HK1082397B - Transport carrier adapted for sterilization by application of e-beam radiation - Google Patents

Description

Transport carrier for sterilization by electron beam irradiation

This application is a divisional application of a patent application entitled "flexible multi-chamber drug container and method of making and using the same" filed on 1997, 4, 11, No. 97195877.7. Related application

This application is a continuation-in-part application of co-pending U.S. patent application No.08/647,583 entitled flexible multi-compartment pharmaceutical container and method of making and using the same, filed on 1996, 5/13/s, the disclosure of which is incorporated by reference in its entirety.

Technical Field

The present invention relates to flexible, sterile containers for storing and mixing medicament and diluent liquids in a sterile environment and dispensing the mixture. More specifically, such containers are made from a web of film on a patterned chamber forming apparatus. Such containers have a feed inlet tube during the manufacturing process, allowing the container to be loaded and transported through the modular insulation containment device.

Background

Many pharmacological solutions are typically administered to a patient by Intravenous (IV) administration from a sterile container. Such solutions often contain a mixture of a liquid diluent such as an aqueous glucose or sodium chloride solution and the agent. To prevent degradation of the medicament, the medicament and diluent are preferably stored separately in containers under sterile conditions until they are mixed prior to injection. Since the medicament is likely to be a powder susceptible to moisture attack, or a powder or liquid susceptible to degradation by exposure to light or oxygen, even ordinary packaging of diluents and medicaments is often very complicated.

Many medicaments such as antibiotics, which become unstable in solution form over a long period of time, are stored separately in moisture and air-tight glass vials or containers and the like prior to use. Medicaments stored in this manner must be mixed or diluted in a physiological solution or diluent, which is also stored separately, prior to injection into a patient. Although maintaining the stability and efficacy of the medicament, the separate storage of the components is cumbersome to handle and may be subject to bacterial infection during opening, mixing and injection into the patient. Accordingly, medical containers have been developed that include a chamber for storing an unstable medicament and a chamber for holding a diluent liquid. The chambers are interconnected prior to intravenous administration to a patient so that the medicament and diluent can be mixed in a sterile condition.

Multi-chamber containers capable of storing a liquid diluent and a medicament separately are known. Such containers are disclosed, for example, in U.S. patent nos. 4,608,403(Larkin) and 5,176,634(Smith et al), among others. U.S. patent nos. 4,608,403 and 5,176,634 are hereby incorporated by reference herein in their entirety for all purposes. The chambers of the containers disclosed in these patents are separated from each other by heat seals that are susceptible to failure. The contents of the chambers are mixed together by breaking the seal by manual manipulation of the container to form a pharmacological solution which can be administered to a patient by standard intravenous means.

The medical fluid containers currently on the market are generally made of materials containing polyvinyl chloride plastics. Polyvinyl chloride is generally opaque in appearance and it is not easy to observe the contents of a container made therefrom. It is therefore difficult to observe whether such containers are leaking and contaminated with moisture, and to determine whether the medicament and diluent are sufficiently mixed prior to injection into a patient. Furthermore, because of the many hazardous chemicals used in the manufacture of polyvinyl chloride, polyvinyl chloride must be handled in a manner that is environmentally acceptable. Since polyvinyl chloride emits toxic gases when incinerated and toxic plasticizers contained therein leak into the surrounding environment if the polyvinyl chloride container is buried in soil, great care must be taken in handling the polyvinyl chloride container after use. Toxic plasticizers may also escape into the solution of the medicament, and therefore polyvinyl chloride containers are not suitable for certain types of drugs.

The medicament compartments of such a multi-compartment container should be protected from moisture and air attack and from exposure to ultraviolet light and ambient radiation to prevent degradation of the medicament contained therein. One known method of protecting a medicament chamber from attack by, for example, moisture and oxygen is disclosed in U.S. patent No.5,267,646(Inouye et al) in which the medicament chamber is surrounded by a second chamber containing a desiccant and an oxygen getter. Free oxygen and moisture may penetrate the material of the second chamber but are absorbed by the desiccant and oxygen absorber before they can attack the medicament chamber material.

While this method provides some protection of the medicament chamber from free oxygen and moisture, it requires the addition of a layer of material (the second chamber) to the medicament, making it more difficult to view the contents of the medicament chamber during dispensing. Furthermore, this method also does not provide a means of protection against degradation of the agent in the chamber caused by ultraviolet or ambient radiation.

U.S. patent No.5,176,634(Smith et al) discloses a medication container having a plurality of chambers separated by a peelable seal which can be broken by applying pressure to the exterior of the container by hand. The container is made from two sheets of flexible material sealed together along their periphery. The container contains a diluent chamber and a medicament chamber separated by a breakable heat seal. The back sheet is waterproof and vapor-permeable and is made of a laminate material having an inner layer of polypropylene, a middle layer of aluminum foil and an outer layer of polyester film. The gas barrier properties of the back sheet reduce the amount of diluent vapor that can escape from the container and the amount of moisture in the air that can penetrate into the container cavity by a factor of two, thereby extending the shelf life of the medicament. The gas permeability of the medicament chamber may be further reduced by attaching a third peelable laminate sheet to the front sheet of the container in the region of the medicament chamber, the third peelable laminate sheet being the same as the rear sheet. The third sheet of laminate material is sized to cover the entire medicament compartment and together with the rear sheet forms a gas-impermeable envelope.

However, once the gas impermeable third sheet is peeled away from the medicament chamber, the medicament chamber is no longer completely enclosed as before and moisture in the air readily penetrates into it. Moisture is also able to pass from the diluent chamber into the medicament chamber through the peelable sealing material separating the chambers. The gas-impermeable protective layer is often peeled off from the medicament chamber during hospital admission checks, and the long shelf life of such containers is therefore a problem. When the medicament is a powder which is particularly sensitive to moisture-induced degradation, the storage life of the container stripped of the gas-impermeable protective layer is often less than a few days.

In view of the above, an improvement over existing containers would be to manufacture and handle the medicament container in an environmentally friendly manner. Such containers should be able to protect powdered and other sensitive medicaments from moisture and air attack while also allowing easy viewing of the contents of the medicament chamber. It should also have protection against uv and visible radiation.

In existing multi-compartment containers, a simple breakable or peelable seal is used to separate the medicament and diluent compartments to prevent inadvertent transfer of any of the components prior to mixing. This simple seal traverses the container in the width direction, with the entire seal having a uniform cross-sectional thickness and length. When the container is manipulated to break the seal and mix the medicament and diluent prior to administration, the slight breaking of the seal, as the diluent enters the medicament chamber, immediately releases the pressure of the liquid diluent against the seal. This partial breaking of the seal often does not allow the liquid contents of the diluent chamber to be completely transferred into the medicament chamber. A significant amount of diluent may remain in the diluent chamber, residing in the corners formed by the side walls of the chamber and the sealed left and right ends. This partial destruction also results in inadequate mixing of the medicament with the diluent and does not ensure that the mixed medicament is adequately administered to the patient.

It is therefore necessary to provide a container for an intravenous medical solution having a plurality of chambers for storing diluent and medicament and a peelable seal separating the chambers in the form of a single assembly in which the seal design can be broken substantially completely along its entire length to ensure adequate mixing of the contents of the chambers and to ensure that the final mixed solution is fully administered to a patient.

The design of such a container should further be such that it should prevent inadvertent release of any of the components prior to mixing, and allow visual observation of the condition of the components contained therein after the container is received by a hospital drug delivery system, but prior to storage and subsequent dispensing. Protection should also be enhanced in terms of protecting the contents of one or more chambers of the container from moisture, oxygen, or photodegradation.

Brief summary of the invention

The present invention provides a container having a plurality of chambers separated by peelable seals that can be broken by manually applying pressure to the exterior of the container. The container is made from two sheets of flexible laminate material sealed together along the periphery. The container is divided into a plurality of chambers by peelable heat seals. In a first embodiment of the invention, the container comprises three chambers; the first chamber contains a liquid diluent, the second chamber contains a powdered medicament which can be mixed with the liquid diluent after breaking a peelable seal separating the two chambers, and the third chamber is a lead-out chamber from which the mixed medical fluid is dispensed.

In one aspect, the container of the present invention is formed from a flexible rear sheet and a flexible front sheet sealed to the rear sheet along a common peripheral edge. A first peelable seal extends between the edges of the common perimeter and releasably bonds the front and back sheets together to form a chamber containing the diluent. A second peelable seal extends between the edges of the common perimeter and releasably bonds the front and rear sheets together to define a discharge chamber and a medicament-containing chamber between the discharge chamber and the diluent chamber. A transparent high barrier laminate film is cut to size to cover the medicament chamber and sealingly engage the front sheet. An opaque high barrier protective film is cut to size to cover the transparent high barrier film and the medicament chamber and releasably sealingly adhere to the transparent high barrier laminate film. The transparent high barrier film and the opaque high barrier film together form a high barrier protective cover for the medicament chamber.

In one embodiment, the opaque high barrier protective film comprises an ethylene vinyl acetate polymer layer on its inner surface, a polyester polymer layer having a higher melting point than the ethylene vinyl acetate polymer layer on its outer surface, and an opaque high barrier aluminum foil layer between the ethylene vinyl acetate polymer layer and the polyester layer. To facilitate peeling and viewing of the contents of the medicament chamber, the opaque high barrier protective film is releasably adhered to the medicament chamber.

On the other hand, the transparent high barrier laminate film comprises a transparent moisture and oxygen resistant laminate film constituting an intermediate layer between the front sheet of the container in the region of the medicament chamber and the opaque aluminum-containing foil protective film. Specifically, the transparent high barrier laminate film comprises an inner layer of polypropylene adhered to the front sheet of the container, an outer layer of polyester and a transparent high moisture barrier layer or a transparent high oxygen barrier layer or both barrier layers positioned between the inner and outer layers.

Further, the peelable seal formed by the present invention has a curvilinear resistance to the hydraulic pressure applied to the seal generated by the operation of the container. This resistance characteristic of the curve is stronger in the center of the peelable seal and tapers from the center to the sides. The separation of the seal is achieved by manipulation of the container to apply pressure to the diluent in the first chamber which then causes the seal to be substantially fully hydraulically separated along its length between the chambers, thereby achieving complete mixing of the diluent and medicament. A third chamber adjacent to the second chamber and opposite the first chamber includes an outlet for dispensing the mixed medical fluid. The peelable seal between the second and third chambers prevents the contents of the first two chambers from being dispensed prior to mixing. The container is operated after mixing to create a pressure within the container that causes the second seal to be substantially completely broken along its length, thereby causing the liquid medicament to be dispensed through the outlet.

In another embodiment of the invention, an additional chamber for moisture barrier is created between the diluent and medicament chambers by adding a peelable heat seal prior to the peelable seal separating the diluent and medicament chambers. This additional chamber, which is a barrier to moisture, may also provide further protection to the medicament chamber by preventing inadvertent breach of the medicament chamber seal.

Another aspect of the invention is to prevent the medicament chamber from being prematurely affected by the liquid diluent by folding the container in half along the area of the peelable seal between the medicament and diluent chambers. Folding the container in half causes the material of the container to be compressed together in the area in front of the first peelable seal, enhancing the seal's ability to resist hydraulic pressure caused by inadvertent manipulation of the container. After the container is folded in half, methods are employed to maintain the container in this folded-in-half condition. In one embodiment, the fold is maintained by inserting a protruding tab into a permanent groove, the tab and permanent groove being formed integrally with the container from the container material. The container can be repeatedly opened to constantly view the contents therein and then stored in half.

