Flexible medical container with selectively enlargeable compartments and method for making same

FLEXIBLE MEDICAL CONTAINER WITH SELECTIVELY ENLARGEABLE COMPARTMENTS AND METHOD FOR MAKING SAME

The present invention relates to a flexible sterile container for use in storing and administering pharmaceutical solutions in a sterile environment. In particular, the present invention relates to a flexible medicament container for storage and administration with a permanently elongated side to increase the storage capacity.

Typically, various drug solutions are administered intravenously (IV) to a patient from a sterile container. Such solutions may include fluid-type drugs such as bodily fluid substitutes and solutions containing drugs (drugs). The packing for storage and administration of such a solution includes a flexible container having a compartment for storing the solution. The outlet port is connected to a compartment for administration and delivery of a solution to a patient via a standard IV device.

Often, drug solutions consist of a mixture of a liquid drug and a liquid diluent such as an aqueous dextrose or NaCl solution. Drugs and diluents are stored separately in sterile containers and are not mixed with each other until immediately prior to use to prevent degradation into the final product. Packing diluents and drugs together becomes more complex depending on the properties of the liquid drug, so it becomes sensitive to the water pressure of the container and decomposes upon exposure to light or oxygen.

Accordingly, it has been common that various drugs that become unstable in solution are separately stored in vials, containers, etc. through which gas cannot pass until just before use. Medicaments stored in this manner prior to administration to the patient must be mixed or diluted with separately stored physiological solutions or diluents. It is cumbersome to maintain the sterile state and efficacy of the drug, and there is a risk of contamination with bacteria during handling, mixing and administration. Accordingly, medicament containers have been developed to include a compartment for storing an unstable medicament and a compartment containing a diluent. The ingredients were allowed to circulate with each other just before intravenous administration to the patient, allowing the contents to be mixed under aseptic conditions.

Multi-compartment containers are known which allow for separate storage of diluents and medicaments. For example, such containers are described in US Pat. No. 4,608,043 to Larkin, US Pat. No. 5,176,634 to Smith et al., and US Pat. No. 5,462,526 to Barney et al., which are incorporated herein by reference. The compartments of the container described in this patent are separated from each other by a peelable or frangible heat seal. When the seal is ruptured by manipulating the container by hand, the contents of the compartment mix to form a solution that is delivered to the patient through a standard intravenous administration device.

Containers for solutions on the market today are made of a material containing PVC plastic. The disadvantage of PVC material is that it generally makes it difficult to observe the contents of a container made of the material. Therefore, it is quite difficult to observe leaks or moisture contamination in such containers. When multi-compartment containers are used, it is necessary to ensure that the mixing of the drug and the diluent is complete prior to administration to the patient to check for further complication. In addition, several hazardous chemicals are used in the manufacture of PVC materials and must be disposed of to protect the environment. Since PVC emits toxic gases when incinerated and contains toxic plasticizers that dissolve into the environment when containers are placed in landfills, they must be carefully disposed of after use. Since toxic plasticizers are soluble in solutions for intravenous administration, it is inappropriate to use PVC containers for various types of pharmaceuticals, especially liquid pharmaceuticals.

Typically, flexible containers are made of a pair of opposing flat sheets joined together to form a body or shell. Once a body of a certain size is formed, the skin dose is fixed. In general, such containers are made such that a standardized volume is maintained. This is worked until a standard volume is required. In this situation, one option is to use some solution that is stored in a large container. However, this method is expensive, uneconomical and risky. In addition, the user should use it carefully according to the desired content or the prescription of the contained fluid. Moreover, the residual solution may require special treatment.

Also, the container is typically made to some overall external size or some general overall size. In general, this is because the overall size of the containers determines their volumetric capacity, and these days they are provided in relatively small predetermined volumes. The manufacture, handling, and sterilization of such containers require very complex and expensive machinery. These machines are partially designed to handle the full size of the container. Therefore, it is desirable to provide a medicament container having an overall external size conforming to the standard and having an enlarged volumetric capacity compared to the standard size. In addition, the medicament container is preferably manufactured using the same machinery and handling equipment for the standard size.

Typically, multi-compartment containers, as well as single-compartment containers, are made of a given compartment size. Generally, the diluent compartment is sized to hold an amount of diluent sufficient to mix the stored drug product. In addition, the diluent compartment is based on a specific dose or reservoir of the drug solution. The volume of the diluent compartment may be limited by the overall external size of the container that must be assembled to fit the packaging and handling equipment. However, in some products it may be necessary to increase the diluent content. Until recently this was not possible and a secondary diluent container had to be used. Also, some products may require additional medications. Accordingly, it would be desirable to provide a multi-compartment medicament container having a standardized overall external size having a standardized compartment volumetric capacity that can be permanently enlarged to increase the volumetric capacity of at least one compartment. In addition, it is preferred that the container be manufactured in a predetermined overall external size and shape that is easy to manufacture, sterilize, and handle by the same machine and process.

The present invention provides flexible medicament containers that can be permanently expanded to increase their storage capacity. The present invention also provides a flexible medicament container for use in storing medicament solutions and powders manufactured to a standardized overall external size and optionally enlarged to increase their storage capacity. By providing a flexible container having a front seat and a back seat that can be permanently stretched, the volumetric capacity of the container can be increased to a variety of sizes and shapes. By adding a simple and optional enlargement step to the manufacturing process of the vessel, it is possible to enlarge the volume enclosure of some vessels while others remain generally standardized or not expanded in capacity. This is useful as it allows for the manufacture, handling, and administration of the containers of the present invention using generally conventional methods and equipment.

It is a first aspect of the present invention to provide a flexible container for storage and administration of a medicament fluid. Such a flexible container includes a substantially transparent front sheet having a first surface area. The front sheet consists of a flexible flat layer of polymer film. A back sheet having a second surface area and comprising a planar layer of the flexible laminate is disposed opposite the front sheet. The front and rear seats are sealed along a common perimeter to form a volume enclosure. The ports are supported along a common perimeter and are fluidly connected to the volume enclosure. At least one of the front and rear seats is permanently enlarged to increase the volume enclosure to increase the storage capacity of the container.

According to another feature of the present invention, the flexible container includes a substantially transparent front sheet having a first surface area. The front seat consists of a flexible flat layer of polypropylene-polyethylene copolymer blended with a styrene ethylene butylene styrene thermoplastic elastomer. A similarly sized rear seat having a second surface area is disposed opposite the front seat. The back seat consists of a planar layer of a flexible laminate comprising an inner layer of a polypropylene-polyethylene copolymer blended with a styrene ethylene-butylene styrene thermoplastic elastomer. This inner layer is disposed opposite the front sheet. The back sheet also includes an intermediate layer of aluminum foil having a higher melting point than the inner layer and an outer thermoplastic layer. The front and rear seats are permanently enlarged to increase the volume enclosure, increasing the storage capacity of the container.

A first peelable yarn extends between a first side of the common perimeter and an opposing second side of the common perimeter. The first peelable seal joins the front and back sheets to form a first compartment that is a volume enclosure for containing a diluent. A second peelable seal joins the front and back sheets to form a second compartment containing the medicament and a second outlet compartment. The second compartment is located between the first compartment and the outlet compartment.

The outlet port is supported along a common perimeter and fluidly connected with the outlet compartment. The diluent port is also supported along the common perimeter and is fluidly connected with the first compartment through a break in the seal along the common perimeter. The medicament port is also supported along the common perimeter and is fluidly connected with the second compartment through a second break in the seal along the common perimeter.

According to another aspect of the present invention, there is provided a method of making a flexible container for storage and administration of medicaments and diluents for IV solutions. The method includes providing a substantially transparent front sheet and a flexible vapor impermeable back sheet. The provided front sheet is composed of a flexible flat layer of polymer film. The back sheet consists of a planar layer of a multilayer stack. The front and rear seats are sealed along a common perimeter to define a volume enclosure.

The method also includes providing first and second sacrificial ports supported along a common perimeter and fluidly coupled to the volume enclosure. The first sacrificial port is spaced apart from the second sacrificial port along the first side. The outlet port is supported along the second side of the common perimeter and is fluidly connected with the volume enclosure.

The volume enclosure expands through expansion by the pressurized gas, thereby permanently expanding at least the front seat to increase the volumetric capacity of the container. The pressurized gas is then removed from the expanded vessel. The permanently elongated volume enclosure is filled with a second gas. The sacrificial port and the outlet port are capped to maintain the container in an expanded configuration.

After the vessel has been permanently inflated, each sacrificial port may be removed. This step includes removing the first side portion along the common perimeter. The front sheet is then attached to the back sheet along the first side inside the sacrificial port to form a permanent continuous seal around a common perimeter.

According to another aspect of the present invention, a method of increasing the capacity of a flexible container for storage and administration of a pharmaceutical fluid is provided. The method includes providing a flexible container, such as a container of the present invention. A provided container includes a flexible back flat sheet along a common plane and an opposing flexible front flat sheet. The front seat is attached to the flexible rear seat along a common perimeter to form a volume enclosure. The port is connected to the vessel and fluidly connected to the volume enclosure. The method includes expanding the volume enclosure to permanently stretch at least the front seat and increase the volumetric capacity of the container.

Inflating the volume enclosure includes providing a plurality of tools arranged to receive the volume enclosure. This tool includes a lower tool section and an upper tool section adjoining it. The lower tool portion has a flat lower edge in the lower recess. In a similar fashion, the lower and upper planar sides are generally opposite and are arranged to include a common perimeter. The container is sandwiched between a tool having a back sheet abutting a recessed portion at the bottom and a front sheet abutting a recessed area at the top. Pressurized gas is then used to inflate the volume enclosure to permanently stretch the front and rear seats outward against the recesses of each of the tools. The volume enclosure remains inflated for a period of time sufficient to overcome significant elastic recoil.

According to another aspect of the present invention, there is provided a method of making a flexible container for storage and administration of medicaments and diluents for IV solutions. The method includes the steps of providing a substantially transparent flexible front sheet comprised of a planar layer of polymer and providing a flexible, vapor impermeable back sheet comprised of a planar layer of a multilayer laminate. The front and rear seats are sealed along a common perimeter to define a volume enclosure. The front sheet and the back sheet are sealed in the first local area and joined along the sealed first local area to form a first peelable seal. This first seal extends between a first side of the common perimeter and a second side opposite it. The first seal releasably couples the front seat to the rear seat to form a first compartment within the volume enclosure containing the diluent. The front sheet and the back sheet are sealed along the second localized region to form a second peelable seal. A second seal extends between a first side of the common perimeter and a second side opposite it and releasably couples the front and rear sheets to form a first compartment for use with medicaments. The second compartment is located between the first compartment and the outlet compartment.

The method also includes providing a first sacrificial port inserted between the front seat and the rear seat and in communication with the first compartment. The second sacrificial port is inserted between the front seat and the rear seat. However, the second sacrificial port is remote from the second sacrificial port and is fluidly connected with the second compartment. An outlet port is also inserted between the front and rear seats and is fluidly connected to the outlet compartment. The volume enclosure portion forming the first compartment is then inflated to permanently stretch the front and rear seats and increase the volumetric capacity of the first compartment.

The above and other features and advantages of the present invention may be more clearly understood with reference to the following detailed description, appended claims, and drawings.

