding station 116 is conformably shaped so that when the two halves of the welding matrix are pressed together, they form a substantially elliptical cavity having a shape that is a mirror image of the convex tapering welding surface of the second sacrificial hole .

Then, the web material is moved to the second optional sacrificial welding station 118 of the first chamber, where the material of the front and rear container sheet is pressed and welded to the tapered flange 76 of the first chamber.

It should be noted that the order of sealing the sacrificial holes to the container is arbitrary and that the second sacrificial hole welding station 116 can equally easily follow the first sacrificial hole welding station 118 and vice versa. Furthermore, the welding stations for sacrificial holes 72 and 74 with the container may be located before the peripheral welding station 114. In addition, a further optional welding station, tear weld forming station 120, which is shown in Figure 7 as following sacrificial opening insertion station 110, and before the circumferential welding station 114, is optionally provided for forming tear welds between first side 27 and the opposite second side. 28 of container 10. Tear welds divide container 10 into multiple chambers. Alternatively, the optional tear welding station 120 may be configured to precede the sacrificial opening insertion station 112 only by changing the position of the tear welding station along the path of the film web. It will also be apparent that multiple tear welding stations can be envisaged if the container is to be manufactured with multiple chambers.

It should be obvious to those skilled in the art that many subsequent, but independent, welding stations can be configured to operate automatically when the film web is moved to the appropriate stations. Alternatively, the welding stations may be located in the container making machine, but they are not active, so that their specific welds are not produced at a given production run. In particular, the container may be manufactured without any tear welds, as will be described in more detail below. After the sacrificial holes are welded, the material of the container web is moved to the equalizing welding station 122, which creates a permanent weld of the container material that contacts and overlaps the broken portions of the permanent weld along a common peripheral edge and extends to the edge of the container film material.

After the welding steps, the container can be moved before a hanger punching station 124, which makes a hanger cutout in the middle at the top of the container. Further stations 126 and 128 separate the containers by cutting the web at the lower end 20 (126), and then the upper leveling station 128 cuts off the material of the container at the upper end 18, after which the container is discharged from the machine 88 and its production is substantially completed.

It will be obvious to a skilled person that the number and configuration of the chambers of a container is determined only by the number and positioning of the various welds used in making the container. In addition, depending on the number of containers making up the final product, the appropriate number of sacrificial holes are placed along the respective edges of the material web. It is understood that the modular manufacturing process of the present invention is suitable for the production of medical containers having one main chamber or multi-chamber containers with any number of chambers, the adaptation being only by making additional peelable welds and using additional sacrificial holes through which the chambers are filled . For every confi24

190 598 cavities and sacrificial holes, the pressure zone welding press at the level 122 welding zone can be reconfigured by removing one press surface and replacing with another that is adapted to create one, three, four etc. channels or holes so as to connect multiple holes sacrificial with many chambers.

In a similar manner, it will be apparent to those skilled in the art that the composition of the front and back sheet of the container can be altered by appropriately replacing the spools with the foil of the front sheet and the back sheet with the spools with other suitable materials. In particular, both the front and back sheets can be made of a single-layer 80:20 film, so that the finished container is transparent on both sides. Due to the modular nature of the device producing the transparent barrier application station and the foil barrier application station, they can be turned off, as well as the tear weld production station, which will result in a machine for producing single-chamber containers that are completely transparent and which may have a plurality of outlet openings, such like separate medicine holes and adjustment holes.

The container making machine of the present invention is therefore suitable for producing a wide variety of medical containers with a wide range of sizes, a wide range of weld configurations and hole locations. All containers thus produced will be capable of being expanded to increase their capacity and then filled under aseptic conditions in accordance with the principles of the present invention, as well as for use in conjunction with the final sterilization procedure, if necessary.

Production of welds

The tear weld seams 25 and 26 produced during the production process described above are straight seams of thin rectangular shape. Although they have a similar appearance to conventional straight-line welds, the burst welds of this embodiment are improved in that they exhibit more predictable tearing properties in production batches, i.e., they exhibit equal pressure resistance when manipulated.

Without theoretical restrictions, it is believed that the tearing of the welds is obtained by limiting the time, pressure and temperature to those necessary to melt the transition surface between the inner layers of the front and back sheets that have a lower melting point than the intermediate layer and the outer layer of the back sheet. The depth of structure change in the inner layers in the melting zone is limited, making the weld susceptible to tearing, yet it has sufficient strength to prevent cracking during normal container handling. Preferably the activation force of the container 10 of the present invention is strictly controlled to ensure the integrity of the container under extreme handling conditions and yet easy activation for all users. This activation force is characterized by a burst pressure, which is preferably about 4 ± 1psi (21.6 + 6.9 kPa). Preferably, this pressure may be slightly increased to accommodate the larger volumes associated with the enlarged containers described herein.