Another aspect of the invention is that an opaque high barrier protective film is peelably adhered to the transparent high barrier laminate film to facilitate peeling and viewing of the medicament chamber. Only a part of the surface of the transparent high-barrier laminated film is adhered to the opaque high-barrier protective film, and the adhesion force is directly proportional to the contact area of the surface. An opaque high barrier protective film is affixed to a transparent high barrier laminate film by a patterned heat sealing head which also retains a series of regularly arranged, generally circular, non-contacting areas. The strength of this form of peelable seal can be more easily adjusted by varying the number of non-contact zones.

In yet another aspect of the present invention, a method of making a flexible container having dual functions of storage and administration of intravenous medicaments and diluents, comprising: sealing and adhering a flexible transparent front sheet and a flexible air-impermeable back sheet together along their common peripheral edges; heating the front and rear sheets in a first region to fuse the heated portions of the adjoining surfaces together to form a first peelable seal across both edges of the common perimeter; and heating the front and rear webs in the second localised region to fuse the heated portions of the abutting surfaces together to form a second peelable seal. A first peelable seal releasably attaches the front and back sheets to form a first chamber for holding a diluent. A second peelable seal releasably attaches the front and rear sheets to form a discharge chamber and a chamber for holding the medicament between the discharge chamber and the diluent chamber. First and second feed inlet tubes are interposed between the front and rear sheets and communicate with the diluent and the medicament chamber, respectively. The diluent chamber is filled with diluent solution under sterile conditions through its feed inlet tube and then sealed along the periphery of the container in the region of the feed inlet tube. Also, the medicament chamber is filled with the medicament through its feed inlet tube under aseptic conditions, and the feed inlet tube is sealed along the periphery of the container and then withdrawn from the container. After the chamber filling step, the preparation and filling of the container can be completed without going through a step of sterilization treatment of the container.

In particular, the diluent and medicament chamber is aseptically filled in an aseptic environment with the pre-sterilized diluent and the pre-sterilized medicament. In one embodiment, the sterile environment is provided by an isolator in which the environment is maintained in a sterile condition.

In another embodiment of the invention, the unpackaged containers are placed on a transport carrier that is subsequently sealed to prevent contamination from the environment. The transport carrier and the containers therein are subjected to electron beam (E-beam) sterilization. The transport carrier and the containers therein enter the insulation through the uv disinfection channel, ensuring that a sterile environment is maintained in the insulation.

Brief description of the drawings

In addition to the above, there are other features, aspects, and advantages of the present invention, which will become more fully apparent from the following detailed description, the appended claims, and the accompanying drawings in which:

FIG. 1 is a schematic front view of an exemplary embodiment of a container according to the present invention showing the positional arrangement of the chambers and the curvilinear seals between the chambers, including an outlet tube and a small tether secured in a doubled-over configuration;

FIG. 2 is a schematic view in longitudinal section along the 2-2 axis of FIG. 1, showing more clearly, by magnification, the thickness of the flexible sheets and layers in the sheets that make up the container;

FIG. 3 is a schematic representation of the cross-section taken along the axis 3-3 in FIG. 2 showing the construction of the flexible sheet of the first embodiment of the container of the present invention without the optional transparent high barrier intermediate layer;

FIG. 4 is a schematic cross-sectional view of a first embodiment of a flexible sheet construction of the present invention, including an optional transparent high barrier intermediate film;

FIG. 5 is a schematic cross-sectional view of a laminate construction of a flexible sheet of a second embodiment of a container of the present invention showing a second embodiment of an optionally useful transparent high barrier intermediate film;

FIG. 6 is a schematic front view of the embodiment of the container of FIG. 1, with the container in a folded-over position for storage;

FIG. 7 is a schematic front view of another embodiment of a container according to the present invention with the addition of a peelable seal and a buffer chamber to protect the medicament chamber from moisture penetration;

fig. 8 is a schematic front view of an exemplary embodiment of a container according to the present invention during its manufacture, with several feed inlet pipes provided for holding the container.

FIG. 8a is a schematic side view of an exemplary embodiment of a container detailing the arrangement and configuration of the feed inlet tube for powder and liquid charges of the present invention, further including an inlet tube closure;

FIG. 8b is a schematic top view of the feed inlet tube of FIG. 8a, detailing the shape and location of the flange of the inlet tube;

FIG. 9 is a schematic plan view of a modular container manufacturing apparatus according to the present invention;

FIG. 10 is a schematic perspective view of a transport carrier according to the present invention including a container chassis housing rail mounts and covered by a peelable sealing film;

FIG. 11a is a schematic perspective view of the components of the guide rail bracket of FIG. 10, showing the guide rail bracket exploded into its component form and ready for assembly;

FIG. 11b is a schematic perspective view of the rail bracket of FIG. 11a, once assembled;

FIG. 12a is a schematic plan view of the guide rail bracket of FIGS. 11a and 11b showing a container of the present invention loaded on the guide rail;

FIG. 12b is a schematic front view of the loading rail bracket of FIG. 12a showing how containers are loaded onto the rail through their feed inlet tubes;

FIG. 13 is a flow chart of one embodiment of a process for aseptically containing a container according to one embodiment of the present invention;

FIG. 14 is a schematic plan view of a modular container holding apparatus of the present invention;

FIG. 15a is a schematic representation of a diagrammatic section of a container transfer belt of the present invention;

FIG. 15b is a schematic diagram of a partial perspective view illustrating the position of the powder feed wheel and conveyor belt, showing the direction of conveyance of the containers under the feed wheel;

FIG. 16 is a schematic perspective view showing the peelable medicament chamber cover film peeled away for viewing the medicament prior to mixing and use;

FIG. 17 is a diagrammatic illustration of the container being manually manipulated to separate the first peelable seal to mix the diluent and medicament;

FIG. 18 is a schematic view of the container being manually manipulated to separate the second peelable seal to dispense the pharmaceutical solution;

FIG. 19 is a schematic illustration of a partial front view of an exemplary embodiment of a medicament container showing the configuration and location of a curvilinear seal;

FIG. 20 is a schematic representation of the front face of a typical peelable seal showing in cross-section the reason why the seal failed to peel completely;

fig. 21 is a schematic front view of an exemplary embodiment of a curvilinear peelable seal of the present invention showing, in cross-section, the reason why the seal can be completely peeled away.

Detailed Description

Fig. 1 and 2 are schematic front and side cross-sectional views, respectively, of a preferred embodiment of an aseptic container 10 of the present invention. Although the container 10 may be viewed from any direction, the positions shown in fig. 1 and 2 are chosen for the purpose of illustrating the relative positions of the chambers of the container for ease of illustration. Container 10 is comprised of a front sheet 12 and a back sheet 14 (see only fig. 2). The front and rear sheets may be constructed of a single layer of flexible material or a multi-layer laminate of flexible materials as will be described in more detail below. The sheets making up the container may be prepared separately and then joined together by sealing along their common peripheral edge, with the resulting edge seal 16 encircling the entire periphery of the container. Such perimeter seals may take on different shapes and widths. Shaped seals may be used to provide locations where a user can manipulate the container and where the container can be secured to, for example, a holder for an intravenous injection, such as the top seal area 16a and the bottom seal area 16b shown in fig. 1. The front and rear sheets may be formed of a single sheet of a single-layer film which is substantially folded in half and sealed by heat sealing along the periphery of the container. The sheets sealed together are referred to herein as the "shell" or "body" of the container.

In the embodiment shown in fig. 1, vessel 10 is divided into three separate chambers, upper chamber 18, middle chamber 20 and lower chamber 22, each of which is sterile. The upper chamber 18 and the middle chamber 20 are separated by a first peelable seal 24, and the middle chamber 20 and the lower chamber 22 are separated by a second peelable seal 26. Peelable seals 24 and 26 bond the front and back sheets across the two sides of the container, right side 10a and left side 10 b. A "peelable" seal is one which is sufficiently robust to permit normal operation of the container, but which can be peeled away under the fluid pressure generated by manual manipulation of the container to cause separation of the front and rear sheets at the location of the seal to permit mixing and dispensing of the contents of the container. The peelable seal is formed by fusing together portions of the polymer in two films adjacent the front and back sheets. The seals are made by heat sealing under various time, temperature and pressure conditions as will be described in detail below. However, the perimeter seal 16 is much stronger than a "peelable" seal, and it is not broken under the pressure created by separating the "peelable" seal. The hydraulic pressure generated by the manually operated container has a non-linear force-bearing peelable seal which, unlike conventional linear seals, is configured to allow substantially complete peeling of the entire seal during use of the container, as will be described in more detail below.

In a typical application of the container 10 of the present invention, upper chamber 18 contains a liquid diluent and middle chamber 20 contains a generally powdered medicament. The lower chamber 22 acts as a protective interface for the outlet tube 30, remaining empty until the container is used. The outlet duct 30 extends downwardly from a generally oval base which is flattened at its focal end as viewed from above, centrally of the lower edge of the container between the front and rear sheets 12, 14. The flattened focal end of the base 32 forms a flange 34 which tapers in the direction of the flattened edge of the base 32, see fig. 1. The flattened oval shape creates a smooth curved surface against which the front and rear wafers are tightly adhered, such as by a permanent heat seal (referred to herein as an "outlet tube seal") 36 (see fig. 2). The outlet tube 30 includes a body 38 and a nozzle 40, the nozzle 40 being shaped to connect with a standard intravenous device. A closure (not shown) conceals the nozzle to maintain sterility. The cap is removed before the outlet tube is connected to the intravenous device. The body 38 of the outlet tube 30 is fitted with ribs 39 that provide a surface for easy gripping when the iv set and container are connected. In this illustrated embodiment, there are a total of 4 ribs 39 longitudinally on the surface of the outlet body 38 of the vessel 10. Although 4 longitudinal ribs are shown, those skilled in the art will recognize that many other forms of surface attachment may be used to facilitate grasping the outlet, such as circumferential ribs, transverse ribs, knurling or intersecting lines on the body surface, and the like.

The materials used for the front and rear sheets of the container 10 depend on the substance stored therein. Preferably at least one of the sheets is transparent to facilitate viewing of the contents of the container and the level of solution in the container during dispensing. Materials suitable for making transparent sheets are typically single or multi-layer laminated polymeric films.

In particular, whether a single or multi-layer laminated polymeric film is used, the material comprising the front and back sheets 12, 14 should be selected to be clear and transparent. Typical polyvinyl chloride (PVC) container materials are often very hazy in appearance, making it difficult to clearly view the interior of the container and determine the level of liquid contained therein or the presence of particulate matter. This situation is very dangerous when intravenous injection is performed. It is necessary for nurses and medical staff to be able to see at a glance that the liquid medicine being injected from the medicine container does not contain granular materials.