1 is a schematic front view of an embodiment of a representative container made in accordance with the present invention;

Fig. 2 is a cross-sectional view schematically illustrating a flexible flat sheet formed in a container along the line 2-2 of Fig. 1 in an enlarged thickness of the sheet;

Fig. 3 is a schematic cross-sectional view of a flexible flat sheet formed in a container, enlarged in thickness of the sheet along line 2-2 of Fig. 1;

Fig. 4 is a schematic partial cross-sectional view of the form of a flexible sheet of a first embodiment of the present invention showing an optional and transparent highly barrier interlayer;

FIG. 5 is a schematic cross-sectional view along line 2-2 of FIG. 1 of the first permanently enlarged section associated with FIG. 2; FIG.

6 is a schematic front view of a preferred embodiment manufactured according to the invention;

7 is a plan view schematically showing an embodiment of the modular container manufacture of the present invention;

Fig. 8 shows a modified embodiment of the flexible container of the present invention;

Fig. 9 is an enlarged side view of the flexible container of Fig. 8;

FIG. 10 is an enlarged side view of the flexible container of FIG. 8 with a permanently enlarged front seat and rear seat; FIG.

11 is a perspective view of an embodiment of a tool for permanently stretching the front and rear seats of the flexible container of the present invention;

Fig. 12 is a perspective view of the top of the tool of Fig. 11 showing the upper cavity;

13 is a perspective view of an embodiment of an actuator housing for use with the tool of FIG. 11;

14 is a schematic perspective view of a handling container comprising a rail cartridge and a sealable film lid manufactured according to the present invention;

Fig. 15 is a schematic plan view of the rail cartridge of Fig. 14 showing a plurality of flexible containers loaded on the rail;

FIG. 16 is a schematic enlarged side view of the loaded rail cartridge of FIG. 15 showing a method of retaining a flexible container within a rail using a sacrificial port;

17 is an enlarged side view of the flexible container of FIG. 8 showing the completed permanent seal with the sacrificial port removed along a common perimeter;

1 and 2 show schematic front and cross-sectional views, respectively, of a flexible sterilization container 10 made in accordance with features of the present invention. Although the vessel can be viewed from all directions, descriptions will be made with reference to the orientations of FIGS. 1 and 2 to illustrate the position of the compartments of the vessel relative to each. The container 10 consists of a front seat 12 and a rear seat 14 (shown only in FIG. 2 ). The front and rear sheets 12 and 14 may be constructed from a single layer of flexible material or a multilayer stack of flexible materials, which will be described in detail below.

The sheets 12 and 14 forming the container are manufactured separately and sealed with a permanent seal along the common perimeter 16 of the container (FIG. 2). The sealed common perimeter 16 extends to the entire cavity perimeter of the container 10 to form a volume enclosure 17 . These edge seals may vary in arrangement and width. The seal patterned as shown in the top seal portion 18 and bottom seal portion 20 of FIG. 1 provides the healthcare practitioner with the handle portion required to handle the container, for example, when the container is mounted on a TV support stand. to be attached in place. Also, the front sheet 12 and the back sheet 14 may be formed from a single membrane sheet that can be sealed together by folding or extending to the side of an overlapping portion of the container membrane by a heat seal. The formed sealing sheet will be referred to herein as the "shell" or "body" of the container.

In an embodiment the vessel is divided into three independent compartments, each of which is a sterilized upper compartment 22 , an intermediate compartment 23 , and a lower compartment 24 . The upper compartment 22 and the middle compartment 23 are separated by a first peelable seal 25 , while the middle compartment 23 and the lower compartment 24 are separated by a second peelable seal 26 . . Peelable seals 25 and 26 extend between a first side 27 of the container 10 and an opposite second side 28 . Peelable seals 25 and 26 connect from a sealed common perimeter on the first side 27 to a sealed common perimeter 16 on the second side 28 . Peelable seals 25 and 26 join the interior surfaces of the front seat 12 and the rear seat 14 at the seal area or portion.

The term "peelable" seal as used herein has sufficient durability to allow normal handling of the container, but the back sheet and front sheet of the seal area are separated and peeled by the pressure generated by manipulating the container by hand. means a seal that is opened to allow the contents of the container to be mixed and dispensed. The peelable seal is made by melting together the polymeric material present where the inner surfaces of the front and rear seats come into contact. These seals are obtained by heat sealing by applying heat and pressure at different times, temperatures and pressures for each seal area. This process will be described in detail below. Conversely, the edge seal 26 is significantly more robust than a "peelable" seal and will not rupture under pressure separating the peelable seal. Each peelable seal 25 and 26 is configured individually so that the liquid medicament and diluent have been pre-mixed and then peel-opened in such a way that the mixed ingredients are administered.

A typical use of the container 10 of the present invention is that the upper compartment 22 is filled with a diluent and the middle compartment 23 is filled with a medicament, typically in liquid form. The lower compartment 24 serves as a safe interface for the outlet port 30 and remains empty until the container is used. The outlet port 30 includes a nozzle 40 and a body portion 38 that extends downward and is configured to attach to a standard intravenous administration device. A cap (not shown) is provided to cover the nozzle to maintain sterilization. The cap is removed just before connecting the IV set to the outlet port. The plurality of ribs 39 are provided to the body portion 38 of the outlet port 30 spaced apart from each other when the IV set is attached to the container.

The materials used for assembling the front and rear seats of the container are selected according to the material to be stored in the container. Preferably, the at least one sheet is transparent so that the contents of the container can be visually observed and the content of the solution in the solution can be visually observed during administration. As raw materials suitable for the production of transparent sheets, there are usually single-layer and multi-layer laminated polymer films.

In particular, the materials constituting the front sheet 12 and the rear sheet 14, whether composed of a single-layer or multi-layer laminated polymer film, are selected according to their transparency. Because conventional polyvinyl chloride (PVC) container materials are generally opaque, it is difficult to properly observe the interior of the container and it is difficult to determine whether particulate matter is present or the content of the solution in the container. This can be very dangerous when the drug is administered intravenously. It is essential for a nurse or health care provider to simply ensure that all medications administered from a medical container are free of particulate matter.

3 is a partial cross-sectional view schematically illustrating an embodiment of the container 10 . As shown, the front sheet 12 is comprised of a transparent single layer thermoplastic polymer film 44 . Transparent membrane 44 includes 80% by weight of a polypropylene-polyethylene copolymer sold as Z9450 by Fina Oil and Chemical Company of Deerpa, TX and styrene ethylene-butyl under the trade designation KRATON sold by Shell Chemical Corporation as G1652. There is a mixture of 20% by weight of ren styrene thermoplastic elastomer. The G1652 thermoplastic elastomer is a two-phase polymer having polystyrene domains (end blocks) in a rubbery poly(ethylene-butylene) matrix, usually provided in crumb form. A membrane was prepared by mixing Z9450 copolymer resin and pellets of G1652 thermoplastic elastomer in a high-speed shear mixer at a ratio of 80 wt%/20 wt% and re-pelletizing the mixture. Compounding G1652 crumb in a high-speed shear mixer should not raise the temperature above about 500°F as hardening will occur due to elevated temperature. As a result, a transparent film 44 is formed from pellets mixed in a commercially available extrusion apparatus.

The transparent polymer film 44 included in the front sheet 12 is configured to have various thicknesses depending on the purpose of the container and durability required for a specific application. A suitable thickness of the material comprising the front sheet 12 will range from about 3 to about 15 mils, although in the illustrated container embodiment the transparent polymer film 44 with the front sheet is preferably about 12 mils thick.

Although the composite raw materials selected to form the transparent polymer film 44 are selected according to their transparency, the film is specifically formed along the common perimeter 16 of the container 10 and the "peelable" seal of the container 10 . It is suitable for forming a permanent seal. As will be described in detail below, the 80:20 film according to the present invention makes it possible to form a peelable seal at low temperature and a permanent seal at high temperature without affecting the properties of the raw material and the ability to form a peelable seal. .

For some medicament solutions comprising a mixture of several diluents and medicaments, the back sheet 14 may be formed of the same single layer composition and arrangement as the front sheet 12 . In addition, a multilayer membrane that can extend the shelf life of the filled container, including a moisture and light impermeable layer, is a preferred membrane for the back sheet. As shown, a three-layer laminate back sheet 14 may be used. The laminate back sheet 14 is preferably a flexible flat sheet that is impermeable to water vapor and light. This configuration preserves the potency and activity of the solution in the single compartment container 10 and the potency and activity of the two components (unmixed drug and diluent) in the multi-compartment container, thereby extending the shelf life of the filled container.

In a preferred embodiment, the back seat 14 includes an inner seal or seal layer 46 on its interior facing surface. This inner seal layer 46 is made of a mixture of 80%/20% by weight of polypropylene-polyethylene copolymer and styrene ethylene-butyrene styrene thermoplastic elastomer, and the thickness of the mixture is about 3 to 6 mils (80:20). is just). The inner seal layer (80:20 membrane layer) 46 may be approximately 6 mils thick and is bonded to the intermediate layer 50 by a transparent inner adhesive 48 . This interlayer 50 may be a high barrier aluminum foil 50 of approximately 0.7 to 1.3 mils, more preferably about 1.0 mils. An outer layer 54 is provided on the outer facing side of the back sheet 14 and is bonded to the highly barrier aluminum foil layer 50 by a suitable transparent adhesive 52 .

The inner adhesive 48 may comprise a modified aliphatic polyester polyurethane adhesive sold as TYCEL 7909 by the Liofol Company of Cary, NC, USA. Exterior adhesive 52 comprises a degraded aromatic polyester polyurethane adhesive sold as TYCEL 7900 by the Liofol Company of Cary, NC, USA. The aliphatic adhesive contained in the inner adhesive layer 48 may also be used as the outer adhesive layer 52 but not vice versa. The aromatic adhesive layer 52 provides a stronger bond than the aliphatic adhesive, but has the potential to introduce highly undesirable aromatic compounds either as a diluent or liquid medicament through the 80:20 membrane layer. Thus, if used, the aromatic adhesive layer 52 is used only when the aluminum foil layer 50 is inserted as a barrier between the adhesive layer and the volumetric container 17 in the container 10 .

The aluminum foil layer 50 is preferably made of a commercially available 1.0 mil aluminum foil such as ALCAN 1145 from Alcan Rolled Products Company, Louisville, Kentucky, USA. When the aluminum foil layer 50 is exposed as the outer layer of the back sheet 14, the heat sealing treatment used to form the common outer perimeter seal and the transverse peelable seals 25 and 26 damages the foil layer and The properties and capabilities provided by the barrier layer may be degraded. An outer hot layer 54 is provided to prevent such damage. The outer layer 54 is preferably made of a relatively high melting point polymer that functions as a protective layer over the aluminum and prevents contact between the intermediate foil layer 50 and the high temperature platen of the heat seal device. The high temperature outer layer 54 prevents direct contact between the foil layer and the high temperature platen of the heat seal device and the foil layer, thereby acting as a protective layer for aluminum. The hot outer layer 54 also acts as a heat seal release layer (also referred to as a mold release layer) because the material melts and does not stick by the heat seal platen at the temperature used during the seal forming process. Thus, pressure and temperature can be applied to the outside of the vessel without the need for a special coating on the platen. The outer layer 54 preferably has a higher melting point than the inner seal layer 46 .

The hot outer layer 54 is polyethylene terephthalate having a thickness of about 0.4 to about 0.6 mils commercially available from Rhone-Poulanc as TERPHANE 10.21. In the illustrated embodiment, the thickness of the multilayer laminated film 14 is about 0.48 mils for the high temperature polyester outer layer 54, about 1.0 mils for the high barrier aluminum foil layer 50, and an 80:20 inner seal layer film 46 ) is preferably about 6.0 mils.