To achieve such a uniform burst pressure, the previous paragraph of a substantially rectangular weld, the critical parameter that must be controlled is, as stated, the temperature. Uniform burst pressure characteristics are obtained by controlling the welding temperature within ± 2 ° F (1.1 ° C). Commercially available production welding devices are not suitable for controlling changes in welding temperature within this desired range. However, the welding time can be controlled very accurately. Therefore, the time was chosen as a controlled parameter and it is adjusted to compensate for the change in welding temperature. The time and pressure of the welding head are controlled to ensure that they are within acceptable ranges as described above, and the welding time is adjusted accordingly. Although the contact pressure is preferably in the range of 1.6-2.3 MPa (230-340 psi), those skilled in the art will recognize that the lower range limit (about 230 psi (1.6 MPa)) is established for convenient setting of welding machine production parameters. Until the pressure exerted by the welding rods on the material

190 598 of the container is enough to bring the layers of welded material into contact with each other in the surface of the desired weld, at a suitable temperature and time a burst will be formed. Indeed, it has been experimentally found that changes in welding temperature and time beyond the limits contemplated by the present invention cause welds that not only do not exhibit the desired property of uniform strength, but also do not tear completely along the length of the weld. Incomplete rupture of the weld often causes diluent residues to remain, e.g., enclosed in 90 ° corners, where the torn weld is in contact with permanent container circumferential welds. Therefore, the ratio between the diluent and drug mix may not be as expected and the drug may be administered at a higher concentration than necessary.

Examples of specific time, temperature and pressure settings that will produce tear welds in 80:20 film in the embodiments shown at a burst pressure of 4 ± 1 psi (27.6 ± 6.9 kPa, include: 235 psi (1.6 MPa) , temperature 257 ° F (125 ° C) and time 1.9 s, as well as pressure 235 psi (1.6 MPa), temperature 263 ° F (128 ° C), time 1.75 s.

Higher temperatures and associated pressures and times are used to ensure permanent peripheral welds and welding of the outlet holes, which affects the change of structure over a larger part or depth of the welded layers. Such welds can be formed by welding at 143 ° C (290 ° F) and pressure up to 200 psi (1.4 MPa) for about 2 s. It will be appreciated by those skilled in the art that various techniques for making both permanent and peelable welds can be used in the construction of the container of the present invention. In particular, it is obvious that controlling the welding temperature to a greater extent (i.e. within about ± 1.1 ° C (2 ° F)) will also allow the formation of tear welds with uniform burst pressure. In addition, time was chosen as the parameter for controlling weld formation because it can be accurately controlled. The same results can be obtained by accurately controlling temperature and / or pressure.

Ventricular enlargement

After bringing the container 10 into the state of manufacture shown in Fig. 6, its volumetric capacity can be increased according to the principles of the present invention. In particular, each of the chambers 22, 23 and 24 can be expanded or otherwise enlarged to increase capacity. For example, the first chamber 22 can be stretched permanently to increase the amount of diluent stored. This can be advantageous especially where a smaller dose is needed or where a more concentrated drug is used.

The first chamber 22 can be stretched by stretching the front sheet 12 and / or back sheet 14 outward from the common plane 70. Such stretching lengthens the film layers that form the front or back sheet 12, 14 in both longitudinal and transverse directions. Chambers 22, 23 and 24 can be extended or extended to varying degrees to accommodate various increases in volumetric capacity.

For example, as best seen in Figure 5 in conjunction with Figure 6, the first chamber 22 can be enlarged by temporarily supplying compressed gas to the first sacrificial opening 72. The compressed gas inflates the first chamber 22 and exerts an expanding force on the surface of each sheet 12 and 14, front and rear. This force permanently stretches the materials of the front and back sheets 12, 14. Preferably, the first chamber 22 is permanently stretched or extended both in the machine direction and in the transverse direction by compressed gas to the desired capacity. In order to facilitate the proper stretching and shaping of each of the sheets 12, 14, front and rear, a tool or mold with shaped cavities may be used, as will be described in more detail below. The compressed gas may be compressed air. However, other compressed gases or even liquids can also be used. Preferably the compressed gas is air or nitrogen filtered through 0.2 micrometres.

Figures 8-10 show an alternative embodiment of a single-chamber flexible medical container according to the principles of the present invention. In this embodiment, features similar to those of the previous embodiment have similar reference numerals with the letter a. As shown, the flexible container 10a can be used for joint storage and administration of a medical solution.

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In this example, the front sheet 12a and usually the opposite back sheet 14a are welded together along a substantial portion of the common peripheral edge 16a to form one volume cover 17a. If desired, this volume cover 17a can be divided into two or more separate chambers by means of peelable welds that extend from the first side 27a of the common peripheral edge 16a to the opposite second side 28a of the common peripheral edge 16a and separately connect the front and back sheets 12a and 14a with each other as previously described.

A pair of spaced apart sacred holes 72a and 74a may be supported along the first side 27a of the common peripheral edge 16, and the outlet opening 30a may be supported along the bottom 20a. Holes 72a, 74a and 30a are placed between the front and back sheets 12a and 14a along breaks in the permanent weld and are welded in place as previously described. Openings 72a, 74a and 30a are preferably provided as part of this single-chamber container 10a to facilitate the expansion of the volume cover 17a, as well as to use conventional handling and manufacturing devices. Openings 72a, 74a and 30a and their preparation may be the same as in the case of the multi-chamber container described above.