First embodiment

In a first embodiment of the invention, schematically illustrated in cross-section in fig. 3, the front sheet 12 is made of a transparent single layer of thermoplastic polymer film 44. In this embodiment the transparent film 44 comprises about 80% by weight polyethylene-polypropylene copolymer (Fina oil and chemical company, Deerpark, Texas, trade designation Z9450) and about 20% by weight styrene ethylene-butylene styrene thermoplastic elastomer (SEBS) (Shell chemical company, trade designationThe contents of the brand number G1652,the G1652 thermoplastic elastomer is a triblock copolymer having polystyrene end blocks and a rubbery poly (ethylene-butylene) mid block). In practice, the film is prepared by contacting pellets of the copolymer resin withThe crumb was mixed in a ratio of 80%/20% in a high shear mixer and the mixture was melted and re-granulated; a transparent film 44 is then made from the blended pellets on a commercial extruder. The transparent polymer film 44 that makes up the front sheet 12 can have different thicknesses depending on the use of the container and the durability required for the application. A suitable thickness for the material comprising front sheet 12 may be about 3 to about 15 mils. In a preferred embodiment, the transparent polymer film 44 comprising the front sheet 12 has a thickness of 12 mils.

In addition to transparency, the transparent polymeric film 44 (which may also be referred to as an "80: 20 film") is particularly useful for forming "peelable" seals and permanently sealed edges around the perimeter of the container 10. As will be described in detail below, according to the present invention, 80:20 films are capable of providing both low temperature peelable seals and high temperature permanent seals without the molding process affecting the integrity of the material and the ability to form an effective peelable seal.

In the case where certain diluents are mixed with the medicament, the rear sheet 14 may have the same monolayer composition and structure as the front sheet 12. It may also be preferred to use a multilayer film comprising, for example, a moisture barrier and a light barrier layer as a backsheet to extend the shelf life of the container holding the drug. To maintain the efficacy and activity of the two components (unmixed medicament and diluent) in the container, a three-layer laminated back sheet 14 having moisture and light barrier properties is used in the embodiment of the container shown in fig. 3, thereby extending the shelf life of the container containing the medicament.

In the exemplary embodiment, the rear sheet 14 includes an inner seal layer 46(80:20 film) of 80%/20% (by weight) polypropylene-polyethylene copolymer and styrene ethylene-butylene styrene thermoplastic elastomer having a thickness of about 3 to 6 mils on its inwardly facing surface. In a preferred embodiment, the inner seal 80:20 film layer 46 is a 6 mil thick film of the composition adhered by a suitable transparent adhesive 48 to a high barrier aluminum foil layer 50 having a thickness of about 0.7 to 1.3 mils (preferably 1.0 mil). On the outward facing surface of the rear sheet is a high melt temperature outer layer 54 which is bonded to the high barrier aluminum foil layer 50 by a suitable transparent adhesive 52. In the embodiment of fig. 3, adhesive layers 48 and 52 comprise Tycel 7909 adhesive from liosol corporation (lioto co. of Cary, North Carolina), which is a modified aliphatic polyester polyurethane adhesive. Aluminum foil layer 50 is formed from a commercially available aluminum foil having a thickness of 1 mil, such as Alcan 1145 aluminum foil available from Alcan rolling products Company of louis ville, Kentucky.

Since the heat sealing process used to form the perimeter seal and the reversible peelable seal may damage the high barrier aluminum foil layer when it is directly exposed, the outer high temperature layer 54 is formed using a polymer having a relatively high melting point to prevent contact between the aluminum foil and the heated portion of the heat sealing apparatus. The high temperature layer 54 further acts as a release agent (also referred to as a mold release agent) for the heat seal because it does not melt and bond with the heat seal plate at the temperature at which the seal is formed.

The outer high temperature layer 54 is preferably polyethylene terephthalate (referred to herein as PET or polyester) available from Rhone-poulen under the trade name terphane10.21 having a thickness of from about 0.4 to about 0.6 mils. In a preferred embodiment, the thickness of each layer of the multilayer laminate film 14 is 0.48 mil for the high temperature polyester outer layer 54, 1.0 mil for the high barrier aluminum foil layer, and 6.0 mil for the 80:20 in-film sealing layer 46.

For best performance peelable seals, the front and back sheet materials are selected so that an intermediate seal layer comprising an 80:20 film is formed between the front and back sheets. The intermediate seal layers between the front and rear sheets, however, may differ in relative percentage composition, although they all comprise a blend of polypropylene-polyethylene copolymer and styrene ethylene-butylene styrene thermoplastic elastomer. The relative percentages depend on the desired characteristics of the different seals and the temperature and pressure parameters in the sealing process associated with the use of a particular drug container. Other types of flexible films that may be used to form the front and rear sheets and the intermediate seal layer between the two sheets of the shell of the container 10 of the present invention are described in U.S. Pat. Nos. 4,803,102, 4,910,085, 5,157,634 and 5,462,526, the disclosures of all of which are expressly incorporated herein by reference.

In some applications, particularly when the medicament is a powder, it is preferred to also provide further protection to the second or intermediate chamber 20 of the container 10. This further protection is employed to prevent moisture, oxygen and/or light from passing through the film of the front sheet forming the intermediate chamber, thereby protecting the drug powder from degradation. This further protection extends the shelf life of the container 10 without losing the efficacy of the medicament.

In the embodiment shown in fig. 2 and 3, an opaque high barrier protective film 55 is specifically used to cover the intermediate chamber 20. The protective film 55 acts as a barrier to prevent moisture and free oxygen from penetrating into the medication chamber. In an exemplary embodiment, the high barrier protective film 55 is a multi-layer laminate structure including a high barrier aluminum foil layer. The use of an opaque aluminum foil laminate film further helps to prevent degradation of the drug in the intermediate chamber 20 by exposure to light and ultraviolet radiation. Thus, in this embodiment, the opaque aluminum foil constituting the protective film 55 and the rear sheet 14 prevents the ultraviolet rays and visible light from penetrating into the intermediate chamber 20 of the container.

The high-barrier protective film 55 is a multilayer laminated film having an inner seal layer 56 on its inward surface. In an exemplary embodiment, inner seal layer 56 is a soft co-extrusion coated resin having a thickness of about 0.2 mils to 0.4 mils comprising a modified ethylene vinyl acetate polymer available from dupont under the trade designation Appeel 118. An aluminum foil layer 58, such as Alcan 1145, having a thickness of about 0.7 to 1.3 mils (preferably about 1.0 mil) is adhered to inner sealant layer 56 by a suitable transparent adhesive 57. On the outside, a heat seal release layer 60 of approximately 0.48 mil thickness comprising a polyethylene terephthalate (PET) film, such as terpane 10.21, forms the outward facing surface of the high barrier protective film 55, which is adhered to the aluminum foil layer 58 by a suitable clear adhesive 59. In this embodiment, adhesive layers 57 and 59 comprise Tycel 7909 adhesive from liosol corporation (lioto co. of Cary, North Carolina), a modified aliphatic polyester polyurethane adhesive.

Since the inner seal layer 56 of the high barrier protective film 55 is a co-extruded coated resin, it can form a peelable seal over a wide temperature range when used on many different materials. Materials on which such co-extruded coated resins form peelable seals include acrylonitrile-butadiene-styrene resins (ABS resins), High Density Polyethylene (HDPE), High Impact Polystyrene (HIPS), polypropylene (PP), Polystyrene (PS), polyvinyl chloride (PVC) and 80:20 films that make up the front sheet. The high barrier protective film 55 may be releasably adhered to the outer surface of the front sheet 12 covering the intermediate chamber 20.

The high barrier protective film 55 is preferably peelable from the container 10 before use of the container so that the state of the medicament powder inside the intermediate chamber 20 can be observed. In an exemplary embodiment, the protective film 55 includes a protruding tab 62 (best seen in fig. 1) through which the protective film 55 can be peeled away from the transparent front sheet 12. So that the contents of the intermediate chamber 20 are exposed and can be viewed by the naked eye.

As shown in fig. 1, the high barrier protective film 55 is not hermetically attached to the container over the entire area thereof; the film 55 is only partially adhered to the substrate material. Those portions of the high barrier protective film 55 which are not sealed are regularly arranged, typically circular, raised bubbles 51 which are formed by pressing against a hot sealing plate on which a plurality of circular holes in a rectangular arrangement have been precut. When the heat sealing plate is hot-pressed on the surface of the high barrier protective film 55, heat sealing is formed only in the area in contact with the surface of the heat sealing plate, and heat sealing is not formed in the area (circular hole) where the material of the heat sealing plate is cut out. Since pressure is applied while heating in the process, the high barrier protective film 55 is impressed by the heat sealing head, thereby forming the surface of the raised bubble structure.

The plurality of bubbles 51 firmly seal the high barrier protective film 55 to the base material of the drug container, and also allows the film 55 to be easily peeled off without requiring excessive force. If the entire protective film 55 is heat sealed to the container surface, a greater force is required to completely peel the film than intended. By reducing the area of the seal, the peelable aluminum strip can be peeled off with less force (proportional to the area of the seal). As is clear from the above, the force required to strip the peelable aluminum strip is inversely proportional to the number of bubbles (51 in fig. 1) formed on the film 55. Depending on the use of the pharmaceutical container, a more or less easily peelable protective layer with high barrier properties can be easily obtained in a heat sealing process simply by increasing or decreasing the number of bubbles 51 on the protective film.

In practice, the pharmacy of the hospital purchases the containers containing the pharmaceutical agents and the diluents and then stores them for a certain period of time in order to be ready for use. The pharmacist typically peels the high barrier aluminum foil layer 55 from the surface of the container prior to dispensing, exposing the medicament chamber 20 for visual inspection of the overall condition of the contents therein. If the container is not used at this time, it is returned to the pharmacy for dispensing the next time it is needed. Peeling the peelable high barrier film 55 from the medicament chamber makes the contents of the medicament chamber susceptible to degradation by attack by moisture, light and permeated oxygen. Thus, after the high barrier protective film covering the medicament chamber is peeled off, the container of the present invention containing the medicament and diluent should be stored in the pharmacy for up to 30 days before use without significant degradation of the medicament due to exposure to moisture and free oxygen. Therefore, in one embodiment of the present invention as shown in fig. 4, a transparent high-barrier interlayer laminate film 64 may be selectively inserted between the protective film 55 containing a high-barrier aluminum foil and the medicine chamber 20. After the peelable protective film 55 is peeled off from the container, the transparent high barrier intermediate film 64 covers and protects the contents of the medicament chamber 20 from osmotic attack by moisture and free oxygen for a relatively long period of time, which may be up to 30 days depending on the activity of the contents of the medicament chamber. In other words, the opaque high-barrier protective film 55 and the transparent high-barrier intermediate film 64 together form a high-barrier protective cover layer of the drug chamber.

Polymers may be classified according to their resistance to the passage of permeating gases. The species can range from high barrier (low permeability) to low barrier (high permeability). The classification of polymers varies from permeation gas to permeation gas. In this specification, the term "high barrier" when expressed in terms of moisture vapor permeability means that the permeability of the film is less than about 1.5 g/mil/m at 38 ℃ and 100% relative humidity²24 hours/1 atmosphere. The term "high barrier" when expressed in terms of oxygen permeability means that the membrane has a permeability of less than about 50 ml/mil/m at 25 ℃ and 100% relative humidity²24 hours/1 atmosphere.