The inventors have found that a preferred material for the front sheet 12 and back sheet 14 that provides optimal performance of the peelable seals 25 and 26 is that the interfacial seal layer of each sheet comprises an 80:20 membrane. In addition, the seal layer in contact with the interior of the front and rear seats may include a polypropylene-polyethylene copolymer and a styrene-ethylene-butylene-styrene thermoplastic elastomer mixture in different content ratios. The relative proportions used will depend on the characteristics of the various seals to meet the specific medicament container, the application related to the temperature and pressure parameters of the seal forming process. Other forms of flexible membranes useful in the construction of the front and rear sheets of the shell of the container 10 of the present invention and other forms of inwardly facing seal layers in both sheets are disclosed in U.S. Patent Nos. 4,803,102 and 4,910,085, which are incorporated herein by reference. , 5,176,634, and 5,462,526.

In some applications, it may be desirable to provide additional protection, such as a multi-compartment container such as the container shown in FIGS. 1 and 2 . This is preferable if the medicament is sensitive to contamination by water vapor or degradation caused by visible or UV radiation and it is necessary to additionally protect the portion of the front sheet 12 covering the intermediate (pharmaceutical) compartment 23 . . However, this additional protection may be provided across a plurality of medicament compartments, or even the front sheet 12 as a whole. This additional protection may be provided to prevent the transmission of moisture, oxygen, and/or light through the portion of the front sheet 12 comprising the second or intermediate compartment 23 and to prevent degradation of the medicament. This additional protection allows the container 10 to be stored for an extended period of time without loss of medical efficacy.

In particular, referring to FIGS. 2 and 3 , an opaque film 55 having high blocking properties is used to cover the middle or middle compartment 23 . The opaque membrane 55 is used to block the permeation of water vapor and liberated oxygen into the drug compartment, and in an embodiment comprises a multilayer laminate structure comprising a highly barrier aluminum foil layer. The use of an opaque aluminum foil laminate helps to prevent the drug contained in the intermediate compartment 23 from decomposing upon exposure to visible and UV radiation. Therefore, in the embodiment of the present invention, the opaque aluminum foil included in both the protective film 55 and the back sheet 14 covers the middle section 23 to prevent the UV spectrum from being transmitted to the middle section 23 in any direction. . An inner seal layer 56 made of a multilayer laminate is positioned on the inwardly facing surface of the highly barrier protective film 55 . In an embodiment, the seal layer 56 is a soft, coextruded coating resin comprising a modified ethylenevinylacetate polymer commercially available from Dupont Chemical Company as APPEEL1181, providing a thickness of from about 0.2 mils to about 0.4 mils. An aluminum foil layer, such as ALCAN 1145, having a thickness of about 0.7 to 1.3 mils, preferably about 1.0 mils, is adhered to the inner seal layer 56 with a suitable clear adhesive 57 . An outer heat seal release layer 60 comprising a polyethylene terephthalate (PET) film having a thickness of about 0.48 mils, such as TERPHANE 10.21, forms the outward facing side of the highly barrier protective layer 55 . The heat seal release layer 60 is bonded to the aluminum foil layer 58 by a suitable transparent adhesive 59 . Adhesive layers 57 and 59 of an embodiment of the present invention comprise a modified aliphatic polyester polyurethane adhesive sold as TYCEL 7909 from the Liofol Company. Alternatively, the outer clear adhesive 59 may comprise a modified aromatic polyester polyurethane adhesive sold as TYCEL 7900 from The Liofol Company. Aromatic adhesives are only used on the outside of the aluminum foil layer because of the potential for an attendant risk that the aromatic compound may be dissolved in either the diluent or the liquid drug. The inner adhesive layer 57 preferably includes an aliphatic adhesive.

Since the inner seal layer 56 of the highly barrier protective layer 55 is a co-extrusion coated resin, when a plurality of different materials are added, a peelable seal can be formed over a wide temperature range. Raw materials that can form the coextrusion coated resin include acrylonitrile-butadiene-styrene (ABS), high-density polyethylene (HDPE), high-impact polystyrene (HIPS), polypropylene (PP), polystyrene (PS), and polyvinyl. chloride (PVC) and an 80:20 membrane contained in the front sheet 12 of the container. Accordingly, the highly barrier protective film 55 may be removably (removably or releasably) attached to the outer surface of the front sheet 12 covering the intermediate or medicament compartment 23 .

The highly barrier protective film 55 is preferably removable (removable or detachable) from the container 10 prior to use, so that the state of the medicament in the medicament compartment 20 can be visually inspected. In the embodiment shown in FIG. 1 , the protective film 55 includes an extension tab 62 that can be gripped to peel the protective film 55 from the transparent front sheet 12 . This exposes the contents of the medicament compartment 20 to be visually observed.

The highly barrier protective film 55 may be sealed and adhered to only a portion of the front sheet 12 . This highly barrier protective film 55, which is not sealed to the main material of the front sheet 12, defines a regular arrangement or pattern of protruding dimples 51 of a generally cylindrical shape. The dimples are residues left by the heat seal bar in which the squarely arranged holes have been cut. When the heat seal bar is compressed on the surface of the highly barrier protective layer 55, it is heat-sealed only on the surface in contact with the heat seal bar, and is not heat-sealed in the area where the heat seal bar is not in contact. Since pressure is applied during heat treatment, the highly barrier protective film 55 has an opposite phase to that of the heat seal head, so that the protruding dimple surface protrudes. The dimples 51 allow the highly barrier protective film 55 to be suitably sealed to the underlying material (front sheet) of the medicament container, but at the same time allow the film 55 to be easily removed without applying undue force.

If the entire protective layer 55 is heat-sealed to the front sheet 12, a relatively strong bond is created and the amount of force required to completely remove it will be greater than the required magnitude. By reducing the surface area of the seal, the opaque barrier layer that can be peeled off with a small force (proportional to the seal area) must be removed. The amount of force required to remove the aluminum strip is inversely proportional to the number of dimples (51 in FIG. 1 ) formed in the film 55 . The highly barrier protective layer, which can be easily removed depending on the application of the medicament container, is removed with difficulty or ease by increasing or decreasing the number of dimples formed in the layer during heat seal treatment. However, the high barrier membrane 55 is heat-sealed to the entire mutagenesis container except for the tab 62 . Forming a fecal seal around the high barrier film 55 ensures a barrier layer of the film to the medicament compartment 23 .

In practice, the filled container 10 can be stored for a required period of time. Typically, prior to administration, a pharmacist or other user removes the highly barrier foil layer 55 from the front sheet 12 of the container 10 in order to visually check the condition of the contents. When the container 10 is not used immediately, it is recovered to the storage unit and administered when needed next time. When the peelable high barrier protective film 55 is removed from the drug compartment 23, the contents of the drug compartment are easily decomposed by moisture, light and permeable oxygen. The filling container according to the present invention is capable of preserving the drug without serious degradation even when exposed to moisture and free oxygen for a period of less than 30 days from the time the highly barrier protective film is removed from the drug compartment until use.

Thus, as shown in Fig. 4, a transparent, highly barrier interlayer film 64 is selectively interposed between the protective film 55 comprising a highly barrier aluminum foil and the 80:20 material of the front sheet 12 of the container. do. This intermediate laminated film 64 is disposed on the portion of the front sheet 12 that covers the intermediate compartment 23 . In this arrangement, the transparent high barrier interlayer 64 covers and protects the contents of the medicament compartment 23 after the peelable protective film 55 is removed from the container 10 . The transparent highly barrier interlayer exhibits barrier properties that protect the drug solution and drug from permeation of at least water vapor and oxygen for up to 30 days, depending on the specific activity of the drug. That is, the transparent highly barrier interlayer 64 together with the opaque highly barrier protective film 55 forms a highly barrier protective packing for the medicament compartment 23 .

As a "highly" barrier layer, the protective layer is characterized by its impermeability to various permeable gases. Polymers are classified according to their ability to limit the permeation of permeable gases, such as oxygen or water vapor. Classifications can range from "high" barrier layers (low permeability) to "poor" barrier layers (high permeability). The classification that separates the polymer will vary depending on the gas passed through. As used herein, "highly" barrier layer, when expressed in terms of permeability to water vapor, means a permeable membrane of at least about 1.5 g/mil/m2/24 hours/atm at 30°C, 100% relative humidity.

The transparent highly barrier interlayer 64 includes a triple layer of highly barrier laminate structure that significantly prevents the permeation of liberated oxygen and water vapor to protect the contents of the drug compartment and extend the shelf life of the two-component container. extend In the illustrated embodiment, the interlayer layer 64 is a silica-stacked polyethylene terephthalate (SiO) commercially available as TECH BARRIER H from Mitsubishi Kasei.<sb>X</sb> coated polyester or SiO<sb>x</sb> an outer layer 66 of coated PET). The seal layer 56 of the highly barrier protective film 55 is positioned in contact with the outer layer 66 of the interlayer 64 . Laminated silica (SiO2) sold as TECH BARRIER S from Mitsubishi Kasei<sb>x</sb> An intermediate layer 68 comprising a polyvinyl alcohol (PVA) film (coated) is combined with an outer layer 66 . The highly barrier interlayer 64, which is transparent on the inner side, includes an inner seal layer 69 formed of a polypropylene-polyethylene copolymer. The copolymer can be mixed with the styrene ethylene-butylene-styrene thermoplastic elastomer in various proportions, but a 100% polypropylene-polyethylene copolymer layer is preferred. The individual layers of the intermediate laminated film 64 are bonded by an adhesive. For the sake of clarity, the adhesive comprises a modified polyester polyurethane laminate not shown in the figures but sold as TYCEL 7909 from the Liofol Company. The inner seal layer 69 is securely attached to the outer surface of the front sheet 12 of the container by a suitable permanent heated or ultrasonic seal, adhesive pressure seal, or the like. A transparent, highly barrier interlayer 64 is sized vertically or horizontally to cover the entire surface area of the drug compartment and extends to cover the permanent seal and the peelable seal from which adjacent drug compartments are formed.

When using the flexible thermoplastic material included in the front sheet 12 , the three-layer laminate structure of the intermediate layer 64 is optically transparent to permit observation of the contents of the medicament compartment 23 . Thus, unlike polyvinylchloride (PVC) and other similar materials that are fairly opaque (translucent), the interlayer 64 of the present invention is visually transparent while being able to significantly protect against the decomposition of moisture and liberated oxygen.

In particular, the barrier properties of the laminated film 64 of the transparent highly barrier intermediate material are low density polyethylene (LDPE), medium density polyethylene (MDPE), linear low density polyethylene (LLDPE), ethylene-vinyl acetate copolymer (EVA) or these Functionally important parts of the container, for example moisture and oxygen permeability, are significantly superior to properties of conventional membranes, such as mixtures of polymers. The oxygen permeability of the intermediate layer 64 is about 10 cc/mil/m 2 /24 hours/atm. In contrast, the oxygen permeability of EVA copolymer, LDPE and MDPE is about 2500 (EVA 5%), 8300 (LDPE), and 8500 (MDPE) cc/and/m2/24 hours/atm, respectively. The oxygen permeability of LLDPE is approximately equal to or slightly higher than that of LDPE. Thus, the oxygen permeability of the transparent high barrier interlayer 64 is lower than that of conventional polymers used to make two-component medicament containers. That is, the barrier properties of the high barrier interlayer 64 are several times improved over those of polymers commonly used to make these containers.