At this stage in the manufacturing process, the container may be enlarged or, alternatively, it may retain its unstretched volume cover as it is after manufacture and proceed to the aseptic filling step. In the example of Fig. 8 the container 10a may be manufactured having a substantially flat front sheet 12a composed of a single polymer layer as previously described, and a similarly sized opposing flat back sheet 14a of a multilayer laminate, as also described previously. The previously described transparent layers and opaque barrier layers were omitted. Without a drug chamber, these barriers are essentially unnecessary. However, these barrier layers can be added or otherwise used if, as will be described below, a multi-chamber embodiment with an enlarged chamber or chambers is needed.

The container 10a of Fig. 8 has a length or vertical height, respectively, along the first and second sides 27a and 27a of approximately 21 cm (8.25 inches) and a width across the upper end and bottom 18a and 20a of approximately 13.3 cm (5, 25 inches). In this embodiment, a permanent weld along the common peripheral edge 16a may form a volume cover 17a with maximum flat dimensions of approximately 18 x 9 cm (7.0 x 3.5 inches). These dimensions are approximate and do not include open spaces between sacrificial holes 72a and 74a and volume cover 17a. The described container 10a thus has an area of ​​70a approximately 158 cm² (24.5 square inches) for each of the 12a and 14a sheets, front and back.

In the manufactured state, this single-chamber container 10a has a capacity of approximately 130-150 ml. By way of example only, this capacity is simply determined by filling the volume cover 17a with liquid and then measuring the amount of liquid in the graduated cylinder. However, within the general rectangular limits of the container described, a larger capacity may be desirable. As already discussed, the total capacity of the container 10a can be significantly increased by stretching at least one of the sheets, front or rear, volume cover 17a. This may include stretching each of the sheets 12a and 14a to a different degree. Preferably, the stretched front and back sheets 12a, 14a are stretched outwards or away from the common plane 71 a, as best shown in Fig. 9, so that each of them forms the curvilinear surface best shown in Fig. 10. The flat adjective used here with respect to the front and back sheets 12a, 14a relates to the respective sheets before enlargement.

In some applications it may be desirable to stretch only one of the front or rear sheets 12a, 14a. In such cases, the front sheet 12a is the most likely candidate for enlargement. This is usually because the back sheet 14a contains an aluminum foil layer or similar barrier layer and necessarily has a smaller modulus of elasticity and generally inferior tensile properties. Since the front sheet 12a is a substantially homogeneous layer with better tensile properties, greater stretching is obtained when the front sheet 12a is lengthened compared to the back sheet 14a. In addition, the back sheet 14a is often used for markings,

190 598 such as administration and mixing instructions. Printing may be less effective on stretched and curved sheets. Reading printed information on a permanently stretched curvilinear sheet can also be difficult. However, for specific applications, only back sheet 14a can also be stretched.

Regarding the elongation of the front sheet 12a or back sheet 14a in a container made according to the present invention, it is worth noting that the elongation properties of the front and back sheets depend on the specific materials from which they are made. The physical tensile properties of the various monolayer and multilayer films used in making the medical container are relatively easily determined by the methods given in ASTM D-882-81. Typical tensile properties of the various monolayer and multilayer film components described above can be obtained from the film manufacturer based on the film's technical datasheets. For example, the KRATON G1652 ethylene-butylene styrene elastomer usually has a tensile strength of about 31 MPa (4500 psi), has approximately 500% elongation at break, and has a 5 MPa (700 psi) modulus at 300% elongation. Similarly, the Fina Z9450 copolymer usually has a tensile strength of 17.25 MPa (2500 psi), while the aluminum foil layer (ALCAN 1145) has a tensile strength of approximately 64 MPa (9300 psi) (0.001 thickness) and usually a stretch of about 4.2% (at 0.001 thickness). It is understood by those skilled in the art that other films having different tensile strengths and different tensile properties will necessarily be stretched to a greater or lesser degree than the films described above. These other elongation properties can easily be calculated from data from ordinary tests carried out at uniform jaw spacing speeds, uniform temperatures and uniform sample shapes, such as a oarsaw sample cut using the ASTM C matrix.

Referring to Figs. 11-12, an embodiment of a tool or mold 130 according to the present invention for use in enlarging the container 10a according to the present invention will be described. The tool 130 is configured to receive at least part of the volume cover 17a. This tool 130 includes an upper part 132 and an opposite lower part 134. In the embodiment shown, the lower tool part 134 has a cavity 136 inside, and the upper tool part 132 has an opposite internal cavity 138. A flat outer surface 140 surrounds each of the cavities except for the opening 142 at one of the holes 72a, 74a and 30a. Other tool configurations may include a part 132 or 134 of the tool that has no cavity but has a substantially flat surface. This configuration is advantageous when only the front sheet 12a or rear sheet 14a expands. Other configurations include changing the dimensions and shape of each cavity 136 and 138 to adjust the longitudinal shape of the front and rear sheets 12a, 14a.