In an exemplary embodiment, the transparent high barrier middle film 64 comprises a three layer high barrier laminate structure that is highly resistant to free oxygen and water vapor permeability to protect the contents of the medicament chamber and extend the shelf life of the dual container. In one embodiment, the intermediate film 64 contains a silica-deposited polyethylene terephthalate outer layer 66 (also known as SiO)_xCoating of polyester or SiO_xCoated PET, product of Mitusbishi Kasei Corp, tradename TechBarrier^TMH) It is adhered to the adhesive layer 66 on the high barrier protective film 55. Outer layer 66 and silica deposited (SiO)_xCoating) of polyvinyl alcohol film (Mitusbishi Kasei Corp., Tech Barrier^TMS) is blocking of the intermediate layer 68 of composition. On its inward facing surface, the transparent high barrier interlayer film 64 contains an inner sealant layer 70 composed of a polypropylene-polyethylene copolymer compounded with styrene ethylene-butylene styrene thermoplastic elastomer in various proportions. But is preferably a 100% polypropylene-polyethylene copolymer layer. The layers of the intermediate laminate film 64 are bonded to one another by an adhesive. For the sake of clarity, these adhesive layers are not shown, but they contain Tycel 790 from Liofol9 adhesive, which is a modified aliphatic polyester polyurethane adhesive. The inner seal layer 70 is firmly bonded to the outer surface of the front sheet 12 of the container by suitable means such as permanent heat sealing, ultrasonic sealing, adhesive touch sealing, or the like. The transparent high barrier intermediate laminate film 64 is sized to cover the entire surface of the medicament chamber from both the horizontal and vertical directions, and to further cover the peelable and permanent seal adjacent the medicament chamber.

As with the flexible plastic material of which the front sheet 12 of the container is composed, the three-layer laminate of the intermediate layer 64 should be substantially transparent to facilitate viewing of the contents of the medicament chamber 20. Thus, unlike polyvinyl chloride (PVC) and other similar materials, the intermediate layer 64 of the present invention is substantially clear and transparent while providing substantial protection against degradation by moisture and free oxygen, thereby facilitating viewing of the contents of the medicament chamber.

In particular, the barrier properties of the transparent high barrier intermediate laminate film 64 are much greater in terms of the important aspects of the function of the container, such as moisture and oxygen resistance, than conventional polymeric films, such as Low Density Polyethylene (LDPE), Medium Density Polyethylene (MDPE), Linear Low Density Polyethylene (LLDPE), Ethylene Vinyl Acetate (EVA), and blends of these polymers. The oxygen permeability of the middle layer 64 is approximately 10 ml/mil/m²24 hours/1 atmosphere. In contrast, the oxygen permeability of EVA copolymer, LDPE and MDPE was about 2500(EVA 5%), 8300(LDPE) and 8500(MDPE) ml/mil/m, respectively²24 hours/1 atmosphere. The oxygen permeability of LLDPE is about equal to or slightly higher than that of LDPE. Thus, the oxygen permeability of the transparent high barrier interlayer 64 is to an order of magnitude less than the oxygen permeability of the polymers typically used to make binary drug containers.

Due to the barrier properties of the intermediate laminate film, a pharmacist may peel off the peelable aluminum-containing foil protective film 55 prior to dispensing to view the contents of the container, and the container may then be stored for a period of time without the risk of oxygen or moisture causing degradation of the medicament. Once the protective layer of aluminium foil is peeled off, the storage life of the container should be about 30 days. The exact shelf life of the container containing the transparent high barrier laminate film 64 is dependent upon the sensitivity of the medicament contained in the medicament chamber to moisture when the aluminium foil layer is peeled off. For a drug having a relatively low sensitivity to moisture, the drug effect thereof can be substantially maintained for more than 30 days due to the protection of the transparent high barrier laminated film 64. Whereas for drugs that are very moisture sensitive, i.e. those that generally begin to lose their potency immediately after peeling the aluminum foil layer, they can be stored for up to two weeks without losing potency due to the moisture barrier properties of the transparent high barrier film covering the drug cavity.

Although the intermediate barrier film 64 is described in the exemplary embodiment as being affixed to the outer surface of the medicament chamber, it will be apparent to those skilled in the art that the intermediate layer may be enlarged as needed to a size that covers both the medicament chamber and the diluent chamber. The manner in which the intermediate layer is affixed to the outer surface of the container may also vary without departing from the scope of the present invention. The intermediate layer 64 may be permanently adhered to the outer surface of the container by means of a suitable adhesive and permanent heat or ultrasonic sealing. In addition, the intermediate film 64 may have peelability, and for this purpose, the peelability intermediate film 64 may be seal-bonded to the surface of the container by adjusting the temperature and pressure of the heat seal. In which case the film 64 may be peeled from the container 10 as the film 55.

It should be noted that the medicaments disclosed in the exemplary embodiments are in the form of dry powders. Such dry powders may be, for example, antibiotic or antiemetic compositions, non-limiting examples being cefazolin, cefuroxime, cefotaxime, cefoxitin, ampicillin, nafcillin, erythromycin, ceftriaxone, metoclopramide and carbothienylpenicillin/clav. However, liquid agents may also be used in the system. The system of the present invention is particularly useful when liquid medicaments and liquid diluents are difficult to coexist for long periods of time but must be mixed together at the time of dispensing to a patient. The medicament may also be in the form of a colloid, crystal, liquid concentrate, emulsion, or other similar form. The medicament chamber does not have to be used to hold a medicament. Other medical compositions, such as freeze-dried blood isolates, blood factor 8, blood factor 9, coagulation factor complexes, and the like, are also suitable for inclusion in the medicament chamber. Although a single medicament and diluent chamber are disclosed in the container of the present invention, containers having multiple chambers containing different diluents and/or different medicaments may also be provided according to the present invention.

Second embodiment

In a second embodiment of the invention, shown in cross-section in figure 5, the medicament chamber is covered with another structure instead of a transparent high barrier intermediate laminate film (64 in figure 4).

As in the first embodiment shown in fig. 2, 3 and 4, the transparent high-barrier intermediate laminate film 71 in fig. 5 may be coated on the medicament chamber of the container together with an opaque high-barrier aluminum foil-containing protective film (55 in fig. 2 and 3) adhered to the intermediate film 71. Therefore, the transparent high-barrier intermediate film 71 and the opaque high-barrier protective film together constitute a high-barrier protective cover film to be stuck to the drug chamber. As will be described in more detail below, the high barrier protective cover film may contain a high moisture barrier layer or a high oxygen barrier layer or both. An opaque aluminum-containing foil protective film 55 is used to prevent ultraviolet and visible light from penetrating into the medicament chamber of the container as desired.

The high barrier intermediate laminate film is comprised of a transparent multilayer thermoplastic polymer laminate film, generally designated 71, having high moisture and oxygen barrier properties. In the exemplary embodiment shown in fig. 5, the transparent multi-layer high barrier film 71 is a seal layer 72 of 100% polypropylene having a thickness of about 3.0 mils on its inward facing surface. The oxygen barrier layer 74 and the sealing layer 72 are laminated together by a first adhesive layer 76 consisting of a commercial Low Density Polyethylene (LDPE) extrusion and a substrate, which is located between the oxygen barrier layer 74 and the sealing layer 72. As will be described later, several flexible polymeric films have been identified that provide suitable oxygen barrier properties, but it is preferred that the oxygen barrier layer 74 of the multi-layer high barrier film 71 be comprised of a commercially available ethylene vinyl alcohol polymer (EVOH) having a thickness of about 0.55 mils.

Ethylene vinyl alcohol polymers are preferred herein primarily for their barrier properties against oxygen permeation. Its oxygen permeation barrier properties are generally greater than conventional package materials such as Ethylene Vinyl Acetate (EVA),Medium and high density polyethylene (MDPE and HDPE) are 4 orders of magnitude greater. Although providing a high barrier to oxygen permeation, ethylene vinyl alcohol polymers alone do not have sufficient resistance to moisture. Thus, a moisture barrier layer 78 is laminated to the ethylene vinyl alcohol polymer oxygen barrier layer 74 by a second Low Density Polyethylene (LDPE) adhesive layer 80. The moisture barrier layer 78 is manufactured from oriented high density polyethylene (oHDPE, Tredegar Co. of Richmond, Virginia, Inc. under the trade designation Monax^TMGrade HD) is used. The resulting composite barrier structure is on its outward facing surface a Polyester (PET) heat seal release layer 82 (e.g., terpane 10.21) that is laminated to the moisture barrier layer 78 by a third low density polyethylene extrudate adhesive layer 84.

The multi-layer high barrier polymer laminate film 71 of the exemplary embodiment shown in fig. 5 is a high oxygen barrier and moisture barrier flexible film suitable for forming an intermediate layer (64 in fig. 1) covering the drug chamber (20 in fig. 1) in the drug container. All materials constituting the laminated film are clear transparent materials substantially free from coloring. Thus, the compound membrane of the embodiment shown in fig. 5 is particularly suitable for covering the medicament compartment of a medicament container, in which the state of the contents can be observed by a person with a simple glance.

And FIG. 4 contains SiO_xUnlike the laminate film 64, the multilayer laminate film 71 in fig. 5 is one that can obtain high transparency. In particular, although containing SiO_xThe film is transparent, but it has a slight yellow color, so that SiO is not contained in the multilayer laminate film 71_xIs considered to be a main reason why the laminated film has high transparency.

Further, contains SiO_xThe material of (a) is relatively rigid and brittle and can break during the original container manufacturing, containment and/or handling process. Due to its inherent stiffness, if SiO_xThe film is stretched over 1% of its length and contains SiO_xThe barrier property of the film of (a) is lowered due to SiO_xThe membrane matrix itself has been broken. In addition, SiO_xThe current state of the art of application is SiO_xThe barrier properties of the film may be different at every point on the film surface. This is because the conventional SiO_xThe spray coating method cannot obtain a smooth coating film having a uniform thickness. This variation in barrier properties is generally much greater than that of extruded polymeric materials, which have less variation in barrier properties due to their inherently uniform nature. The barrier properties of a uniform polymeric barrier film are largely dependent on the thickness of the film, which can be very precisely controlled during the manufacturing process.

Although the preferred material for the transparent high barrier intermediate film should include both an oxygen barrier and a moisture barrier, other materials may be selected to cover the medicament compartment to suit the particular application. For example, one barrier layer may be omitted, resulting in a high barrier intermediate film that includes only a moisture barrier layer or only an oxygen barrier layer. The high barrier interlayer may also include a moisture barrier layer as previously described and a heat seal release layer of a high melting point material and having oxygen barrier properties.

Table 1 lists, without limitation, the exemplary film 71 of fig. 5 and four other examples of multilayer films or laminates that are suitable for use in making various embodiments of the transparent high barrier interlayers of the present invention. In the table, oHDPE means an oriented high density polyethylene such as HD grade Monax, and polyvinylidene chloride coated PET isAclar, a product of DuPont chemical company under the trade designation 50M44^TMReferred to as a polychlorotrifluoroethylene film available from Allied Signal Corporation, which is also known as ULTRX 2000.

TABLE 1

Material of laminate film 71

Thickness, mil

Description of the invention

1.

PET (outer layer)	0.48	Heat seal release layer
			LDPE extrudate	0.5-1	Adhesive layer
oHDPE	2	Moisture barrier
			LDPE	0.5-1	Adhesive layer
EVOH	0.55	Oxygen barrier layer
			LDPE extrudate/substrate	0.5-1	Adhesive layer
Polypropylene (100%) (inner layer)	3	Sealing layer

2.

PET	0.50	Heat seal release layer
			Adhesive agent		Adhesive layer
0???HDPE	2	Moisture barrier
			Adhesive agent		Adhesive layer
Polypropylene (100%)	3	Sealing layer

3.