Because of the barrier properties of the interlayer film, the peelable aluminum foil including the protective film 55 is removed by the pharmacist for visual observation of the contents of the container prior to administration, and thereafter, a reasonable addition without risk of oxygen or moisture causing decomposition of the drug can be stored for a period of Once the protective foil layer is removed, the container can be stored for about 30 days. After the aluminum foil layer is removed, the exact shelf life of a container containing the transparent highly barrier laminate 64 depends on the moisture or oxygen sensitivity of the drug contained in the drug compartment. A drug having a relatively low moisture sensitivity is protected by the transparent high barrier layer 64, so it can substantially maintain its efficacy for 30 days or more. In addition, the drug with the highest moisture sensitivity begins to lose its efficacy when exposed to water vapor when the aluminum foil layer is removed, but due to the moisture barrier properties of the transparent high barrier film packaging the drug compartment, the drug can be stored for 2 weeks without loss. have.

Although the interlayer 64 is described in the examples as being attached to the outer surface of the medicament compartment, one of ordinary skill in the art will appreciate that the size of the interlayer may be large enough to cover the medicament compartment and the first compartment, if desired. Also, the interlayer 64 may be used to cover the entire anterior membrane 12 . The method of attaching the intermediate layer to the outer surface of the container may be changed without departing from the spirit or scope of the present invention. The intermediate layer 64 may be permanently secured to the outer surface of the container by suitable adhesive and permanent heating or ultrasonic sealing. In addition, in order to make the interlayer film 64 peelable, the temperature and pressure characteristics of the heat seal may be adjusted to be removably provided on the surface of the container. In this case, the film 64 can be peeled from the container as in the case of the opaque highly barrier laminate 55 .

It should be noted that in a preferred embodiment the medicament is described in the form of a drug. Pharmaceuticals may also be in the form of colloids, crystals, liquid concentrates, emulsions, and the like. In addition, the medicament may be provided as a dry powder such as an antibiotic composition or an antiemetic composition. Examples include cefizolin, cefuroxime, cefotaxime, cefoxitin, ampicillin, nafcillin, erythromycin, ceftriaxone, matoclo pramide (matoclopramiad) and ticar/clav. It is not necessary to fill the drug compartment only with the drug itself. It is particularly suitable for administering from a container other medical compositions such as lipophilized blood fractions, blood factor IX, factor IX, prothrombin complex, and the like. While the containers of the present invention are described with multiple compartments and single agent and diluent compartments, single compartment containers may be provided in accordance with the present invention as detailed below. Also, containers having multiple compartments filled with different diluents and/or different medicaments may be provided in accordance with the present invention.

Preferred materials for the transparent, highly barrier interlayer 64 include oxygen barriers and moisture barriers, while other materials may be used to provide a medicament compartment cover that can be applied to a variety of applications. For example, it is possible to provide a highly interlayer film in which one of the high barrier layers is omitted and includes only a moisture barrier layer or an oxygen barrier layer. Furthermore, the highly interlayer 64 may include a moisture barrier layer combined with a heat seal release layer made of a refractory material having some oxygen barrier properties, as described above.

The flexible container 10 may be manufactured in full size or partial size. This limits the requirements for setting up and operating a pair of machines or multiple machines. As described above, the overall size of a single container of rectangular shape is measured by a common perimeter 16 , which facilitates the handling of the container as well as the administration of the contained medicament solution. In particular, this allows for the manufacture, handling, sterilization, and marking of containers 10 using similar or identical machines and methods and eliminates the need for multiple tooling and machine operation. However, limiting the overall size of the container 10 limits the volume of medicament solution that can be held in each compartment.

To increase the capacity of the container 10 in accordance with the principles of the present invention, at least one of the front seat 12 and the rear seat 14 is extended or permanently stretched. Enlarging the volumetric capacity of the container 10 can make a single container for storing and administering a very versatile and drug solution and drug mixture. Because the enlarged container is no different from a conventionally sized container, there is no need to improve the tool to make a bag of a specific size. This is particularly useful where small amounts of containers are needed that could not be manufactured due to cost concerns.

FIG. 5 shows a container 10 of a conventional or standardized size with each of the front and rear seats 12 and 14 permanently stretched to increase the capacity of the first compartment 22 . In particular, the front seat 12 and the rear seat 14 each include a respective surface area 70 . Each of these surface areas 70 faces one another through a common plane 71 that is generally defined along a common perimeter 16 . The front seat 12 and the rear seat 14 are enlarged by permanently extending the respective surface area 70 .

In the embodiment, only the first compartment 22 is enlarged. This form may be particularly useful when a standard dose of the drug is used and a diluent greater than the standard dose is required. The front seat 12 is further stretched or elongated relative to the rear seat 14 . This is what happens when the back seat 14 includes aluminum or other less extensible layers.

<b><u>Manufacturing and assembly of containers</u></b>

6 illustrates a method of manufacturing and assembling a flexible container 10 in accordance with the principles of the present invention. The front seat 12 and the rear seat 14 are arranged to face each other. The inner abutting layer of the front sheet 12 includes an 80:20 membrane, which is placed in contact with the inner facing 80:20 membrane layer of the back sheet 14 . Other interfacial membranes may be used within the spirit and scope of the present invention.

The composition of the front sheet 12 and the back sheet 14 of the container 10 uses a heat sealing method to achieve a seal along the common perimeter 16 and the peelable sheets 25 and 26 . The use of hot bars or dies at different temperatures, pressures, and times of application to bring the interfacial portions of the materials and laminates used to temperatures near or above their melting points, so that the materials cross the interface and form bonds with the desired strength and properties. let it do

With respect to a single-layer film or a multi-layer laminate film comprising an aluminum foil laminate comprising a front sheet 12 and a rear sheet 14, the manufacturing method of the container 10 has been described. The method includes cutting the front and back sheets of the container to a desired vertical container size that does not exceed the horizontal dimension.

When the container 10 consists of a single-layer front sheet 12 , a highly shielded aluminum foil-containing protective layer 55 ( FIG. 3 ) comprising a barrier cover for the second compartment 23 and a transparent high barrier interlayer 64 (FIG. 4) is cut to size to be placed over the area that will be the middle or medicament compartment and attached to the front sheet 12 of the container. According to the present invention, a transparent high barrier interlayer 64 is first laminated on the front sheet 12 surface, followed by an aluminum foil-containing protective layer 55 laminated thereon.

In particular, a transparent high barrier interlayer 64 is disposed over the second compartment laminated on the surface of the front sheet 12 and secured thereto by a pair of rods or similar devices. Accordingly, since the portion of the layer 64 in contact with the rod is difficult to heat-seal, for example, a small portion of the film is not sealed to the surface of the front sheet. In general, the rod contact surface is annular, resulting in two unsealed annular portions 41 that remain visible due to the reverse stamping caused by the pressure applied during the sealing process. After laminating the intermediate layer 64, an aluminum foil layer 55 is applied over their surface using a template heat seal die as described above.

After attaching the aluminum foil layer 55 and the transparent high barrier layer, the front sheet 12 and the back sheet 14 can be connected along a common perimeter 16 and permanently sealed. The outlet port 30 may include a flange 34 that is inserted into the desired final location between the front seat 12 and the rear seat 14 and is fluidly connected with the outlet compartment 24 . The outlet port 30 may be injection molded and may comprise 40% FUINA Z9450 polyethylene-polypropylene copolymer and 60% Shell Kraton G1652 styrene ethylene-butylene styrene thermoplastic elastomer composition. After pouring the outlet port 30 along the common perimeter 16, a heated die is used to the outlet port flange 34 and the bottom surface of the front seat 12 and the rear seat 14 near the flange 34. (20) to permanently seal between.

For example, between the seals 25 and 26 using a pair of hot bars including the front bar in line with the rear bar pressing the front seat 12 and the rear seat 14 between the seals 25 and 26, for example. Peelable seals 25 and 26 separating the compartment and container 10 and additional peelable seals are formed. For example, the front bar may be in contact with the pre-bonded highly barrier protective film 55 , the interlayer 64 , and the front sheet 12 . This front bar is maintained at a temperature of about 245 to 265 degrees Fahrenheit. The back bar in contact with the back seat 14 is maintained at about the same temperature as the burn bar (about 245 to 265° F.) and optionally includes a thin rubber coating to ensure uniform pressure. A pair of bars is pressed to a pressure of about 230 psi to 340 psi to contact the front and rear seats and hold this temperature and pressure for about 1.5 to 2.5 seconds. In addition, the peelable seals 25 and 26 can be made individually by setting up a pair of bars, or at the same time by setting up a pair of bars. Additional peelable seals can be easily applied by means of a three pair bar set-up.

After forming the peelable seals 25 and 26 , the front sheet 12 and the back sheet 14 are joined and sealed using a peripheral permanent heat seal extending along a common perimeter 16 . This permanent seal is spaced apart from the rear edge of the first side 27 of the container. In other words, the permanent seal breaks at the first side 27 along the vertical upper side 18 , the second side 28 , and the vertical lower side 20 into the first compartment 22 and the second compartment 23 . approach The permanent seal does not affect the fluid compartment of the outlet port 30 having the outlet compartment 24 .

The first sacrificial port 72 may be inserted between the front seat 12 and the rear seat 14 to be fluidly connected with the first compartment 22 . In a similar form, the second sacrificial port 74 may be inserted between the front seat 12 and the rear seat 14 to be fluidly connected with the second compartment 22 . Each sacrificial port 72 is disposed and supported along a common perimeter 16 of the first side 27 within the gap of the permanent heat seal. The sacrificial port may be supported by a common perimeter 16 in a similar arrangement to the outlet port 30 . Accordingly, each of the sacrificial ports 72 and 74 includes a tapered mounting flange 76 that is inserted and sealed between the front seat 12 and the rear seat 14 along a common perimeter of the first side 27 . The sacrificial ports 72 and 74 may be implant formed. Because the sacrificial ports 72 and 74 are removed and disposed at a later stage in the process, the sacrificial ports 72 and 74 are preferably made of inexpensive thermoplastic materials. In particular, the sacrificial ports 72 and 74 may be made of an 80:20 film "regrind" material, simple polypropylene, or other similar material.

The sacrificial ports 72 and 74 are an important feature of the present invention and are an important means of filling a single compartment container with a medicament solution or a liquid diluent in the first compartment 22 and medicament or the second compartment 23 into a multi-compartment vessel. provides In addition, the sacrificial ports 72 and 74 provide the port and flexible medicament container 10 with a structure that is supported and manipulated by an automated robotic machine.

As noted above, each sacrificial port 72 and 74 includes a bottom flange 78 and a spaced top flange 80 . In general, each of the flanges 78 and 80 may be of a type actuated by support and handling equipment. An internal aperture through each of the sacrificial ports 72 and 74 provides a means of flow between the respective compartments 23 and 24 .

A common cylindrical cap or plug 82 is provided for each sacrificial port 72 and 74 . The cap 82 may be of a structure having an outer diameter slightly larger than the inner hole of each of the sacrificial ports 72 and 74 so that when the cap 82 is inserted, it is welded to the boundary between the outer diameter of the cap and the inner diameter of the port. seal is provided. Such friction seals are necessary to prevent particles from entering the container and to prevent escape of the powdered drug or liquid diluent after the container has been aseptically filled. Each cap 82 may have a beveled bottom surface to fit a similar chamfer to each sacrificial port 72 and 74 .

In addition to the flanges 78 and 80 on the port, a vertically spaced flange may be provided on the cap 82 . In a preferred embodiment, a generally circumferential upper flange 84 defines the top of the cap 82 . The upper flange provides a "lifting" mechanism to the underside of the upper flange 110 and provides a means to lift the cap vertically from the respective port barrels 72 and 74 . Also, a lower flange 86 may be provided near the cap 82 . The lower flange 86 limits the penetration depth of the cap 82 while being inserted into the port barrels 72 and 74 that are repositioned after the filling operation. The lower flange 86 may be full circumferential, or it may act as a partial flange defining a simple lateral extension from the body of the cap 82 . The upper flange 84 and the lower flange 86 are spaced apart from each other along the body of the cap 82 .