The tool 130 may also include coupling devices 144, such as wall plugs and corresponding holes, to ensure that the upper and lower tool parts 132, 134 remain stationary and locked together when the tool is used. However, any other device or method may be used to keep the upper parts 132 and 134 in a position compatible with each other and together. Sealing lip 146 may circumferentially surround at least one of the cavities 136 and 138 and follow the weld seam of the enlarged chamber. This sealing lip 146 holds the front sheet 12a and back sheet 14a together during the stretching process and retains the compressed gas within its limits. Due to this, the inflating forces are not substantially transferred to the permanent weld along the common peripheral edge 16a. Sealing lip 146 may include an O-ring or similar device and may be provided on each of the tool parts 132 and 134, or alternatively only on one of these tool parts. Sealing lip 146 is preferably broken around the opening 142. Thus, compressed gas can flow into and out of the volume cover 17a. Preferably, the opening 142 is located at one of the openings 30a, 72a or 74a to allow inflation through this opening and the evacuation of gas.

In the embodiment shown in Fig. 11, the tool 130 is configured to receive the entire volume cover 17a of the single-chamber container 10a. The container 10a is placed on the lower part 134 of the tool with the outer surface of the front sheet

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12a facing the inside of the lower cavity 136 and with a common peripheral edge 16a supported by a flat surface 140. The welding boundary 146 is located just on the inside of the permanent weld along the common peripheral edge 16a. A pair of spaced apart slots 148 for sacrificial holes are located along the common side of each of tool parts 132 and 134, each of which is configured to receive one of sacrificial holes 72a and 74a. The outlet opening 150 is located along the second common side of the tool parts 132 and 134 and is adapted to receive the outlet opening 30a.

After positioning the container 10a within one of the tool parts 132 and 134, and preferably the bottom of the tool, as described above, opposing tool parts can be connected to each other. The upper part 132 of the tool can be positioned at the lower part 134 of the tool and in accordance with it such that the outer surface of the rear sheet 14a faces the upper cavity 138 and the holes 30, 72a and 74a are located in the slots 148 and 150. The flat surface 140 of the upper tool part 132 is mounted on the flat surface 140 of the lower tool part 134 and immobilizes the entire common peripheral edge 16a except for the opening 142. The opening 142 allows the inflow of compressed gas to the first sacrificial opening 72a and the outflow of that gas. The layered container 10a can now be inflated with compressed gas to inflate the volume cover 17a and forcibly stretch the front and rear sheets 12a, 14a into cavities 136 and 138.

The tool 130 can also be provided in any other number of configurations that can be determined by those skilled in the art, and therefore the embodiment should not be considered limiting. Additional exemplary embodiments may include a tool with differently sized upper and lower cavities, or a tool in which one part has a cavity and the opposite surface of the tool is flat. Such an embodiment can be particularly useful where only one of the sheets 12a, 14a is to be stretched. Alternatively, the tool may have a number of different cavities in each part of the tool for use with multi-chamber containers. Such an embodiment may require an opening in each of the various cavities for inflating different chambers or flat surface sections on each of the parts of the tool to support the tear welds forming each of the chambers. When only one chamber of a multi-chamber container is enlarged, each part of the tool may contain only a single cavity, but the cavity has a size slightly smaller than e.g. the outer diameter of the chambers.

Slots 148 for sacrificial holes and slot 150 for outlet can be configured so that the container 10a is aligned in position within tool 130. They can therefore include grooves for receiving flanges 78a and 80a on sacrificial holes 72a and 74a, or have other configurations for fixing the location of each hole. Alternatively, only one or two of the apertures 148 and 150 may be configured in this way. However, other devices and methods known to those skilled in the art can also be used to align the container 10a within the tool 130. For example, alignment grooves may be provided along the flat surface 140 for receiving at least part of the top, bottom or sides 18a, 20a, 27a and 28a of the container 10a. Alternatively, a slot, cut, or other positioning element (not shown) may be provided on the container 10a, and a complementary positioning post, etc., may be provided on the tool 130.

In a preferred embodiment, the tool 130 together with the gripped container 10a is actuated by the stretching machine 152 to inflate and enlarge, as best shown in Fig. 13. The stretching machine 152 preferably includes a table or work base 154 for receiving and manipulating the tool 130 . Tool 130 is then placed in throat 156 of machine 152. Once placed inside the machine 152, cylinders 157 are used to clamp or otherwise hold opposing tool parts 132 and 134 together. The cylinders 157 may be hydraulic, driven by an electric motor etc., but are preferably pneumatic. Other tools and methods, such as pressure clamps, can also be used to hold the tool halves together during the stretching process.

The compressed gas supply 158 engages with the opening 142 inside the tool 130 and the container 10a is inflated with compressed gas 158 to fully extend the front sheet 12a into the lower cavity 136 and the rear sheet 14a into the upper cavity 138. Such inflation permanently extends and extends both the front sheet 12a as well as rear sheet 14a out from a common plane defined by the common edge edge 16a inside the tool 130. The compressed gas 158 can be held inside the tool 130 for a short time to hold the front and rear sheets 12a, 14a against the respective cavities 136 and 138. Keeping the volume shield 17a inflated reduces shrinkage or elastic recovery. Usually this time is less than one minute for previously described foil construction materials. Then the compressed gas 158 can be released, the tool 130 removed from the machines 152 and the enlarged container 10a removed from the tool 130. Preferably, such stretching operation is automated.