Polyvinylidene chloride coated PET	0.50	Heat seal release and oxygen barrier layers
			Adhesive agent		Adhesive layer
oHDPE	2	Moisture barrier
			Adhesive agent		Adhesive layer
Polypropylene (100%)	3	Sealing layer

4.

PET	0.48	Heat seal release layer
			Adhesive agent		Adhesive layer
Aclar	2	Moisture barrier
			Adhesive agent		Adhesive layer
EVOH	0.55	Oxygen barrier layer
			Adhesive agent		Adhesive layer
Polypropylene (100%)	3	Sealing layer

5.

Polyvinylidene chloride coated PET	0.50	Heat seal release and oxygen barrier layers
			Adhesive agent		Adhesive layer
Aclar	2	Moisture barrier
			Adhesive agent		Adhesive layer
Polypropylene (100%)	3	Sealing layer

According to an embodiment of the present invention, each of the above-described multi-layer laminated films may be used as a transparent high-barrier covering layer for the medicine chamber 20 of the medicine container 10. Preferably, the rear sheet 14 of each container is made of a multi-layer laminate structure comprising a high temperature gas barrier film comprising aluminum foil, the inwardly facing surface of the laminate structure containing 80%/20% film (by weight) as described in the embodiment of fig. 3.

The rear sheet 14 of the container made of an opaque high barrier laminate film containing aluminum foil protects the contents of the container from ultraviolet and visible light which can degrade it. In practice, the peelable aluminum-containing foil film covering the medicament chamber is typically peeled off by a hospital supply department prior to dispensing. Since the high barrier intermediate films are transparent, they do not provide protection against light exposure, and therefore care must be taken to prevent the contents of the medicament chamber from being unintentionally exposed to ultraviolet or relatively strong visible light during subsequent storage. Therefore, folding the container in half in a peelable seal area allows the aluminum foil-containing film (or back sheet) to form the outer surface of the folded-over container, which helps to protect the contents of the medicament chamber from ultraviolet or intense visible radiation.

In fig. 6, the container 10 is shown folded in half along or before one of the peelable seals. After being folded in half, the material of the front and back sheets of the package are folded in half and compressed together, providing additional protection for the seal. This doubling back also provides additional resistance to hydraulic pressure, such as against hydraulic pressure caused by inadvertent squeezing of the diluent chamber in the container.

Preferred embodiments of the present invention provide means to ensure that the container is in a folded-over condition, with the result that accidental activation of the medicament is avoided and the contents of the container are protected from radiation simply by subjecting the rear sheet containing the aluminium foil to ambient light.

In fig. 1 and 6, suitable means for maintaining the package in a folded-over condition include a securing tab 28 and a mating engagement groove 27 formed from the original package material along one edge of the container, the engagement groove 27 receiving the tab 28 when the package is folded-over along a line in the region of the first peelable seal 24 between the diluent and medicament compartments. Once the container is folded in half and the securing tabs 28 engage the mating recesses 27, the contents of the medicament chamber are protected from accidental radiation from both front and rear directions by the rear foil comprising aluminium foil.

Thus, it can be seen that folding the package in half helps to provide protection from radiation degradation to the contents of the medicament chamber, and also helps to prevent inadvertent activation of the package by increasing the strength of the seal along which the package is folded in half. In addition, the means for maintaining the packing bag in the folded state is easily implemented or removed, so that the transparent inner surface of the medicine container is periodically exposed, and the contents in the medicine container are periodically known by visually observing the complete cavity.

In the exemplary embodiment of fig. 7, further protection of the medicament chamber is provided by providing an additional moisture vapor permeation pathway for moisture that may form in the liquid-containing diluent chamber. A further peelable seal 25 is formed across the left and right of the container a short distance before or above the peelable seal 24 separating the medicament and diluent chambers, thus providing an additional moisture permeable path. This additional peelable seal 25 is preferably located above the peelable seal 24, i.e., about 1/8 to 1/2 inches in the direction of the diluent chamber 18. The first peelable seal 24 and the additional peelable seal 25 together define a buffer chamber 29 between the diluent chamber 18 and the medicament chamber 20. The buffer chamber is preferably empty.

When the medicament container contains the additional peelable seal 25 and the buffer chamber 29, the container provides an additional moisture permeation pathway that protects the powdered medicament in the medicament chamber 20 from moisture that permeates from the diluent chamber through the container material. Although the medicament chamber 20 is covered by one of the high barrier protective cover layers as described above, there is a passage for moisture to transfer from the diluent chamber to the medicament chamber through the base container material with the first peelable seal 24. In the embodiment of the invention shown in fig. 7, moisture from the diluent chamber that may permeate through the base container material in the region of the additional seal 25 is confined to the buffer chamber 29. Since the surface area of the buffer chamber 29 through which moisture is to permeate is much larger than the permeation area provided by the peelable seals 24, moisture in the buffer chamber will preferentially escape to the atmosphere rather than permeating through the material of the first peelable seal 24 into the medicament chamber.

Thus, the additional peelable seal 25 and the buffer chamber 29 provide a means of protecting the dry medicament in the medicament chamber from degradation by moisture.

Manufacture and assembly of containers

In accordance with the subject invention, the front sheet 12 and the back sheet 14 of one exemplary embodiment of the container 10 face each other through an 80:20 film. In each of the embodiments described above, the inward surface of the front sheet 12 comprises an 80:20 film which faces the 80:20 inner surface film of the rear sheet 14, although other interface films are within the scope and contemplation of the present invention.

This composition of the front and back sheets 12, 14 of the container 10 allows for the formation of a perimeter seal and a peelable seal thereon using heat sealing techniques. The intersecting regions of the front and back sheet materials and the laminating film are heated to near or above their melting points by means of heat sealing bars or dies at different temperatures, pressures and application times so that their constituent materials are transferred at the intersecting surfaces and a seal of desired strength and properties is formed.

Fig. 8 shows a method of manufacturing the container 10 of the exemplary embodiment for both the single-layer film or the multi-layer laminated film constituting the front sheet 12 and the aluminum foil laminated film constituting the rear sheet. The method includes cutting front and rear sheets of the container to a desired vertical dimension, but to a larger dimension in the horizontal direction.

If the container 10 is a single film front sheet 12, the high-barrier protective layer 55 (see fig. 3) containing aluminum foil and the transparent high-barrier intermediate layer (64 in fig. 4 or 71 in fig. 5) constitute the high-barrier cover film of the medicament chambers 20, which are cut to the desired size, placed at the positions where the medicament chambers are to be formed and then adhered to the front sheet of the container. According to the present invention, the transparent high-barrier interlayer is first laminated and adhered to the surface of the front sheet, and then the protective layer 55 containing aluminum foil is adhered thereto.

Specifically, the transparent high-barrier intermediate layer 64 or 71 is placed over the medicine chamber and fixed by a pair of fixing bars when it is laminated and stuck on the surface of the front sheet 12. The area of the intermediate layer in contact with the fixing bar is not acted upon by, for example, a heat sealing head, so that a small area of the film is not sealed to the surface of the front sheet. The fixing bar used to fix the position of the transparent high barrier interlayer leaves a non-sealing area on the membrane surface with a footprint of the contact end of the fixing bar. In the embodiment shown in fig. 1, the surface that the retaining bar contacts is generally circular and forms two circular unsealed areas 41, the two unsealed areas 41 being easily visible due to the contrast of the reverse footprint caused by the pressure applied during the sealing process.

After the intermediate layer 64 or 71 is laminated, the aluminum foil layer 55 is adhered thereto using a shaped heat seal die as described above.

After the aluminum foil layer 55 and the transparent high barrier layer 64 or 71 are adhered, the front and rear sheets are mated and the outlet tube 30 is inserted between the front and rear sheets at the final desired position. The outlet tube 30 in the exemplary embodiment is formed by injection molding and has a formulation that includes 40% polyethylene-polypropylene copolymer having the FINA Z9450 designation and 60% ShellKraton designation^TM1652 styrene ethylene-butylene styrene thermoplastic elastomer. After insertion of the outlet tube, a hot die is used to form a seal between the flange 34 of the outlet tube and the lower edges of the front and rear sheets attached to the flange.

The constituent materials of the container are then compressed in the area where the seal is to be formed, for example, with a double heat seal bar containing mating front and back seal bars to form peelable seals 24 and 26 (which may also include an additional peelable seal 25) separating the chamber and the container 10. In an exemplary embodiment, the front heat seal bar in contact with the previously combined high barrier protective film 55, intermediate film 64 or 71 and front sheet 12 is heated to maintain a temperature between about 245 ° f and about 265 ° f. The rear heat seal bar in contact with the rear wafer 14 maintains substantially the same temperature as the front seal bar (between about 245 f and about 265 f) and may also contain a thin rubber coating to ensure uniformity of applied pressure. The amount of contact pressure between the sheets before and after pressing with the dual sealing bars is from about 230 to about 340 psi and the pressing time at this pressure and the aforementioned temperature is from about 1.5 to 2.5 seconds. Peelable seals 24 and 26 shown in figure 2 may be formed by separate pressing from a single dual sealing bar or by simultaneous pressing from two dual sealing bars. The additional peelable seal 25 may be simply formed by pressing a three double seal bar.

A further improvement to the above described embodiments of peelable seal formation is to form a heat seal head from dual seal bars wherein one end of the dual seal bars is joined together with transverse seal bars to form a right angle U-shaped configuration of the seal bars. When such a sealing head is pressed against the front and back sheets and maintained at the temperature and pressure conditions described above, an additional peelable seal 25 separating peelable seals 24 and 26 is obtained, adjacent and parallel to the permanent peripheral seal 16 formed on the edge of the container opposite the outlet tube. When the manufactured container has a high barrier protective film on the surface of its medicament chamber, it is preferred that the container contains an additional seal 25.

In this case, the thickness of the material processed by the heat sealing head is different (thicker) in the area defined by the medicament chamber 20 than in the area defined by the material constituting the permanent perimeter 16. The difference in material thickness between these two regions requires that the heat sealing head apply pressure in the presence of a conformal gasket, such as rubber, which ensures that a uniform sealing pressure is achieved across the intersecting surfaces. Forming the additional peelable seal 25 around the perimeter of the medicament chamber avoids the need for a conformal gasket for the sealing head. In this way, the thickness of the material subjected to the heat-sealing treatment will also be uniform, ensuring uniformity and leakage resistance of the peelable seal.

After the peelable seal is formed, the front and back sheets are bonded together by a permanent peripheral heat seal 16 across the top, bottom and one continuous edge of the container, wherein a portion of the peelable seal 25 separating the transverse seals 24 and 26 overlaps, thus ensuring a leak resistant seal between the diluent chamber, the medicament chamber and the lower chamber. As shown in fig. 8, on the other side of the container, the broad edge region of the front and rear sheets away from the permanent seal 16, is broken into several sections along the desired edge of the finished package, i.e., along the top vertical region 110a, the bottom vertical region 110b and the middle vertical region 110c, thus creating an insertable space between the three vertical sealed regions.

Feed inlet tubes 102 and 104 are interposed between the front and rear sheets at locations along the wide edges of the sheets and adjacent to the gaps in the permanent heat seal. For the same purpose, the front and rear sheets are sealed to the feed inlet tubes 102 and 104 at their tapered flanges 106 and 108, respectively, in a manner similar to that employed at the outlet tube 30. The feed inlet tubes 102 and 104 are also injection molded and may be formed from any of the currently available inexpensive thermoplastic materials since they are removed at a later stage of use of the container. In particular, the feed inlet tube may be constructed of an 80:20 membrane "regrind" material, simple polypropylene or similar material.