This manufacturing step forms a flexible container 10 of a conventional type having unexpanded compartments 22 and 23 . As noted above, the first compartment 22 may be enlarged to increase the useful storage volume for the diluent. Likewise, the second compartment 23 and the outlet compartment 24 can also be enlarged. This includes permanently stretching at least one front seat 12 or rear seat 14 by inflating each compartment 22 , 23 , 24 using pressurized gas as described below.

<b><u>container manufacturing equipment</u></b>

A method and apparatus for manufacturing the container of FIG. 6 according to the principles of the present invention has been described in conjunction with FIG. 7 . As with the description of the apparatus for manufacturing a container below, the apparatus and method are suitably applied to the manufacture of a medicament container having a front sheet and a back sheet comprising a single-layer or multi-layer laminated film. In addition, the number, shape, arrangement, and position of various seals of the container 10 of FIG. 6 can be easily changed due to the module arrangement of the device components, and may be omitted if necessary.

7 is a schematic plan view of a preferred embodiment of a container maker 88 of the present invention, showing the arrangement and arrangement of the various seals forming a station and the arrangement and arrangement of the container's primary web feed roll.

Bulk material for the front and back sheets of the container (eg, 12 and 14 in FIG. 2 ) is provided to the container maker 88 in the form of respective bulk membrane web feed rolls 90 and 92 to the container maker 88 . at the intake end of the web feed roll station. For example, web material from the front sheet feed roll 90 passes through a dancer station 94 which functions to hold the web material at an appropriate strength and the web is pulled through a retention station of a maker 88 .

After the dancer station 94, the web material is conveyed by way of a vacuum feed wheel past a first web cleaning station 96 and behind a series of optional barrier application stations 98 and 100 to be placed continuously along the web path. When the container 10 is configured in the manner described above, i.e., in the manner comprising a single-layer front sheet 12, a transparent highly barrier interlayer (64 in FIG. 4), and a protective layer 55 containing a highly barrier aluminum foil. , the high barrier cover of the second compartment 23 is first cut and placed over the portion of the surface area 70 that will be the second compartment, then at each barrier application station 98 and 100 the front sheet of the container 10 ( 12) is sequentially attached. In accordance with the present invention, a transparent high barrier interlayer is first laminated on the surface 70 of the front sheet 12 at an application station 98 and then an aluminum foil-containing protective layer 55 is applied thereto at the application station 100 . put it on top

In a similar manner, the web material forming the back sheet of the container is passed from each bulk web feed roll 92 through a corresponding dancer station 102 to a corresponding web cleaning station 104 by vacuum feed wheels. When the successive films of the web material 90 and 92 of the front sheet and the back sheet exit their respective preparation steps, they are fed into each other's registration and the 80:20 surface of each successive planar film is 80:20 of the other film. 20 Placed facing the flat membrane. As continuous film webs 90 and 92 are fed into the registration, the web material is continuously indexed and moved longitudinally through the sealing core 106 of the fabrication apparatus 88 . First (diluent) and second (medical) loss ports 72 and 74 are arranged along the web sandwich and disposed between the front and back sheet membrane webs. Various seals are formed on the web sandwich to bond the webs and make the container 10 with intermediate steps suitable for inflation and aseptic filling. This is shown in FIG. 6 .

A seal core 106 of a maker according to the principles of the present invention comprises a plurality of seal press and port insertion stations arranged in a line along the travel path of a container membrane web sandwich. This first station is the set port loading station 108 in which the set port or outlet port 30 is inserted in a suitable position between the front seat 12 and the rear seat 14 . A hot press containing a forming die is compressed over the web material to form a seal at the set port sealing station 110 between the outlet port 34 and the lower sides of the front and rear sheets near the flange.

The set or outlet port 30 is made of plastic material and is injection molded from 40% FINA Z9450 polyethylene copolymer and 60% Shell Kraton G1652 styrene ethylene-butylene styrene thermoplastic elastomer composition. Because of the similarity between the material composition of the set port 30 and the material of the inner seal forming surfaces of the front seat and rear seat, a heat sealing method similar to the method used to form the permanent outer peripheral seal described in detail below is used for the front seat. and sealing the rear seat to the set port flange 34 .

After inserting and sealing the set port into the container material, the membrane web sandwich is indexed into the sacrificial port insertion station 112 and loss forks (72 and 74 in FIG. 6) are inserted between the front and rear seats. The sacrificial ports 72 and 74 are preferably injection formed from 100% polypropylene material, but may be made of a material having a composition similar to that of the outlet port 30 . In a manner similar to the outlet port 30, the front and rear seats are sealed with sacrificial ports 72 and 74 along the tapered flange 76 provided for this purpose.

After insertion of the sacrificial ports 72 and 74, a common perimeter 16 extending beyond what will be the top 18, bottom 20, and continuous face 28 of the finished vessel using a permanent heat seal. to bond the front and rear sheet membrane materials along the Along the opposite side 27 of the vessel 10 , a permanent heat seal is provided parallel to and supporting the gap to the perimeter 16 of the membrane web sandwich along the desired side of the finished vessel within the common perimeter 16 . formed in a broken form.

After the perimeter seal is formed at the perimeter seal station 114 , the container material is indexed into an optional first medicament sacrificial port seal station 116 . The front and rear sheet materials are sealed to the tapered flange 76 of the second sacrificial port 74 by pressing the front and rear sheet material to the tapered flange of the port by means of a pair of concave conformal heat sealing dies. When using a set port die, the station heat seal die of the second or medicament sealing station 116 is elliptical when the halves of the sealing die are compressed together, they are typically mirror images of the convex, slender sealing surface of the second sacrificial port. It is shaped like a pocket.

The web material is then indexed into a second, optional, second compartment sacrificial port sealing station 118 , and the front and rear sheet materials are pressed and sealed to the tapered flange 76 of the first compartment sacrificial port 72 . do.

The order of sealing the sacrificial port to the container is not in any way, and the second sacrificial port seal station 116 may only follow the first sacrificial port seal station 118 . Also, the seal station that seals the sacrificial ports 72 and 74 to the container 10 must come before the perimeter seal station 114 . An additional optional seal station, a sacrificial port insertion station 110 followed by a perimeter seal station 114, is optionally provided with a peelable seal forming station 120 shown in FIG. A peelable seal is formed between (27) and the opposite second side (28). The peelable seal subdivides the container 10 into a plurality of compartments. Additionally, the optional peelable seal station 120 may be configured to realign the peelable seal station along the membrane web path to advance the sacrificial port insertion station 112 . If the container is manufactured to have a plurality of compartments, a plurality of peelable seal stations may be provided.

Those skilled in the art will appreciate that the membrane web can be indexed into their respective stations so that a plurality of sequential and individual seal stations can be configured to automatically operate. In addition, seal stations may exist within the container maker, but are deactivated so that their characteristic seal is not formed in a particular manufacturing process. In particular, the container can be made without a peelable seal, as detailed below. Following application of the sacrificial port seal, the web material of the container is brought into contact with and overlaps several broken portions of the permanent seal along a common permanent perimeter, applying a heat seal to the overlapping container material and sealing station in the trim area extending to the side of the container membrane material. It is indexed at (122).

After the heat seal treatment step, the container may be indexed via a hanger punch station 124 or the like, which forms a hanger cutout in the upper center of the container. The next station 126 and 128 cuts the raw material web at the lower end 20 (126) to separate the vessel, and the trim upper station 128 removes the vessel material at the upper end (18). Then, when the container is withdrawn from the maker 88, the structure of the container is generally completed.

Those skilled in the art will appreciate that the number and arrangement of compartments containing the vessel is determined solely by the number and location of the various heating seals used to form the vessel. Also, depending on the number of containers expected to be finished products, a suitable number of sacrificial ports are provided and disposed along their respective web edges of material. The module manufacturing process according to the present invention is applied to manufacture a medicament container having a single primary compartment or a multi-compartment container having a plurality of compartments by providing an additional peelable seal and an additional sacrificial port for filling the compartments. For each batch of compartments and sacrificial pots, one press face can be removed and replaced with another so that the trim area seal press can be properly grown in the first trim area seal station 122 . It provides one, three or four channels or openings to connect the plurality of sacrificial ports to the plurality of compartments.

In a similar manner, those skilled in the art will appreciate that the front and rear sheets of the container may be modified by suitably replacing the front and rear membrane feed web rolls with other suitable materials. In particular, the front and rear sheet feed rolls may be a single layer of 80:20 membrane with the finish container reflected on both sides. Because of the modular nature of the manufacturing apparatus, the transparent barrier application station and the foil application station are fully transparent, as well as a peelable seal forming station, the container maker is fully transparent and a single compartment that can contain a plurality of outlet ports such as separate med and set ports. It may not be possible to make the container into a form that provides it.

Accordingly, it has been found that the container maker of the present invention is suitable for making a wide variety of medicament containers having a variety of sizes, seal arrangements, and port locations. All containers manufactured according to the present invention appear suitable for aseptic filling after expansion to increase their capacity according to the present invention, as well as for use in conjunction with a final sterilization process.

<b><u>seal formation</u></b>

The peelable seals 25 and 26 formed in the manufacturing process described above are thin, cylindrical, straight seals. While they are similar to conventional straight seals, the peelable seals of this embodiment have been improved in that they exhibit more predictable rupture characteristics across the manufacturing compartment, ie, exhibit uniform resistance to steering pressure.

While not supported by theory, it is believed that the peelability of the seal is achieved by limiting the time, pressure and temperature required to melt the interface between the inner layers of the front and back sheets of the container. That is, the melting temperature of the inner layer has a lower melting temperature than that of the intermediate layer and the outer layer of the back sheet. It imparts peelable properties to the seal that limit the structure of the inner layer of the melt zone, providing strength strong enough to prevent rupture during normal handling of the container. Preferably, the activation force of the container of the present invention is tightly controlled to ensure ease of use by all users, while allowing the container to be preserved under extreme handling conditions. Efforts and forces to activate are caused by bursting pressures that vary according to the shape, width (W), or function of each seal (ie, a first selectively peelable seal, a second selectively peelable seal, or a safety seal). Although specified, it is uniform in the range of about ±1 pound per square inch (psi) for one particular seal.

It is considered that the critical variable that must be controlled in order to impart such uniformity in burst pressure is temperature. Uniform burst pressure response can be achieved by adjusting the seal temperature to ±2°F. Commercially available heat seal devices cannot control the temperature of the heat seal within the desired range as described above. However, the seal time can be controlled very precisely. Therefore, time is selected as a control factor and controlled to compensate for changes in the four heat seal temperature. The time and pressure of the seal heads are irradiated to ensure they are within acceptable ranges and the heat seal time is adjusted accordingly. Where it is desirable for the contact pressure to be in the range of about 230 psi to about 340 psi, one skilled in the art will appreciate that the lower limit of this range (230 psi) is readily provided in setting the parameters of the heat seal device. If the pressure applied by the heat seal bar on the container material is sufficient to force the material seal layer into contact with the desired surface area of the seal, a peelable seal will be formed at a given suitable temperature and time. Also, changing the heat seal temperature and time outside the ranges contemplated by the present invention will not only result in the seal not exhibiting the desired uniform resistance characteristics, but will also fail to completely rupture over the entire length of the seal. Incomplete seal rupture often results in a residue of diluent or agent, leaving the peelable seal trapped in the 90° corner in contact with the permanent edge seal of the container. Therefore, the diluent/drug mixing ratio may not be as intended and the delivered drug may be in a higher concentration than desired.