In the embodiment shown, the container 10a extends from an initial capacity or a non-enlarged capacity of approximately 130-150 ml to an enlarged capacity of approximately 250-300 ml. Preferably, the container 10a is increased to a capacity of approximately 260-280 ml, more preferably 280 ± 5 ml. To obtain such final dimensions of the single-chamber container shown, for example, in Fig. 8, the upper and lower tool cavities 136, 138 are configured to have a trace area corresponding to the container chamber area, i.e., approximately 18 x 9 cm (7 x 3.5), each of which is hollow to a depth sufficient to form approximately 300 ml volumes for the lower tool cavity 136 and approximately 100 ml volumes for the upper tool cavity 138. In particular, the lower tool cavity 136 is hollow to a depth of approximately 3.8 cm (1.5 inches), while the upper tool cavity 138 is hollow to a depth of approximately 1.5 cm (0.6 inches). In addition, the sides of each of the cavities pass into the bottom of the cavity with continuous curvature so as to minimize the hard corners into which the material of the container could be forced, which would cause the material to stretch.

Opposite cavities 136 and 138 of the tool when joined together have a total volume of approximately 400 ml and a surface area of ​​the longitudinal section of approximately 158 cm²(24.5 square inches). These volumes and surface areas are not accurate because the areas inside the apertures 148 and 150 are necessarily not included. It should also be noted that due to the greater depth of the lower tool cavity 136 (and consequently its increased volume), the front sheet 12a will be able to stretch much more than the rear sheet 14a. The reason for the difference in volume between the upper and lower cavities of the tool is that the materials of the front and back sheets are stretched to contact with the inner surfaces of the cavities. The depth of each cavity and its appropriate volume are configured to correspond to the typical properties of the film when stretching the film into this cavity.

The volume cover 17a is preferably blown with compressed air at 69-207 kPa (10-30 psi) for about 1-30 s. Pressures less than 69 kPa (10 psi) may be used, however, the force generated is usually not sufficient to permanently stretch the described front and back sheets 12a and 14a in a cavity. The use of different materials, such as a container having two homogeneous layers similar to the described single layer front sheet 12a, may allow effective stretching at 69 kPa (10 psi) or at a lower pressure. Pressures of approximately 207 kPa (30 psi) and more tend to quickly stretch the front and rear sheets 12a, 14a in cavities 136, 138. Such rapid expansion can stretch the material too quickly, which can lead to wrinkling of the material, delamination in the laminate back sheet 14a, and other undesirable disadvantages. It may be possible to use higher pressures with slower or progressive inflation of the volume shield 17a in stages or alternatively with compressed gas heating. You can also heat a stretched sheet or cavity surfaces. Other known methods and devices can also be used to modify the preferred pressures and times needed to achieve the desired increased capacity of the container 10a.

In a preferred embodiment, the volume cover 17a is inflated within the described tool 130 with compressed air at a pressure in the range of 103-172 kPa (15-25 psi) for 15-25 s. More preferably, the pressure is regulated at about 140 kPa (20 psi ) and held for about 15 s at ambient temperature. increasing

190 598 pressure or time can additionally stretch each of the films if the volumetric capacity of the stretching tool is increased accordingly. This increased stretching would of course provide an increased volume of the stretched container. Similarly, reducing pressure or reducing time results in less stretch and smaller capacities. Favorable parameters stretch the front sheet 12a completely to 300 ml in the lower cavity 136 and the rear sheet 14a completely to 100 ml in the upper cavity 138 and result in a total enlarged capacity of approximately 280 ml ± 5 ml. The shrinkage due to material relaxation causes the increased capacity of the container 10a to be less than the combined volume of cavities 136 and 138. To minimize further contraction, the unlocking process can be used, which will be described in more detail below.

The exemplary enlargement process described causes the surface area of ​​the front sheet 12a to be increased by about 10% and the back sheet 14a by about 6%. However, preferred materials can be subjected to permanent deformation to a much greater extent, which allows the production of containers with even larger volumes. For example, the surface area of ​​the front sheet 12a from the preferred 80:20 material can be increased by at least about 16%, while the surface area of ​​the rear sheet 14a from the preferred laminate can be increased by about 10%. The surface area of ​​the front sheet 12a from the preferred 80:20 material can be increased more than the surface area of ​​the preferred back sheet 14a partly due to the low elasticity of the aluminum layer in the laminate structure of the back sheet.

After enlarging the container 10a, it is unlocked. This process maintains a certain volume of gas inside the enlarged volume cover 17a sufficient to keep the cover extended. Unlocking protects the enlarged volume cover 17a against further shrinkage due to the elasticity of the material during annealing. This can be particularly advantageous for the front sheet 12a, which is usually more stretched and not supported by an adhered aluminum layer.