Fig. 8a and 8b show in more detail the feed inlet tubes 102 and 104, fig. 8a showing the diluent feed inlet tube 102 and the powder feed inlet 104 tube from the side, respectively, and fig. 8b is a schematic plan view of these inlet tubes. The feed inlet tubes 102 and 104 each contain a closure 109, the closure being shown interposed between the diluent feed inlet tube 102 and the closure being shown above the powder feed inlet tube.

Feed inlet tubes 102 and 104 are an important feature of the present invention and will be described in detail below. They provide a means for aseptically containing powdered medicaments and liquid diluents and the like into single or multi-compartment containers. In addition, the feed inlet tube also provides a structure that enables the feed inlet tube, and thus the drug container, to be carried and handled by automated instrumentation.

As shown in fig. 8a, each feed inlet pipe 102 and 104 comprises two separate flanges in the vertical direction, a lower flange 103 and an upper flange 105. Each flange is generally rectangular (see fig. 8b) with a long edge extending approximately 3 mm on both sides beyond the generally tubular barrel 107 of the feed inlet tube. As shown in fig. 8b, the short side (i.e. width) of each flange has the same dimensions as the outer diameter (12 mm) of the generally tubular barrel of the inlet tube. Each flange 103 and 105 is approximately 1.5 mm thick and is separated from each other and from each inlet cylinder and their respective tapered flanges (106 and 108). On each inlet tube, the lowest flange 103 is located at a distance of about 4 to 5 mm above the intersection of the inlet barrel and inlet tube tapered flanges, while the bottom surface of the highest flange 105 is about 4 mm from the top surface of the bottom flange 103, thus maintaining a distance of about 4 mm between the flanges and between the bottom flange and the rim of the vessel.

According to the present invention, the generally tubular barrel 107 of each feed inlet tube 102 and 104 has an outer diameter of about 12 mm and a length or height that varies depending on whether it is the diluent feed inlet tube 102 or the powder feed inlet tube 104. In the case of diluent feed inlet tube 102, the height of the cartridge in one exemplary embodiment is about 13 mm, and in the case of powder feed inlet tube 104, the height of the cartridge is about 18 mm. As will be appreciated by those skilled in the art, the inner and outer diameters of the feed cylinder may be generally the same as the inner and outer diameters of a glass or plastic vial. Such a size allows the feed cylinder of the feed inlet tube to be connected to a conventional vial feeding device.

Each of the generally tubular cartridges contains an internal bore therethrough so that the cartridge has a cylindrical configuration. In an exemplary embodiment, the diameter of each through bore is about 10.4 mm, and thus the wall thickness of the cartridge is about 0.8 mm. The upper edge of each cartridge had an approximately 45 degree bevel into the cartridge.

Each inlet tube has a generally cylindrical closure (or plug) 109 with an outer diameter (10.5 mm) slightly larger than the inner diameter (10.4 mm) of the feed cylinder of each inlet tube so that when the closure 109 is inserted into the inlet, the interface between the outer diameter of the closure and the inner diameter of the inlet acts as a seal. The seal is intended to prevent the ingress of particulate matter into the container prior to filling and to prevent loss of powdered medicament or liquid diluent after the container has been aseptically filled. As shown in fig. 8a, the bottom edge 109a of the lid 109 is chamfered at an angle of about 45 degrees to match the 45 degree chamfer of each cartridge to facilitate insertion of the lid into the cartridge.

In addition to the flanges 103 and 105 of the inlet tube, there is also a pair of flanges on the cover that are vertically spaced from each other. In the exemplary embodiment shown in fig. 8a, the generally annular upper flange 110 defines a top end of the closure having a thickness of about 1.0 mm and a diameter of about 12.0 mm, which exceeds the diameter of the closure body by about 0.75 mm. Such a protruding upper flange 110 allows a "lifting" mechanism to engage the lower end of the lifting upper flange 110 and provide a means for vertical lifting removal of the closure from its respective inlet cartridge. The lower flange 111 is used to control the depth of insertion of the closure, for example when the closure is inserted into the inlet cartridge or reinserted into the inlet cartridge after the loading operation is complete. The lower flange 111 may be a complete ring or may be in the form of a partial flange constituting a simple lateral extension of the closure body. As with the upper flange 110, the lower flange 111 has a thickness of about 1.0 mm and extends outwardly from the main body of the closure by about 0.75 mm. The upper flange 110 and the lower flange 111 are vertically spaced apart from each other along the body of the closure by a distance of about 3 mm.

Thus, we can see that each cap 109, after insertion, adds about 5 mm to the overall height of their respective feed inlet tube. It should also be noted that the height of the diluent inlet tube 102 and the closure together is 18 mm, the same as the height of the medicament inlet tube 104 without the closure inserted. This feature allows the closure of the medicament feed inlet 104 to be opened while the diluent chamber inlet remains sealed, and the container can also be used in conventional rotary-type powder feed mechanisms. Keeping the height of the sealed diluent chamber inlet tube equal to or lower than the height of the medicament chamber inlet tube in the unsealed state allows both inlet tubes to pass under the powder feed wheel in an efficient on-line operation.

Referring back to fig. 8, the permanent seals 110a, 110b, and 110c can extend to the wider edges of the container through the seal extension regions 110d, 110e, and 110f, respectively. These extended regions of the seal are of a suitable width to allow the bulky excess area of the container, including the feed inlet tube, to be cut away from the contained container after the container manufacturing process is complete without fear of weakening the peripheral seal of the container along the cut edges.

In particular, the enlarged areas 110e and 110f have a width sufficient to cut away and retain the lower groove (27 in FIG. 1) and tab (28 in FIG. 1), respectively, of the relatively rigid material of the seal extension areas 110e and 110 f.

The seals and seal extensions of the broad area of the container form voids or channels 112a and 112b in the container material between the seals. The channel 112a provides communication between the feed inlet tube 102 and the interior of the diluent chamber 18, while the channel 112b provides communication between the feed inlet tube 104 and the open medicament chamber 20. The channels 112a and 112b are closed by subsequently permanently heat sealing various separate vertical seal areas (110a-f) within the broad area of the container, as will be described further below.

Container manufacturing apparatus

We describe by means of fig. 9a method and apparatus for manufacturing the container 10 of fig. 8, according to the present invention. It will be apparent from the following description of the container manufacturing apparatus that the apparatus and method are suitable for manufacturing pharmaceutical containers having front and rear sheets of single or multi-layer laminated film, and further, from the following description, it will be apparent that the number, shape, configuration and location of the various seals in the container 10 shown in fig. 8 may be readily changed or even omitted due to the standard alignment of the components of the apparatus.

Fig. 9 is a schematic plan view of an exemplary embodiment of a container manufacturing apparatus 120 consistent with the present invention showing various arrangements and locations for forming sealing devices, and the arrangement and configuration of the base film-forming supply rolls of containers.

The bulk material forming the front and rear sheets of the container (e.g., 12 and 14 in fig. 2) is supplied to the container manufacturing apparatus 120 in the form of respective bulk film-forming supply rolls 122 and 124, which are mounted in a large roll supply roll arrangement that is connected to the inlet end of the container manufacturing apparatus 120. The web material, for example from the front web supply roll 122, passes through an equalizing device 123 that maintains the web material in a suitably taut state as it is drawn through the other devices of the manufacturing apparatus 120. After passing through the equalization apparatus, the web of film material is conveyed by the vacuum feed wheel through a first web film cleaning apparatus 125 and then through an optional series of barrier film application apparatus 126 and 127, which are distributed in series on the web film supply line. If the container (10 in fig. 1) is made in the form of the construction described above, i.e. comprising a single-film front sheet 12, a transparent high-barrier intermediate film (64 in fig. 4 or 71 in fig. 5) and a high-barrier protective layer of aluminum-containing foil (55 in fig. 3), the high-barrier cover layer of the medicament chamber 20 is first cut to the appropriate size in the barrier film application devices 126 and 127, respectively, then adjusted to the place where the medicament chamber is to be formed and then glued to the front sheet of the container. According to the invention, a transparent high-barrier intermediate layer is first laminated on the surface of the front sheet in an application device 126, and then a protective layer containing aluminum foil is re-pasted thereon in an application device 127.

In a similar manner, the web material to be formed into the container back sheet is passed from its large web supply roll 124 through a corresponding equalizing device 128 and then conveyed by the vacuum feed wheel through a corresponding web cleaning device 129.

As the continuous films of the leading and trailing web materials exit their respective manufacturing facilities, the two continuous films enter the entrance of the manufacturing apparatus together in a position where the 80:20 surface of one of the continuous films is opposite the 80:20 surface of the other film. Once the continuous film is fed into the inlet, the web of film material is continuously fed and longitudinally through the sealed cylindrical die 130 of the manufacturing apparatus 120. The diluent and agent feed inlet tubes are placed in a sandwich of rolled film, in the rolled film of front and rear sheets, and various seals are then formed on the rolled film sandwich to bond the two rolled films together and create a container suitable for sterile containment in an intermediate state.

According to the present invention, the sealing cylinder mold 130 of the manufacturing apparatus contains a large number of sealing molding devices and mouth-tube inserting devices arranged in series along the passage of the sandwich web of containers. The first of these is a device 131 for receiving the outlet tube, in which the outlet tube (30 in fig. 8) is inserted in place in the front and rear sheets. In the outlet duct sealing means 132, a hot die press comprising a shaped die is hot pressed against the web material to form a seal between the flange (34 in fig. 8) of the outlet duct and the material of the final bottom edge of the front and rear sheets adjacent the flange. The outlet tube 30 is injection molded from a thermoplastic material formulated with 40% of a polypropylene copolymer sold under the trade designation FINA Z9450 and 60% of a thermoplastic elastomer sold under the trade designation Shell Kraton G1652 styrene ethylene-butylene styrene. Due to the similarity of the material comprising the outlet duct 30 and the material of the inner surface forming the seal between the front and rear sheets, it will be seen that the front and rear sheets can be sealed to the outlet duct flange by heat sealing in a manner substantially similar to the method used to form the permanent peripheral seal described in detail below.

After the outlet tube 30 is inserted and sealed to the container material, the sandwich web is then fed to a feed inlet tube inserter 134 in which feed inlet tubes (102 and 104 in fig. 8) are inserted between the front and rear sheets at locations along the edges of the container that will form the respective areas of the diluent chamber 18 and the medicament chamber 20. The feed inlet tubes 102 and 104 are preferably injection molded from 100% polypropylene material, but may be made from the same material as the outlet tube 30 formulation. For the same purpose, the front and rear tabs are sealed to the feed inlet tubes 102 and 104 along tapered flanges 106 and 108, respectively, in a manner similar to the outlet tube 30.

After insertion of feed inlet tubes 102 and 104, the film materials of the front and rear sheets are joined by permanent heat seals (16 in fig. 8) along the top, bottom and one continuous side of the finished container to be formed. A permanent heat seal 16 is formed at the opposite side of the container, at a distance from the edge of the sandwich web and along the intended edge of the finished container, and is broken into segments (110a, 110b and 110c in fig. 8).