An example of a specific time, temperature, and pressure setting that can form a peelable seal would be to have a burst pressure uniformity of about 4±1 psi in the embodiment described as an 80:20 membrane, pressure = 235 psi, temperature = 257 °F, and time = 1.9 seconds; and pressure = 235 psi, temperature = 263 °F, and time = 1.75 seconds.

High temperatures and associated pressure and time are required to form permanent edge heat seals and outlet port seals. The seal may be formed by heat sealing at a temperature of 290°F and a pressure of 200 psi or less for about 2 seconds. Those skilled in the art will appreciate that a variety of techniques for forming permanent and peelable seals may be used to construct the container of the present invention. In particular, it will be apparent that a high degree of control of the seal temperature (within about ±2°F) makes it possible to form a peelable seal with a uniform burst pressure. Time is also chosen as the control factor for seal formation because it can be removed accurately. Accurately controlling temperature, pressure, or both will give the same result.

<b><u>compartment enlargement</u></b>

After placing the containers 10 in the manufacturing step shown in FIG. 6, their volume can be enlarged according to the principles of the present invention. In particular, compartments 22 , 23 , and 24 can be inflated or enlarged to increase their volumetric capacity. For example, the first compartment 22 can be permanently inflated to increase the capacity of the storage diluent. This can be particularly useful where lower doses of the drug are required or where more concentrated drugs are used.

The first compartment 22 may be inflated by stretching the front seat 12 , the rear seat 14 , or both. This stretching extends the membrane layer comprising the anterior and posterior sheets 12 and 14 in the longitudinal and transverse directions. Compartments 22 , 23 , and 24 may be extended or elongated to different degrees to accommodate various increases in volume.

For example, as shown in FIG. 5 in conjunction with FIG. 6 , the first compartment 22 can be inflated by temporarily supplying pressurized gas to the first sacrificial port 72 . The pressurized gas expands the first compartment 22 and applies an expanding force over the surface area of each of the front and rear seats 12 and 14 . The first compartment 22 is preferably permanently stretched or extended in the machine direction and in the transverse direction to the desired volumetric capacity by pressurized gas. To facilitate proper stretching and shaping of each of the anterior and posterior sheets 12 and 14, a tool or form having molded cavities described in detail below may be used. The pressurized gas may include compressed air. However, other compressed gases or liquids may be used. As the pressurized gas, 0.2 microns of filtered air or nitrogen is preferred.

8-10 illustrate another embodiment of a single compartment flexible medicament container constructed in accordance with the present invention. In this embodiment, parts similar to those in the above embodiment are indicated by the same reference number and "a" after it. As shown, a flexible container 10a is provided for storage and administration of a medicament solution.

In this embodiment, the front seat 12a and the generally facing rear seat 14a are sealed along a substantial portion of the common perimeter 16a to form a single volume enclosure 17a. If desired, the volume enclosure 17a can be separated into two or more separate compartments using a peelable seal that extends from a first side 27a of the common perimeter 16a to an opposite second side 28a of the common perimeter 16a. can be separated to connect the front and rear sheets 12a and 14a as described above.

A separate pair of sacrificial ports 72a and 74a may run along the first side 27a of the common perimeter 16a, and the outlet port 30a may run along the bottom 20a. Ports 72a and 74a are disposed between the front and rear seats 12a and 14a along the rupture in the permanent seal and heat sealed in place as described above. Ports 72a, 74a, and 30a are preferably provided as part of this single out-of-mouth container 10a to facilitate expansion of volume enclosure 17a and to use universal handling and manufacturing equipment. Accordingly, ports 72a, 74a, and 30a and their structures may be the same as the multi-compartment vessel described above.

The container 10a is manufactured in a standardized or non-expanded size. At this stage of the manufacturing process, the container may be expanded or maintained in an unexpanded volume enclosure as manufactured to proceed with the aseptic filling step. In the embodiment of Fig. 8, the container 10a is of a configuration having a substantially planar front sheet 12a composed of a layered polymer layer as described above and a similarly sized opposite planar back sheet 14a composed of a multilayer laminate. can be manufactured. The transparent blocking layer and the opaque blocking layer described above are omitted. In general, such a barrier layer is not necessary if there is no compartment for the medicament. However, such a barrier layer may be added or provided if a multilayer-compartment embodiment with enlarged compartments is desired.

The container 10a of FIG. 8 suitably has a vertical length of about 8.25 inches along the first and second sides 27a, 28a, and a width of about 5.25 inches across the top and bottom 18a, 20a. . In this embodiment, the permanent seal formed along the common perimeter 16a may define a volume enclosure 17a having a maximum planar dimension of about 7.0 inches by 3.5 inches. These dimensions are approximate and do not include the open space between the sacrificial ports 72a, 74a and the volume enclosure 17a. The vessel 10a described above provides a surface area 70a of about 24.5 square inches for each of the front and rear sheets 12a, 14a.

As manufactured, the single compartment container 10a has a specific capacity of about 130-150 ml. For illustrative purposes only, this capacity is defined simply by filling the volume enclosure 17a with fluid and then measuring its quantity in a graduated cylinder. However, a larger capacity may be required within the boundaries of the substantially rectangular container. As discussed, the total capacity of the container 10a can be greatly increased by stretching at least one of the front and rear sheets of the volume enclosure 17a. This involves spreading each sheet 12a, 14a to a different degree. Preferably, the inflated anterior and posterior sheets 12a, 14a are each unfolded outwardly, i.e. away from the common plane 71a, as well illustrated in FIG. form a surface). The term "planar" as used herein, with respect to the front and rear sheets 12a and 14a, refers to each sheet before being expanded.

In some applications, it may be desirable to unfold only one of the front and rear sheets 12a, 14a. In that case, the front seat 12a is the most preferential expansion target. This is because, in general, the back sheet 14a includes a layer of aluminum foil or a similar barrier layer and has essentially a low modulus of elasticity, and has substantially low responsiveness tensile properties. Since the front sheet 12a is generally a homogeneous layer with highly sensitive tensile properties, greater elongation is achieved when the front sheet 12a is stretched over the rear sheet 14a. In addition, the back seat 14a is often used for marking, including care and mixing instructions. Printing may be less efficient on stretched and curved sheets. Reading information printed on a permanently stretched curved sheet may also not be easy. However, in certain applications, the back seat 14a may be stretched alone.

In stretching either of the front and rear sheets 12a, 14a of a container made in accordance with the present invention, it is appropriate to recognize that the stretching properties of the front and rear sheets depend on the particular material from which they are made. The physical tensile properties of various single-layer and multi-layer laminates used in the construction of medical containers are relatively easily determined by the method presented in ASTM D-882-81. The general tensile properties of the various members of the monolayer and multilayer membranes described above can be obtained from the membrane manufacturer through the technical data sheet for the specific membrane. For example, KRATON G1652 styreneethylene-butyleneethylene elastomer generally has a tensile strength of about 4500 psi, exhibits an elongation at break of about 500%, and has a modulus of about 700 psi at 300% elongation. Similarly, the Fina Z9450 copolymer has a tensile strength of about 2500 psi, and the aluminum foil layer (ALCAN 1145) has a tensile strength of about 9300 psi (0.001 gauge) and an elongation property of about 4.2% (at 0.001 gauge). It will be understood by those skilled in the art that other membranes having different tensile strengths and different elongation properties may necessarily expand more or less than the aforementioned membranes. Such different elongation measurements are readily reliant on routine test data obtained with uniform sample shapes, such as dumbbell samples cut with ASTM die C, under uniform jaw separation rates and uniform temperatures. can be calculated.

Referring to FIGS. 11 and 12 , an embodiment of an instrument according to the present invention, ie a tool 130 , used for expansion of a container 10a of the present invention is described. The tool 130 is shaped to receive at least a portion of the volume enclosure 17a. The tool 130 includes an upper tool 132 and a lower tool 134 opposed thereto. In the illustrated embodiment, the lower tool 134 has an inner cavity 136 and the upper tool 132 has an opposing inner cavity 138 . A planar outer surface 140 surrounds each cavity except for an opening 142 in one of the ports 72a, 74a, 30a. Other shaped tools may include tools 132 or 134 that are not provided with a cavity and have a substantially flat surface. This shape is advantageous when only one of the front and rear sheets 12a, 14a is inflated. Other shapes include cavities 136 and 138 of different sizes and shapes to match the shape of the front and rear seats 12a, 14a being stretched.

The tool 130 may also include coupling devices 144, such as dowels and corresponding apertures, that allow the upper and lower tools 132, 134 to be secured and interlocked during use. However, other devices or methods may be used to keep the upper ends 132 and 134 aligned with each other. A sealing lip 146 circumferentially surrounds at least one of the cavities 136 , 138 and follows the seal footprint of the expanding compartment. The sealing lip 146 holds the front seat 12a and the rear seat 14a together during the inflation process and keeps the pressurized gas within their boundaries. This prevents the expansion force from being substantially transmitted into the permanent seal along the common edge face 16a 16a. The sealing lip 146 may engage an o-ring or the like and may be provided on each tool 132 , 134 , or alternatively only one tool. The sealing lip 146 is preferably ruptured or obstructed around the opening 142 . This allows pressurized gas to enter and exit the volume enclosure 17a. Preferably, the opening 142 is formed adjacent to one of the ports 30a, 72a, 74a to allow expansion and contraction through the port.

In the embodiment shown in FIG. 11 , the tool 130 is shaped to receive the entire volume enclosure 17a of the single compartment container 10a . The container 10a rests on the lower tool 134 with the outer surface of the front sheet 12a facing the common edge face 16a supported by the lower cavity 136 and the planar surface 140 . The sealing boundary 146 is aligned directly inside the permanent seal along the common edge face 16a. A pair of spaced apart sacrificial port slots 148 are disposed along a common side of each of the tools 132 , 134 , each configured to receive one of the sacrificial ports 72a , 74a . The evacuation port slot 150 is disposed along the second common side of the tools 132 , 134 and is configured to receive the evacuation port 30a.

Once the vessel 10a is aligned with one of the tools 132 , 134 , preferably within the lower tool as described above, the other tool can be mated. An upper tool 132 is disposed against the lower tool 134, the outer surface of the back seat 14a faces the upper cavity 138 and ports 30a, 72a, 74a are positioned within the port slots 148, 150. can be arranged to be accommodated. The planar surface of the upper tool 132 rests against the planar surface 1400 of the lower tool 134 and is sandwiched in such a manner as to constrain the entire common perimeter 16a except for the opening 142. Opening 142 allows pressurized gas to enter and exit the first sacrificial port 72a. The interposed vessel 10a is thereby inflated by the pressurized gas to inflate the volume enclosure 17a and abut against the cavities 136, 138. The front and rear seats 12a and 14a are forcibly extended.

Tool 130 may also be provided in any number of shapes as can be determined by one of ordinary skill in the art, and thus the illustrated embodiments are not intended to be limiting. Additional embodiments may include tools having different sized upper and lower cavities, or tool configurations in which one tool has a cavity and the other tool has a planar surface. This embodiment is particularly useful when only one of the front and rear sheets 12a and 14a is stretched. Alternatively, a tool may have a plurality of different cavities within each tool for use with multi-compartment containers. This embodiment may require an opening formed into each different cavity to inflate the different compartments and a planar surface formed in each tool for supporting a peelable seal defining each compartment. When expanding only a single compartment in a multi-compartment vessel, each tool may have only one cavity but its size may be, for example, slightly smaller than the outer diameter of the compartments.