Unlocking involves filling the container 10a with gas under low pressure so that the volume cover 17a is fully extended to the enlarged configuration. Low-pressure gas can be compressed gas with a pressure of several dozen kPa (several pounds per square inch). However, other gases, such as dry nitrogen, can also be used. Preferably, the unblocking pressure is adjusted below about 69 kPa (10 psi), and more preferably in the range of 6.9-35 kPa (1-5 psi). This prevents continuous shrinkage, stress on welds etc. When the volume cover 17a is fully extended, the sacrificial holes 72a and outlet opening 30a are blocked. Further shrinkage of the volume shield 17a will now encounter resistance in the form of gas pressure within the sealed volume shield 17a. Unlocking may be carried out in the stretching machine 52. Preferably, however, an unlocking station may be used.

An additional example of a medical container made with an enlarged chamber volume will now be described from Figs. 6, 11 and 12. Fig. 6 is a semi-schematic front view of a particular embodiment of the multi-chamber container at the same stage of the manufacturing process as the single-chamber container shown in Figure 8. The multi-chamber container of fig. 6 differs from the single-chamber embodiment in that the tear welds 25 and 26 run between permanent circumferential welds 16 on each side of the container to form an intermediate chamber 23, for example, for a medicament. The tear welds 25 and 26 are also intended to form a separate chamber 22 for liquid diluent and an outlet chamber 24, which is initially empty. The multi-chamber container according to the embodiment of Fig. 6, made using the films and methods described above, is capable of holding a relatively limited volume of diluted liquid in the diluent chamber 22. The back sheet of multilayer laminate is a relatively stiff barrier material, the rigidity of which, as mentioned above, limits the volume of diluent that can be introduced into the diluent chamber 22 to about 60 ml. Indeed, containers of the type shown in Fig. 1 and 6 are usually sold as 50 ml containers, i.e. containing 50 ml of liquid diluent to be mixed with the drug before dispensing. The effectiveness of various infusion therapies usually requires that intravenous containers may contain a much larger amount than the approximately 60 ml volume of diluent chamber 22 in the container of Figures 1 and 6. In particular, the PAB container manufactured and sold by McGaw, Inc. from Irvine, California, usually contains 100 ml of 0.9% sodium chloride in a condition called partial filling. Thus, it can be seen that enlargement of the multi-chamber diluent chamber 22 of the container shown in Figs. 1 and 6 is particularly desirable.

As described above with reference to the embodiment of Fig. 8, the container is enclosed in a tool having a hollow cavity or cavities and is filled with gas under pressure to thereby stretch the material of the front and rear sheet of the container (alternatively only the front sheet) to permanently increase the capacity volumetric of a specific chamber. The process and apparatus described with reference to Figs. 9-13 are also applicable to the multi-chamber container of Fig. 6. All that is needed is to reduce the surface trace of the upper and lower cavities 136 and 138, or to modify it to match the trace 22 of the diluent chamber 22 of the multi-chamber container 10 of Fig. 6.

The trace of the diluent chamber in the sense as used herein is substantially rectangular in shape and is defined on three sides by a permanent circumferential weld 16, and on the fourth by a tear weld 25 that separates the diluent chamber 22 from the drug chamber 23. Apart from the channel 41 formed between the diluent chamber 22 and its respective sacrificial opening 72, the chamber trace has a rectangular shape 8.9 cm (3.5) wide and 12.7 cm (5.0) long. The weld boundary (146 from fig. 11) has the shape and dimensions consistent with the weld seam chamber 22 of the multi-chamber diluent of the container of Figures 1 and 6.

Since the weld separating the diluent chamber from the drug chamber is a burst seal, care should be taken to ensure that weld boundary 146 of Figure 11 is configured so that the boundary is located somewhat within the welds, especially the burst seal 55. Remembering that the peelable seam is intended to burst under pressure, it should be noted that the application of border 146 within the seam seal, and especially within the seam seam 55, prevents the application of the bursting pressure to the burst seam.

In a similar manner to that described with respect to the embodiment of Fig. 8, the chamber 22 of the multi-chamber diluent container of Figs. 1-6 can be enlarged by stretching the front sheet 12 and / or back sheet 14. Due to the properties of the films used for the front sheet 12 and rear sheet 14 it is understood that the front sheet 12 is more extensible than the rear sheet 14 at the same time and pressure as described with reference to Fig. 8.

An embodiment of the tool for expanding the diluent chamber in a multi-chamber drug container is generally quite similar to the embodiment of the tool described on the basis of Figures 11 and 12. However, due to the smaller surface footprint (8.9-12.7 cm (3.5 x 5 inch) compared to 8.9-17.8 cm (3.5 x 7 inch)) the diluent chamber compared to the entire the container, the depths of the upper and lower cavities 136, 138 are reduced accordingly so as not to stretch the film materials of the diluent chamber excessively. As described above, the lower cavity 136 has a trace of approximately 8.9-12.7 cm (3.5 x 5 inch) and the cavity depth 1.9-2.5 cm (0.75-1.0 inch), to create a cavity volume of 160-175 ml. Preferably, in the example of Fig. 6 only the front sheet is stretched, so that the upper part of the tool has a substantially flat surface without a recess. However, if the recess were used, it would have a 8.9-12.7 cm (3.5 x 5 inch) trace and a recess depth of 0.6-0.9 cm (0.25-0.35 inch) to create a recess volume 50-60 ml. The use of such cavities makes it possible to enlarge the diluent chamber 22 from a nominal standard volume of 50 ml to about 100-150 ml, as previously defined.