After the peripheral seal is formed in the peripheral seal 136, the container material is delivered into the optionally present first medicament feed inlet tube seal 138. The sealing of the front and rear sheet materials to the tapered flange 108 of the medicament chamber inlet tube 104 is achieved by pressing the front and rear sheet materials onto the tapered flange of the inlet tube using a pair of concave heat sealing dies. Similar to the die of the outlet tube, the heat sealing die of the medicament inlet tube sealing means 138 has a configuration such that when the two halves of the sealing die are pressed together they form a small space, generally elliptical, having the mirror image of the convex conical sealing surface of the medicament inlet tube.

The web material is then fed into the optional second diluent chamber feed inlet tube seal 140 where the front and rear sheet materials of the container are pressed and heat sealed against the tapered flange 106 of the medicament chamber inlet tube 102.

The order of sealing of the container feed inlet tube should be entirely arbitrary and the medicament inlet tube seal 138 may simply be located behind the diluent inlet tube seal 140 and vice versa. Furthermore, the sealing means for sealing the feed inlet pipe of the container may be located before the peripheral sealing means 136. Alternatively, a seal means, such as peelable seal forming means 142 shown in FIG. 9 after the feed inlet tube insertion means 134 and before the peripheral seal means 136, may be provided as desired to form a peelable seal that bisects or further divides the container 10 into a plurality of compartments. An optional peelable seal forming means 142 may also be placed before the feed inlet tube insertion means 134 simply by relocating the peelable seal forming means on the transport path of the web. If it is desired to form a container having a plurality of chambers, it is obviously necessary to provide a plurality of peelable seal forming means.

It will be apparent to those skilled in the art that each of the successive sealing devices, independent of each other, can be automatically activated when the web of film is delivered to their respective locations. The sealing means may also be present in the container manufacturing apparatus but in an unopened state, so that no specific sealing takes place in a particular manufacturing process.

After the feed inlet tube is sealed, the container web is fed to a trim zone seal assembly 144 which applies a permanent heat seal to the container material in contact with and overlapping the break zone of the permanent peripheral seal and extending to the edge of the container film material. The trim seal area (110 d, 110e and 110f in fig. 8) is located in the area of the film between the perimeter seal of the container and the edge of the rolled film, thus forming a relatively less flexible region in the material having a width sufficient to cut the fastening groove (27 in fig. 1) and fastening tab (28 in fig. 1) in the relatively harder material of the trim seal. In addition, the seal of the cutback region serves to increase the width of the peripheral seal (110a, 110b and 110c), so that the width of the peripheral seal formed in this region is adapted to allow this portion of the container (including the feed inlet) to be cut from the container after the container is manufactured and filled without substantially weakening the peripheral seal of the container along the cut edges and without compromising the integrity of the container after filling.

As shown in fig. 8, the cutback seals (110 d, 110e, and 110f in fig. 8) define voids or channels 112a and 112b in the container material between the seals. The passage 112a provides communication between the feed inlet tube 102 and the interior of the diluent chamber 18, while the passage 112b provides communication between the feed inlet tube 104 and the medicament chamber 20, so that both chambers can be fed through their respective feed inlet tubes. The channels 112a and 112b are closed by subsequent permanent heat sealing that joins the trim region seal portions (110a-f) in these regions of the container, as described further below.

After the heat sealing step, the container is conveyed past a hang off punch 146, which forms a hanging cut in the center of the top end of the container. The latter means 147 and 148 divide the plurality of containers, cut the web of film material at the first outlet end (147), the top trimming means 148 cuts the container material at the hanging end, and the containers are subsequently discharged from the manufacturing facility 120, substantially completing the entire container manufacturing process.

It will be apparent to those skilled in the art that the number and configuration of the chambers contained in the container will depend entirely on the number and location of the various heat seals used in making the container. In addition, depending on the number of containers desired for the final product, an appropriate number of feed inlet tubes are selected and inserted along the edges of their respective rolls of film material where they should be. It is envisioned that the standard manufacturing process of the present invention is suitable for manufacturing drug containers having a single chamber, or that multi-chamber containers having any number of chambers may be manufactured simply by adding a peelable seal and adding a feed inlet tube inserted into the chamber. For each configuration of multiple chambers and feed inlet tubes, the trim seal pressed in the trim seal apparatus 144 can be suitably configured by removing one punch face and replacing it with another punch face that can provide one, three, four, etc. channels or spaces, which facilitates the insertion of multiple feed inlet tubes into multiple chambers.

It will also be apparent to those skilled in the art that the composition of the front and back sheets of the container may be varied by suitably replacing the front and back sheet films fed on the film-winding drum with other suitable materials. In particular, the supply rolls for both the front and rear sheets may be provided with a single 80:20 film layer so that the resulting container is transparent on both the front and rear sides. Since the manufacturing equipment is essentially a standard piece of equipment, the transparent barrier layer application equipment and the aluminium foil barrier layer application equipment, as well as the peelable seal forming equipment, can be adjusted to an inoperative state, the construction of the container manufacturing equipment can provide a completely transparent single-chamber container, which can also contain a plurality of outlet tubes, such as separate medicament inlet and outlet tubes.

The container manufacturing apparatus of the present invention is therefore suitable for manufacturing a number of medicament containers having different sizes, different sealing configurations and different outlet and inlet tube positions. All containers thus obtained will be suitable for aseptic containment according to the invention and, if desired, also for use in connection with a final sterilization step.

Seal formation

The peelable seal formed in the above manufacturing process is an elongate square linear seal. Although they are similar in appearance to the conventional straight seals, the peelable seals of this embodiment have a more predictable failure characteristic, i.e., an improvement in the uniform resistance to manual handling pressure.

While not wishing to be bound by theory, the inventors believe that the peelability of the seal can be achieved by limiting the time, pressure and temperature to a limit that ensures that sufficient melting is achieved to melt the intersection between the inner films of the front and rear sheets that have lower melting points than the intermediate layer and the outer layers of the rear sheet. The depth of the inner film in the melt zone is limited so that sufficient strength is obtained to prevent failure in a properly operating container while also imparting peelable sealing properties.

The activation force of the container of the present invention is preferably tightly controlled to the extent that the container remains intact under extreme operating conditions, but is still relatively easy to activate for all users. This activation force is characterized by a burst pressure of preferably about 4 ± 1 pounds per square inch (psi).

To achieve this uniformity of a generally rectangular seal at rupture pressures, the key parameter that must be controlled is identified as temperature. A uniform burst pressure response can be achieved by controlling the sealing temperature within a tolerance of ± 2 ° f. The existing commercial heat sealing equipment cannot control the error of the heat sealing temperature within the range. But the heat sealing time can be very precisely controlled. The time is therefore chosen as a control parameter and is adjusted to compensate for the variation in heat seal temperature. The time and pressure of the sealing head are controlled to ensure that they are within the acceptable ranges described above, and then the heat sealing time is adjusted. While the contact pressure is preferably from about 230 to about 340 psi, those skilled in the art will recognize that the lower limit of this range (about 230psi) should be employed to facilitate setting the parameters of the heat seal apparatus. A peelable seal can be formed at a given temperature and pressure as appropriate, provided that the pressure applied by the heat-seal bar to the container material is sufficient to bring the heat-seal layer of material into contact with the surface to be sealed. In fact, experimental results have shown that when the temperature and time tolerances of the heat seal are outside the limits defined by the present invention, the seal achieved does not only have the desired uniform resistance characteristics, but also does not achieve complete failure along the length of the seal. Incomplete destruction often results in diluent carryover, such as at the corners where the peelable seal makes 90 ° with the permanent peripheral seal of the container. The mixing ratio of diluent to medicament is thus no longer the desired value and the dispensing of the medicament may be carried out at a higher than desired concentration value.

For an exemplary embodiment 80:20 film with a burst pressure of about 4 ± 1psi, the specific times, temperatures, and pressures at which the peelable seal is formed are: pressure 235psi, temperature 257 ° f and time 1.9 seconds; and a pressure of 235psi, a temperature of 263 ℃ F. and a time of 1.75 seconds.

Higher temperatures and corresponding pressures and times are used to form the perimeter permanent heat seal and the outlet tube seal. Such seals can be obtained by heat sealing at a temperature of 290 ° f and a pressure of up to 200psi for a time of about 2 seconds. Those skilled in the art will recognize that various techniques for simultaneously forming permanent and peelable seals may be used to make the containers of the present invention. In particular, controlling the heat-seal temperature to a higher level (within about ± 2 ° f) clearly results in peelable seals with uniform burst pressure. Furthermore, since it can be controlled very precisely, the time is selected as the control parameter for forming the seal. Precisely controlling time, temperature, or both, can yield the same results.

The order in which the containers 10 of the present invention are manufactured is arbitrary to those skilled in the art and has also been determined to accommodate a particular manufacturing process and a particular embodiment of the final container. The order of the manufacturing steps, as well as the location and orientation of the various components making up the container 10, may be variously modified without departing from the subject matter of the present invention.

After the container is manufactured to the stage illustrated in fig. 8, the container is now in a state in which it can be used to aseptically hold a medicament, a diluent, both, or any combination thereof. In an exemplary containment process, a particular embodiment of the container of the present invention for containing a medicament is a container comprising a single or multiple pre-laminated film sheets and multiple aluminum foil post-laminated film sheets, the formed container comprising a diluent chamber 18 and a medicament chamber 20, both of which have unsealed edges for insertion of feed inlet tubes 102 and 104, respectively, therein. This embodiment of the vessel is at the stage shown in figure 8. The manufacture of a pristine vessel comprising an outlet pipe and a feed inlet pipe may be accomplished by the method and apparatus described previously.

In order to adapt the aseptic filling process to the requirements of pharmaceutical applications, the containers used for filling must be provided in an aseptic environment. In conventional methods, the sterilization of the containers is usually performed in a separate processing area or facility, since sterilization requires rather elaborate and complex instruments and processes. A particularly troublesome aspect of the sterilization process is that the containers must be transported to a sterilization facility, and the sterility of the containers must be maintained subsequently during storage and transport of the containers to the sterile filling facility. The containers must be delivered aseptically into the sterile filling area, which prevents contamination of the sterile area with the containers. Once in the sterile zone, the containers can be filled in a sterile manner, but the latter operations must be carried out in a sterile manner.

According to the invention, after the original containers have been manufactured, a plurality of empty containers are loaded into a container transfer carrier, which is subsequently sealed to protect the containers therein from environmental contamination.

Referring now to fig. 10, a transport carrier, generally referred to herein as a "carrier" and generally indicated at 150 in the figure, is provided as a transportable sterile container isolator for sterilization, transport and introduction of batches of empty containers into a sterile zone. The vector 150 contains three parts: a generally rectangular container tray 152, a sealable lidding film 154 and a rail bracket 162 for supporting a plurality of containers within the tray, the rail bracket 162 being described in more detail below in connection with figures 11a and 11 b.

The generally rectangular container tray 152 is made of a thermoformed polystyrene material that does not significantly degrade after several sterilization cycles. The tray 152 is generally a basin-shaped structure with its upper perimeter curved outwardly to form a straight horizontally oriented perimeter 156 that extends a distance of about 1/4 to 1 inch beyond the edge of the tray 152. The perimeter 156 is preferably about 3/4 inches beyond the edge of the tray, but may have any extension that imparts rigidity to the tray 152 and sufficient surface needed to support the seal. Two opposing recessed areas 158 and 160 are formed at about the middle of the opposing short sides of the tray and extend outwardly from the plane of the short sides. The recessed areas 158 and 160 extend partially down the periphery of the tray and thus form two opposing grooves into which the two ends of the rail brackets 162 can be inserted. The rail brackets 162 rest on the bottom surfaces of the recessed areas 158 and 160 and thus float above the bottom of the tray 152 to a height sufficient to allow containers resting on the rail brackets to hang freely in the space within the tray. Thus, the recessed areas 158 and 160, in combination with the rail brackets 162, maintain a specific orientation alignment of the plurality of containers during transport, storage, and UV sterilization.