The sacrificial port slot 148 and the evacuation port slot 150 may be configured to align with the vessel 10a inside the tool 130 . Thus, both slots may include grooves for receiving flanges 78a, 80a on sacrificial ports 72a, 74a, or may have other shapes to securely position each of the ports. Alternatively, only one or two port slots 148 , 150 may have such a shape. However, other devices and methods for aligning the vessel 10a within the tool 130 may be used as would be known to those skilled in the art. For example, alignment grooves may be provided along the planar surface 1400 to receive at least a portion of the top, bottom, or sides 18a, 20a, 27a, 28a of the container 10a. Alternatively, a slot, notch or other alignment device (not shown) may be provided in the container 10a , a complementary alignment post or the like may be provided on the tool 130 .

In the preferred embodiment, the tool 130 with the container 10a captured is actuated by the inflator 152 for expansion and expansion as illustrated in FIG. 13 . Preferably, the inflator 152 includes a workbench 154 for receiving and handling the tool 130 . The tool 130 is put into the inlet 156 of the inflator 152 . When mounted inside the inflator 152 , the cylinder 157 is used to fasten or hold the opposing tools 132 , 134 together. The cylinder 157 may be driven by a hydraulic type, an electric motor type, or the like, but a pneumatic type is preferable. Other devices and methods, such as pressure clips, may be used to hold the two tools in engagement during the expansion process.

A supply of compressed gas 158 is connected to an opening 142 inside the tool 130 and the vessel 10a is inflated by the compressed gas 158 to force the front seat 12a into the lower cavity 136 and the rear. The seat 14a is fully inflated into the upper cavity 138 . This expansion permanently stretches and stretches both the front seat 12a and the rear seat 14a outward in a common plane defined by a common perimeter 16a inside the tool 130 . Compressed gas 158 may be held inside tool 130 for a short period of time to hold front seat 12a and back seat 14a against their respective cavities 136 , 138 . By holding the expanded volume enclosure 17a, the amount of shrinkage or elastic repulsion is reduced. In general, for the aforementioned membrane structural material, this time is less than 1 minute. The compressed gas 158 is then released and the tool 130 is removed from the inflator 152 so that the expanded vessel 10a is removed from the tool 130 . This expansion operation is preferably automated.

In the illustrated embodiment, container 10a is inflated from an initial volumetric capacity, ie, an unexpanded volume, of about 130-150 ml, to an expanded volumetric capacity, of about 250-300 ml, as the volumetric capacity defined herein. Preferably, vessel 10a expands to a volumetric capacity of about 260 to 280 ml, more preferably about 280 ± 5 ml. To achieve these particular final dimensions for the single compartment vessel illustrated in FIG. 8, the shape of the cavities 136, 138 of the upper and lower tools corresponds to a trajectory area corresponding to the compartment area of the vessel, i.e., approximately 7 inches by 3. formed to have 5 inches, each dug deep enough to provide a volume of about 300 ml for the lower tool cavity 136 and a volume of about 100 ml for the upper tool cavity 138 . Specifically, the lower tool cavity 136 was dug to a depth of about 1.5 inches and the upper tool cavity 138 to a depth of about 6 inches. Additionally, each side of the cavity is fused to the cavity bottom with a continuous curvature to expand the material by minimizing "hard corners" into which the container material is forced into it.

Thus, when the cavities 136, 138 of opposing tools are engaged, they have a total volume of about 400 ml and a longitudinal cross-sectional area of about 24.5 square inches. These volumes and areas are not exact as the area within port slots 148 and 150 is not necessarily taken into account. It should also be noted that, due to the greater depth (and consequently increased volume) of the cavity 136 of the lower tool, the front seat 12a can stretch significantly greater than the rear seat 14a. The reason for the different volumetric capacities between the upper and lower tool cavities is that the front and back sheet material expands until it abuts the inner surface of the cavity. The depth of each cavity and its corresponding volume are formed to correspond to the general tensile properties of the membrane expanding into the cavity.

The volume enclosure 17a is preferably inflated for about 1 to 30 seconds with compressed air having a pressure of about 10 to 30 psi. Pressures of 10 psi or less may be used but the force generated is usually insufficient to permanently stretch the front and rear seats 12a, 14a against the cavities. Stretching at pressures of 10 psi or less may be achieved by utilizing different materials, such as a container having two homogeneous layers similar to the thin layer front sheet 12a described above. Pressures above about 30 psi will rapidly inflate the front and rear seats 12a and 14a against the cavities 136 and 138 . This rapid expansion can lead to corrugated material by stretching the material too quickly, delamination in the back sheet 14a stack, and other undesirable results. Higher pressures may be used by expanding the volume enclosure 17a in a gradual or stepwise manner, or by heating the compressed gas. The surface of the expanded sheet or cavity may also be heated. The above and other methods and devices can be used to vary the desired pressure and time necessary to achieve the desired expansion capacity for the vessel 10a as will be known to those skilled in the art.

In a preferred embodiment, the volume enclosure 17a is inflated for 15-25 seconds using compressed air regulated to a pressure of about 15-25 psi within the tool 130 . More preferably, the pressure is adjusted and maintained at about 20 psi for about 15 seconds at ambient temperature. Each membrane may be further stretched if the volumetric capacity of the expansion tool is correspondingly increased by increasing the pressure or time. This increased inflation provides of course an increase in the volume of the inflated container. Likewise, a decrease in pressure or time results in reduced expansion and reduced volumetric capacity. These desirable factors fully inflate the front seat 12a against a lower cavity 136 of 300 ml, and fully inflate the rear seat 14a against an upper cavity 138 of 100 ml, resulting in a total expanded volume of about 280 ml ± 5 ml. brings Shrinkage due to the relaxation modulus of the material results in the expansion volume of the vessel 10a being less than the sum of the cavities 136 and 138 . To minimize further shrinkage, a deblocking process may be utilized as detailed below.

The above-described exemplary expansion process results in a liquid 10% expansion of the surface area of the front sheet 12a and an approximately 6% expansion of the area of the rear sheet 14a. A preferred material, however, is one that can be permanently deformed to a much greater extent, allowing the manufacture of containers with much larger volumetric capacities. For example, the surface area of the front sheet 12a made of a preferred 80:20 ratio material can be expanded by at least about 16%, and the surface area of the back sheet 14a made of a preferred laminate material can be expanded up to about 10%. do. The surface area of the front sheet 12a made of the preferred 80:20 ratio material can be expanded over the surface area of the preferred back sheet 14a, in part because of the low elasticity of the aluminum layer in the laminate of the back sheet. ) is due to

Vessel 10a is unblocked once established. This process maintains the gas volume within the expanded volume enclosure 17a sufficient to maintain the enclosure in an expanded state. Unblocking prevents the expanded volume enclosure 17a from further retracting due to its intrinsic elasticity defined by the material's modulus of relaxation. This can be particularly advantageous for a front sheet 12a that generally expands to a greater elongation and is not supported by an adhered aluminum layer.

Unblocking involves inflating the container 10a using a low pressure gas to ensure that the volume enclosure 17a is fully inflated to its expanded shape. The low pressure gas includes compressed air adjusted to several psi. However, other gases may be used, such as dry nitrogen. Preferably, the unblocking pressure is controlled to about 10 psi or less, more preferably from 1 to 5 psi. This prevents continuous shrinkage, stress on the sealant, etc. When the volume enclosure 17a is fully inflated, the sacrificial port 72a and the exhaust port 30a are capped. Further contraction of the volume enclosure 17a is resisted in the form of gas pressure within the sealed volume enclosure 17a. Unblocking may occur within the inflator 52 . However, it may also be desirable for an unblocking member to be provided.

A further embodiment of a medical container made with an expanded compartment volume is described below with reference to FIGS. 6 , 11 , and 12 . FIG. 6 is a partial schematic front view of a particular embodiment of a multiple-compartment container at the same manufacturing process step as the single-compartment container shown in FIG. 8 ; The multi-compartment container of FIG. 6 differs from the single-compartment embodiment in that in the single-compartment case peelable seals 25 and 26 extend throughout the container and extend between permanent perimeter seals 16 on either side of the container, e.g. For example, it is a point which forms the intermediate|middle compartment 23 containing a medicament. The peelable seals 25 , 26 also serve to outline a separate compartment 22 for containing the diluent and an initially empty outlet compartment 24 . A multi-compartment container made with the membranes and techniques described above in accordance with the embodiment of FIG. 6 can contain a relatively limited volume of diluent in the diluent compartment 22 . The multilayer laminated backsheet is a relatively stiff barrier material, and as described above, its rigidity limits the volume of diluent that can be introduced into the compartment for diluent 22 to about 60 ml. In fact, containers of the type shown in FIGS. 1 and 6 are commonly marketed as 50 ml, ie 50 ml of diluent for mixing with the medicament prior to dispensing. Many injectable therapeutics typically require an IV container capable of holding a volume substantially greater than the volume of about 60 mL of the diluent compartment 22 of the container of FIGS. 1 and 6 . In particular, a PAB container manufactured and marketed by McGaw, Inc., Irvine, Calif., is commonly used to contain 100 ml of 0.9% sodium chloride solution under partial fill conditions. It can thus be seen that it is particularly desirable to inflate the compartment 22 for the diluent of the multi-compartment container illustrated in FIGS. 1 and 6 .

As noted above, with respect to the embodiment of Figure 8, the container is housed in a tool having a hollow interior cavity and is inflated by a compressed gas thereby dispensing the material of the front and rear seats (or only the front sheet) of the container into a particular compartment. It stretches to permanently expand to a specific volumetric capacity. The process and apparatus described in conjunction with FIGS. 9-13 are equally suitable for use with respect to the multi-compartment vessel of FIG. 6 . All that is needed is that the areal footprints of the upper and lower cavities 136 and 138 are reduced or modified to conform to the trajectory of the compartment 22 for the diluent of the multi-compartment vessel 10 of FIG. 6 .

As used herein, the compartment trajectory for the diluent is generally rectangular and has a permanent perimeter seal 16 on three sides, and a peelable seal 25 on the fourth side, wherein the peelable seal 25 is a diluent compartment ( 22) from the compartment 23 for medicaments. Ignoring the channel 41 formed between the compartment 22 for the diluent and the corresponding sacrificial port 72, the compartment trajectory represents a rectangle about 3.5 inches wide and about 5.0 inches long. Accordingly, the sealing boundary ( 146 in FIG. 11 ) is shaped and dimensioned to conform to the sealing trajectory of the diluent compartment 22 of the multi-compartment container of FIGS. 1 and 6 .

Since the seal 25 separating the diluent compartment from the medicament compartment is a peelable seal, the shape of the sealing boundary ( 146 in FIG. 11 ) is invariably slightly inside the seal, particularly the peelable seal 55 . Special care should be taken to place Given that the peelable seal is designed to rupture under pressure, the sealing boundary 146 is formed inside the seal trajectory, in particular within the trajectory of the peelable seal 55, to counteract the application of burst pressure to the peelable seal. It can be seen that it forms a pressure stop.

In a manner as described with respect to the embodiment of FIG. 8 , compartment 22 for diluent of the multi-compartment container of FIGS. 1 and 6 can accommodate either, or both, front seat 12 and rear seat 14 . It can be expanded by stretching. It will be appreciated that, due to the nature of the membranes used to form the front and rear seats 12 and 14 , the front seat 12 can expand more than the rear seat 14 under the same conditions of time and pressure as those described with respect to FIG. 8 .