After placing the multi-chamber container of Figs. 1 and 6 with a suitable tool, the diluent chamber is inflated through its respective sacrificial opening (72 of Fig. 6) with air or nitrogen filtered through 0.2 Lim meshes with an inlet pressure of approximately 138 kPa (20 psi) . The diluent chamber is kept inflated for about 15 seconds to allow time for the film to stabilize in its stretched state. After increasing the volume, the multi-chamber container is now ready for sterilization, aseptic filling, cutting to final dimensions and transporting to the end user.

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Sterilization, filling and shaping the finished container

After enlarging the container 10a to the desired volumes, it preferably has the configuration shown for example in Fig. 8. The container 10a is now ready for sterilization and aseptic filling with the medical solution. After sterilization and filling, sacrificial holes 72a and 74a can be removed, leaving the enlarged container ready, as best shown in Figure 17.

In the exemplary filling process, an example of a container to be filled according to the invention is a container that comprises a single-layer front sheet 12a film and a multi-layer laminated film 14a with back sheet aluminum foil. The front and back sheets 12a and 14a were made to form a container 17a in which a portion of the common peripheral edge 16a is left unsealed for filling through suitably provided sacrificial holes 72a and 74a. This embodiment of the container 10a in this manufacturing phase is best illustrated in Fig. 8. The production of the primary container, including the use of the outlet opening 30a and sacrificial openings 72a and 74a, takes place by means of the method and device previously described.

For the aseptic filling process to be accepted for medical purposes, the unfilled container 10a must be delivered sterile. Usually, the container is sterilized in a separate room or device due to the rather large and complicated equipment and process required to sterilize the material. A particularly undesirable feature of the sterilization procedure is that the container must be transported to the sterilization device, and after sterilization the container sterility must be maintained during subsequent storage and transport to the aseptic filling device. The container must be introduced into the aseptic filling zone by means of sterile transport to prevent contamination of the aseptic zone by the container. After entering the aseptic zone, the container can be aseptically filled, but must be further sterile treated.

According to the practical principles of the invention, after manufacturing the primary container, many empty containers are loaded into a handling container that is heat sealed to protect the flexible containers 10a contained therein from environmental contamination.

The transport or handling container generally designated 160 in Fig. 14 and referred to herein as the carrier, acts as a transportable sterile contaminant isolator for sterilizing, transporting and entering the aseptic zone of empty containers in a systematic manner. Carrier 160 has three parts: a substantially rectangular tray 162, a welded foil lid 164 and a rail insert 166 for supporting multiple containers 10a in the tray, as will be described in more detail below. The described carrier 160 is only an embodiment and other configurations may also be used as known to those skilled in the art.

The substantially rectangular container tray 162 may be made of thermoformed polystyrene material or other material capable of withstanding several sterilization cycles without significant degradation. Tray 162 can be made essentially bowl-shaped with an upper peripheral edge bent outward to form a flat, horizontally extending peripheral lip or collar 168 that extends beyond the sides of tray 162 to 0.6-2.5 cm (0.25 cm) -1 inch). Preferably lip 168 extends about 1.9 cm (0.75 inches) beyond the sides of the tray, but any dimension is possible that provides the rigidity of tray 162 and sufficient surface for welding. The two opposing recesses 170 and 172 are made approximately in the middle of the two opposite short sides of the tray and extend outward from the plane of these short sides. These recesses 170 and 172 extend only partially downwards along the sides of the tray and thereby form two opposite recesses into which the ends of the rail insert 162 can be inserted. This rail insert 162 rests on the bottom surfaces of the recesses 170 and 172 and is thus suspended above the bottom of the tray 162 at a height sufficient for the containers 10a placed on the rail insert to hang freely into the tray. The recesses 170 and 172, in conjunction with the rail insert 166, therefore maintain a plurality of containers 10a in a specific location during transport, storage, and ultraviolet sterilization.

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After loading the containers 10a on the rail insert 166 and inserting it in cavities 170 and 172, the tray 162 is sealed to the environment by welding the foil lid 164 with the tray flange 168 in a clear orientation. For the purposes of illustration in Fig. 14, the foil cover 164 is shown in the middle of the welding process, part of the cover being raised to show rail insert 166 located in tray 162. The foil cover 164 is placed on the collar 168 so that the material of the foil cover does not protrude beyond the edge of the tray flange around the perimeter of the tray. In the exemplary embodiment, the foil cover 164 is made to have two dimensions that allow the foil cover to be placed on the tray flange 168 such that the edge of the foil cover is retracted inwardly from the edge of the tray flange around the entire periphery of the collar. In addition, the seal of the foil cover extends beyond the edge of the foil cover 164 to ensure that no part of the foil cover edge remains without welding, which would result in a loose edge flap. The orientation of the foil cover, its placement and the avoidance of loose edges are particularly important for the process of ultraviolet disinfection of the surface carried out on the carrier 160 when the carrier is introduced into the aseptic zone. Gaps caused by loose edges of the foil cover and / or lobes may cause local shading when exposed to ultraviolet radiation, which may have a detrimental effect on the ultraviolet disinfection process.