The tool embodiment used to inflate the compartment for the diluent of a multi-compartment medical container is generally very similar to the tool embodiment described with respect to FIGS. 11 and 12 . However, the depth of the upper and lower cavities 136, 138 is not sufficient to overstretch the diluent compartment membrane material due to the small facet trajectory of the compartment for the diluent relative to the entire container (3.5" x 5" versus 3.5" x 7"). correspondingly decreased. As noted above, the lower cavity 136 has a trajectory of about 3.5 inches by 5 inches and a cavity depth of about 0.75 inches to about 1.0 inches, thereby defining a cavity volume from about 160 ml to about 175 ml. Preferably, in the embodiment of FIG. 6 only the front sheet is stretched, so that the upper tool is made substantially flat with no cavities. However, if a cavity is formed, it has a trajectory of about 3.5 inches by 5 inches and a cavity depth of about 0.25 inches to about 0.35 inches, thereby forming a cavity volume of about 50 ml to about 60 ml. Provided that the cavity is provided in this way, the compartment 22 for the diluent allows it to expand from a steady state standard dose of 50 ml to a volumetric capacity (term defined above) of about 100 to 150 ml.

When the multi-compartment vessel of FIGS. 1 and 6 is placed with an appropriate expansion tool, the diluent compartment is drawn through the corresponding sacrificial port (72 in FIG. 6) with an inlet pressure of about 20 psi with 0.2 micron filtered air or nitrogen. is inflated The diluent compartment remains inflated for about 15 seconds to give the membrane time to stabilize in its stretched state. After volumetric expansion, the multi-compartment container is sterilized, aseptically filled, finished to final dimensions and ready for shipment to the end consumer.

Sterilization, filling and final container formation

After the container 10a has been expanded to the desired volumetric capacity, the container preferably has the shape illustrated in FIG. 8 . The container 10a is now ready for aseptic filling with sterile and medical solutions. After sterilization and filling are complete, the sacrificial ports 72a and 74a are removed to result in a finished expanded container as illustrated in FIG. 17 .

In the illustrated filling process, a specific embodiment of a container to be filled according to the present invention is a combination of a single-layer front sheet membrane 12a and a multilayer aluminum foil laminated back sheet membrane 14a. The front and rear seats 12a, 14a are each shaped to contain a volumetric container 17a having a portion of the common perimeter 16a left unsealed for filling through provided sacrificial ports 72a, 74a. An embodiment of a container at this stage of manufacture is best illustrated in FIG. 8 . Primary vessel fabrication, including provision of evacuation ports 30a and sacrificial ports 72a, 74a, is performed by the method and apparatus described above.

In order for the aseptic filling process to be acceptable for medical purposes, the unfilled container 10a must be subjected to sterile conditions. Conventionally, sterilization of containers has been done in separate treatment areas or facilities due to the extensive and complex equipment and processes required for sterilization materials. A particularly undesirable feature of the sterilization process is that the container must be transferred to a sterilization facility for processing, and the container must be maintained sterile during subsequent transfer to a storage and aseptic filling facility. Containers should be introduced into the aseptic filling area by means of a sterile transfer method to prevent contamination by the containers to the aseptic area. Upon introduction into the sterile area, the containers are filled aseptically, but must be further treated in a sterile manner.

In accordance with the practice of the principles of the present invention, following primary container manufacturing, a plurality of empty containers are loaded into a sealed handling container to protect the flexible container 10a contained therein from environmental contamination.

Referring to FIG. 14 , a transfer or handling container generally designated at 160 and designated "carrier" functions as a transportable sterile isolator for introducing empty containers in a systematic manner into a sterilization, transfer, and sterile area. do The carrier 160 supports within the tray three components: a substantially rectangular container tray 162 , a sealable membrane cover 164 , and a plurality of containers 10a within the tray and is described in more detail below. and a rail cartridge 166 as will be described. The carrier 160 described above is exemplary only, and other shapes may be used as will be appreciated by those skilled in the art.

The substantially rectangular container tray 162 may be made of a heated polystyrene material or other material that can withstand multiple sterilization cycles without significant degradation. The tray 162 has an outwardly inclined upper periphery having a flat, horizontal perimeter lip, or flange 168, wherein the flange extends about 1/4 inch to 1 inch off the side of the tray 162. It may be formed in the shape of a basin. Preferably, the lip 168 extends about three-quarters of an inch beyond the sides of the tray, although any extension is suitable as long as it provides the tray 162 with sufficient rigidity and surface to support the seal. Two opposing pockets 170 , 172 are formed approximately at the center of the two opposing short sides of the tray and extend outwardly from the sides. The pockets 170 and 172 extend only partially downward along the sides of the tray to form two opposing recesses into which the end of the rail cartridge 162 can be inserted. do. The rail cartridge 166 rests on the bottom surface of the pockets 170, 172, so that the container 10a arranged on the rail cartridge is above the bottom surface of the tray 162 at a sufficient height to be freely suspended in the interior space of the tray. will be floating Accordingly, the pockets 170 and 172 are coupled with the rail cartridge 166 to function to maintain the multiplicity of the container in a specific posture while the container 10a is transported, stored and UV sterilized.

When the rail cartridge 166 is loaded into the container 10a and inserted into the pockets 170, 172, the tray 162 is heat-sealed to the tray flange or cover 168 with the plastic membrane cover 164 in a clear orientation to the outside. sealed against For illustrative purposes in FIG. 14 the membrane cover 164 is partially shown through a sealing process, and a portion of the cover is lifted to show the rail cartridge 166 seated inside the tray 162 . The membrane cover 164 is a membrane cover material and is arranged around the tray so as not to hang over the sides of the tray flange. In one embodiment the plastic membrane cover 164 is formed with dimensions such that the membrane cover can be disposed on the tray flange 168 such that the membrane cover edge is inserted all the way around the flange from the prey flange edge. Additionally, the membrane sheath is heat sealed to extend beyond the sides of the membrane sheath 164 to ensure that no portion of the membrane sheath edge is unsealed causing a "flap" of the relaxed edge. The orientation, placement, and avoidance of loose edges of the membrane sheath are particularly important for surface ultraviolet (UV) decontamination processes that are performed on carriers as they are introduced into the sterile zone. Cracks caused by slack membrane coverings and/or flaps can create local shade upon exposure to UV irradiation, and this shade-forming effect can fail the UV decontamination process.

When the membrane cover 164 is heat sealed to the tray flange 168, the carrier 160 forms a hermetically sealed environment that functions to isolate its contents from the external environment. Next, the carrier 160 is put into a polybag overwrap or such a cover (not shown) serving as a "dust cover", and is marked with an adhesive label attached to the overwrap.

15 and 16 , a carrier rail cartridge 174 includes a plurality of injection molded polystyrene T-beams 176 spaced apart to define longitudinally drilled slots 178 therebetween. The manufactured container 10A may be loaded on the cartridge 174 . As shown in FIG. 8 , the container 10a is loaded onto the carrier rail cartridge 166 by inserting the sacrificial ports 72a and 74a into the slots 178 formed between the cartridge T-rails 176 . The T-rail 176 may have edges spaced apart enough (about 13.0 mm) to allow the central filling trough of each of the sacrificial ports 72a and 74a to be received therebetween, and each container 10a ) is adapted to fasten the sacrificial port between the peripheral flanges 78a, 80a of the sacrificial port, such that it is captured by the T-rail flange 176 under its uppermost circumferential sacrificial port flange 80a.

In the embodiment of the carrier rail cartridge shown in FIGS. 15 and 16 , four slots 178 are provided to receive the vessel 10a with the vessel 10a loaded alternately from side to side on the rail cartridge 166 . do. The sacrificial ports 72a and 74a of each vessel 10a are inserted into two slots 178 . The first container may be loaded into the second and fourth slots and oriented in a first horizontal direction. The second container may then be loaded onto the rail cartridge 166 with its sacrificial ports 72a and 74a inserted into the first and third cartridge slots 178 . The second container 10 is loaded in a second horizontal direction oriented 180 degrees with respect to the first container. Further containers 10a are loaded on the carrier rail cartridge 166 in the same manner with the horizontal orientation of the container alternating from side to side, and the sacrificial port of the left-oriented container is inserted into the second and fourth slots. and, as described above, the sacrificial port of the right oriented container is loaded into the first and third slots to eventually fully fill the carrier rail cartridge 166 . Obviously each carrier will support a greater number of pre-expanded containers than the expanded containers.

Following loading, the carrier rail cartridge 174 is placed within the tray 162 such that the end of the T-rail 176 is positioned within pockets 170 , 172 formed at the end of the tray. Pockets 170 and 172 support the carrier rail cartridge 166 within the interior volume of the tray and provide additional lateral support to prevent displacement of the cartridge during shipping, sterilization, and storage.

The sealed carrier including the empty container inside is packaged in a poly bag or similar container for irradiation type sterilization in which the carrier 160 and the contained container 10a are sterilized by E-beam sterilization or the like. After the preceding carrier loading and E-beam sterilization are completed, the sterilized medical container 10 can be filled with the medical solution in an aseptic manner. This process may include transferring the carrier 160 and the container 10a contained therein to the aseptic filling area. Filling of volume enclosure 17a may be accomplished using the techniques of related US Patent Application Serial No. 08/837,927, filed April 11, 1997, the contents of which are incorporated herein by reference. These techniques may be applied to a single medical solution, or alternatively to the filling of multiple compartments.

After sterilization and filling are complete, fabrication of the expanded container of FIG. 8 may be completed by removal of the sacrificial ports 72a and 74a and completing a permanent seal around the first side 27a of the common perimeter 16a. The completed container 18a will have an increased storage capacity of medical solution compared to a standard or non-expandable container.

The final manufacturing process includes removing a portion of the first side 27a of the vessel 10a inwardly from the sacrificial ports 72a and 74a, including the sacrificial port. Next, each of the fluid connections or flow paths between the sacrificial ports 72a and 74a and the volume enclosure 17a is sealed. This is accomplished by applying a permanent seal across the first side 17a directly inward from the common perimeter 16 , as described above. This permanent seal completes the volume enclosure 17a. When using a multi-compartment container, the permanent seal can be applied across each of the sacrificial ports 72a, 74a after each fill is complete. A portion of the first side 27a including the sacrificial ports 72a and 74a may then be removed. As can be seen from the difference between FIGS. 8 and 17 , the removed portion is a narrow strip of the sacrificial ports 72a , 74a and the first side 27a of the vessel 10a.

One of ordinary skill in the art will recognize that while the main discussion of embodiments includes liquid diluents and single powdered medicaments, single volume enclosure embodiments do not limit the scope of the present invention. Multiple compartments for the use of liquid medicaments in an intermediate compartment, or for powdered and liquid medicaments to be mixed with a diluent, can be introduced using the present invention. Multiple sacrificial ports and communication channels between sacrificial ports and modified compartments may be readily provided in accordance with the practice of the principles of the present invention. Moreover, depending on the susceptibility of any component comprising the contents of multiple compartments to moisture or free oxygen contamination, the compartments are clean and transparent SiO<sb>x</sb>can be further protected by applying a high barrier laminate containing Such a high barrier laminate may be provided with or without an aluminum foil having a high barrier laminate peelable cover.

The above description of embodiments of flexible sterile containers has been made for illustrative purposes. It is not intended that the present invention be limited to the specific embodiments described above due to variations apparent to those skilled in the art. Such and other modifications and alternatives are included within the scope and aspects of the invention as set forth in the appended claims.