After welding the foil cover 164 to the flange 168 of the tray, the carrier 160 creates a hermetically sealed environment that insulates its contents from external contamination. The carrier 160 can then be placed in a plastic bag or similarly covered (not shown) to protect against dust and marked with a sticker on the outer covering.

As shown in Figs. 15 and 16, the carrier rail insert 174 may include a plurality of injection-molded polystyrene tees 176 spaced apart so as to form longitudinally extending slots 178 between them. The resulting containers 10a can be loaded onto the insert 174. Containers 10a, such as shown in Fig. 8, are loaded onto the carrier rail insert 166 by inserting their sacrificial holes 72a and 74a into slots 178 formed between the insert tees 176. The tees 176 may have edges that are spaced sufficiently apart (about 13.0 mm) so that the central filling sleeve of each sacrificial hole 72a and 74a can be placed between them and they are adapted to place sacrificial holes between peripheral flanges ( 78a and 80a) so that each container 10a is gripped by tee arms 176 below its highest circumferential sacrificial flange 80a.

In the embodiment of the carrier rail insert, shown in Figs. 15 and 16, four slots 1178 are provided for receiving containers 10a with containers loaded on rail insert 166 alternately in left and right positions. The holes 72a and 74a of each container 10a are inserted into two of the slots 178. The first container may be loaded into the second and fourth slots and oriented in the first horizontal direction. The second container may then be loaded onto the rail insert 166 with its sacrificial holes 72a and 74a inserted into the first and third slot 178 of the insert. The second container 10 is loaded in a second horizontal position, set at an angle of 180 ° to the first container. Further containers 10a are loaded onto the carrier rail insert 166 in a similar manner, the horizontal orientation of the container is alternately left and right, the sacrificial holes of the left-oriented containers are inserted into the second and fourth slots, the adjustment holes of the right-oriented containers inserted into the first and a third slot as described above until the carrier rail insert 166 is completely filled. Of course, each carrier will support a larger number of containers before enlargement than enlarged containers.

After loading, the carrier rail insert 174 is placed in tray 162, the ends of tees 176 being located in cavities 170 and 172 formed at the ends of the tray. Recessions 170 and 172 support the carrier rail insert 166 in the internal volume of the tray and provide additional lateral support that protects the insert from slipping during transport, sterilization and storage.

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The sealed carrier, containing empty containers inside, is packaged in a plastic bag or similar container for radiation sterilization, where the carrier 160 and the containers 10a contained therein are sterilized by an electron beam sterilization procedure etc. After the procedure of loading the carrier and electron beam sterilization, the sterilized containers medical devices can be aseptically filled with medical solution. This may involve transporting the carrier 160 and its containers 10a to an aseptic filling station. The filling of the volume cover 17a can be carried out using the technique of the simultaneously associated application 08 / 837.927, filed April 11, 1997, to which this description is incorporated in its entirety. These techniques can be applied to a single medical solution or alternatively to fill multiple chambers.

After sterilization and filling, the production of the enlarged container of Fig. 8 can be completed by removing sacrificial holes 72a and 74a and terminating the permanent weld around the first side 27a of the common peripheral edge 16a. The finished container 180 has an increased storage capacity for the medical solution compared to a standard or non-enlarged container.

The final manufacturing process involves removing a portion of the first side 27a of the container 10a slightly inward from sacrificial holes 72a and 74a including sacrificial holes. Each of the fluid connections or channels between sacrificial holes 72a and 74a and the volume cover 17a is then sealed. This is done by making a permanent weld, as previously described, across the first side 27a slightly inward from the common peripheral edge 16. This permanent weld completes the volume cover 17a. When using a multi-chamber container, a permanent weld can be made through each sacrificial opening 72a and 74a after each corresponding filling. A portion of the first side 27a including sacrificial holes 72a and 74a can then be removed. As can be seen from the differences between Figs. 8 and 17, the removed portion includes sacrificial holes 72a and 74a and a narrow strip of the first side 27a of the container 10a.

It will be appreciated by those skilled in the art that an essential discussion of embodiments including an example of a container for a liquid diluent and one powdered drug, as well as an example of a single-chamber container, does not limit the scope of the invention. According to the invention, liquid drugs can be used in an intermediate chamber or a plurality of chambers for powdered and liquid drugs for mixing with a diluent. According to the practical principles of the invention, a plurality of sacrificial holes and connecting channels between sacrificial holes and a suitable chamber can easily be provided. In addition, depending on the sensitivity of any of the components of the contents of many chambers to moisture or free oxygen contamination, these chambers can be protected by the additional use of a transparent, containing SiOx, highly barrier laminate on the container front sheet in the areas of these chambers. Such highly barrier laminates can be used in conjunction with or without connection to an aluminum foil-peelable covering of a highly barrier laminate.

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UP Department of Publications. Circulation of 50 copies Price PLN 6.00.