Once the rail bracket 162 is loaded with a plurality of containers and inserted into the recessed areas 158 and 160, the plastic lidding film 154 is heat sealed to the tray flange 156 in a well-defined orientation so that the tray 152 is sealed from the surrounding environment. For ease of illustration in fig. 10, the cover film 154 is shown in the middle of the sealing stroke, with a portion of the cover film lifted upward to expose the rail bracket 162 located in the tray 152. The lidding film 154 is positioned over the flange 156 so that no lidding film material "overhangs" the edge of the tray flange around the periphery of the tray. In an exemplary embodiment, the plastic lidding film is sized so that the lidding film can be seated on the flange of the tray such that the edge of the lidding film is indented into the edge of the tray flange around the entire periphery of the flange. In addition, the heat sealing of the lidding film extends beyond the edge of the lidding film 154 to ensure that the edges of the lidding film are fully sealed, leaving no loose edges that could form a "flap up and down". Orientation, sealing placement, and avoidance of loose edges of the cover film after the containers are transferred into the sterile zone are particularly important for surface uv sterilization processes performed on the carrier 150. When exposed to uv radiation, cracks created by loose edges and/or fluttering of the lidding film can initiate localized shadows, which can cause the entire uv sterilization process to fail.

Once the cover film 154 is heat sealed to the tray flange 156, the carrier 150 defines a completely sealed environment that isolates the contents therein from external contaminants. The carrier 150 is then placed in a multi-wrap (not shown) that acts as a dust guard and marked with an adhesive label that is applied to the wrap.

Turning now to fig. 11a and 11b, fig. 11a shows the components of the carrier rail bracket 162 ready for assembly, while fig. 11b shows the carrier rail bracket fully assembled. The carrier rail bracket 162 includes a plurality of T-shaped polystyrene injection molded parts 163a, b, c, d, e and f that are spaced apart from one another to form longitudinally extending slots 164a, b, c and d therebetween. The polystyrene T-shaped rails 163a-f are oriented with the feet of the T-shape facing upward (see perspective views of fig. 11a and 11 b) and include molded or engaged pegs 165 thereon that are adapted to mate with corresponding receptacles 166 on one or more spacers 167. The gasket 167, like the T-shaped rails 163a-f, is made by injection molding from a high impact polystyrene material such as FINA 825 manufactured and sold by the Company Fina Oil and Chemical Company of Deerpark, Texas. The spacers 167 of the carrier rail bracket 162 separate and maintain a predetermined distance between the T-shaped rails 163 a-f. The shim may contain a notch 168 that provides a grip so that the final carrier rail bracket assembly can be easily grasped, lifted, and transferred. Alternatively, a thin flexible plastic handle may be attached across the spacer 167, or in some other well-known manner to allow the carrier rail bracket to be grasped and manipulated.

Once the carrier rail brackets are assembled, the container product may be carried on the rail brackets in the manner shown in fig. 12a and 12b in accordance with the present invention. In FIG. 12a, which shows a plan view of a carried carrier rail bracket, those finished manufactured containers 10 as shown in FIG. 8 are carried on the carrier rail bracket 162 by inserting their feed inlet tubes (102, 104) into the slots 164a-d formed in the T-shaped rails 163a-f in the manner shown in FIG. 12 b. The flange edges of the T-rails 163a-f are spaced apart from each other by a sufficient distance (approximately 13.0 mm) so that the central feed cylinder 107 of each feed inlet tube can be received therebetween and adapted to mate with the feed inlet tube between the surrounding flanges of the inlet (103 and 105 in fig. 8) so that each container 10 is held by the T-rail flange below the topmost surrounding flange 105 of its feed inlet tube.

In the exemplary embodiment of the carrier rail bracket shown in fig. 12a and 12b, four slots (164a, b, c, and d) are provided to carry a plurality of containers, wherein the plurality of containers are carried on the rail bracket 162 in a left-right alternating orientation. Feed inlet tubes 102 and 104 of each vessel are inserted into two of the slots 164 a-f. As shown in fig. 12b, the first container 10' is carried in the second and fourth slots (164b and 164d) and oriented in a first horizontal direction with its suspended end to the right (see perspective view of fig. 12b) and the outlet tube end to the left. The second container 10 (the first container in the perspective view of fig. 12b) is carried on the rail bracket 162 in such a way that its feed inlet pipes 102 and 104 are inserted into the first and third slots 164a and 164 c. The second vessel 10 is carried in a second horizontal orientation with the outlet pipe 30 oriented 180 degrees from the outlet pipe of the first vessel. In the embodiment of fig. 12b, the outlet tube 30 of the first container 10 is located to the right, as seen from the perspective of fig. 12 b. Other containers are carried on the carrier rail bracket 162 in a similar manner, alternating left and right in the horizontal orientation of the containers; as described above, the feed inlet tubes of the leftward oriented containers are inserted into the second and fourth slots, and the feed inlet tubes of the rightward oriented containers are carried in the first and third slots until the carrier rail brackets 162 are fully carried.

Referring back to fig. 12a, the specific design of the flanges of the feed inlet tubes 102 and 104, in combination with the carrier rail brackets 162, maximizes the packing density of the containers in the container tray 152. As shown in fig. 12a, the feed inlet tube flange only protrudes in the direction of the length of each vessel, but not in the width or thickness direction. Thus, when the carrier rail brackets are carrying containers, the thickness of any one container is determined by the width of its feed inlet tube barrel (about 12.0 mm). When the next container is carried on the carrier rail support, only the feed drums of the feed inlet tubes of alternate containers are adjacent to each other. The alternating horizontal orientation of successive containers and the offset position of their slots also contribute to the packing density of the containers on a fully loaded guideway support. As shown in fig. 12a, the addition of another set of slots can substantially double the packing density of the container as compared to a carrier system having only one pair of slots.

It will be apparent to those skilled in the art that the containers are carried on the carrier rail brackets where the other container is systematically oriented at a 180 ° angle to the previous container, and the lateral offset created by the spacing of the slots of the rail brackets. This alternating container orientation maximizes container loading density along the length of the guide rail bracket and determines a particular orientation and positional arrangement of the plurality of containers relative to the guide rail bracket, making the guide rail bracket assembly easy to design as an automated handling system. In addition, the cutouts (or snaps) 168 in the spacer 167 allow an operator to easily place a fully loaded rail bracket into or out of the carrier tray without having to grip the rail bracket excessively, thereby minimizing the possibility of the container disengaging from the rail.

The carrier rail bracket is placed into the tray 152 after being loaded, and the ends of the T-shaped rails 163a-f nest within the grooves 158 and 160 formed in the top of the tray. The grooves 158 and 160 support the carrier rail bracket 162 within the interior space of the tray and provide additional lateral support to prevent movement of the rail bracket during transport, sterilization and storage.

The sealed carrier, including its hollow container, is wrapped in a multi-layer bag and transported to a radiation sterilization unit where the carrier and its contents are sterilized, for example, by electron beam irradiation.

Process for loading container

After the carrier loading and e-beam sterilization process described above is completed, the sterilized drug containers are transferred to a sterile feeding device for aseptically filling the containers as described in the flow chart of an exemplary process of an embodiment of the present invention represented in fig. 13, and fig. 14 is a schematic plan view of an exemplary container filling apparatus.

The original bag will be filled using manufacturing techniques developed from integrated circuit manufacturing that are now becoming more common in the medical industry. This technique is a transition from the usual container contents in a class 100 sterile environment to container contents in an "isolator" device where the environment is sterile. The primary difference between a sterile environment of class 100 and an "isolated body" is the operator's detachment from the environment. The barrier is essentially a "mini-environment" that encompasses direct equipment and container containment operations within a fixed space. The operator is disconnected from the space and access to the contents is provided through the glove box access and/or "half damages". Decoupling the operator from the environment makes it possible to create and maintain a less sterile environment, since the operator is often the main source of bacterial contamination.

The insulation is first sterilized with a sterilizing agent, such as Vaporized Hydrogen Peroxide (VHP). The ambient air inside the insulation is maintained in a sterile condition by supplying HEPA and ULPA filtered air. The ambient air inside the insulation also maintains a state in which its pressure is higher than the air pressure surrounding the insulation. Positive air pressure ensures that the air flow is from the interior of the separator to the exterior. All components and sub-components that are to be introduced into the insulation should be pre-sterilized or sterilized just prior to their introduction into the insulation to ensure that sterility is maintained therein. The various components typically enter the isolator through a channel or port, commonly referred to as an RTP (rapid transport entry). RTP is designed such that they are mechanically linked to each other so that the sterility of the barrier is not compromised. The interior of the container in which the sterile assembly is loaded into the insulation is also sterile and also contains an RTP integral with the container.

Referring now to fig. 13 and 14, and particularly to fig. 13, the bundled multi-layer bag is removed from each of the loaded carriers under HEPA filtered air before the carriers are introduced into the loading line, in order to maintain a low level of particulate matter and bacteria on the outer surfaces of the carriers. After removal of the bundled multi-layer bags, the integrity of the individual seals of each carrier was also checked by pressure let-down method in unidirectional HEPA filtered air.

Referring now to fig. 14, in conjunction with fig. 13, the carriers are introduced into a holding line generally designated 170 in the figure, assuming the integrity of each carrier is maintained after sterilization by transport and electron beam. Before the containers are removed from the carrier for loading, the carrier is first conveyed through a uv disinfection tunnel 172 in which the outer surface of the carrier is disinfected by uv irradiation. The carrier enters the entrance of the uv disinfection tunnel 172 where the uv light surrounds the carrier and irradiates its entire outer surface, thus controlling potential contamination from being carried into the subsequent insulation of the carrier line.

After the irradiation with ultraviolet rays is completed, the carrier is transferred to a carrier loading chamber (not shown) through a transfer chamber entrance, where the cover film of the carrier is opened and the rail holder carrying the plurality of containers is taken out from the carrier. The containers are removed from the rails of the rail support and placed on a track through which they are conveyed to a luffing boom 177 for transport into the first containment isolator 174. In exemplary embodiments of the invention, the barrier is a controlled environment for holding the container, e.g., holding a powdered medicament into the container. Although the aforementioned transport processes can be carried out by automatic means, they are usually carried out manually, for example by means of a "glove box access" or by means of a "half-sit" work arm which reaches into the access opening of the carrier and manually operates the carrier, the cover film and the rail mounts. At this time, the empty guide rail bracket and the carrier are conveyed back into the ultraviolet irradiation chamber, and the conveyance entrance is closed before the guide rail bracket and the carrier are taken out from the ultraviolet irradiation chamber 172.

The luffing boom 177 rotatably positions the container in a position for loading onto a continuous mechanical conveyor, in such a way that the container is guided into the powder containment partitions 174 and subsequently transported through the various steps of the powder containment process. Figure 15a shows a portion of a continuous mechanical conveyor belt 176 formed from a flat strip of a suitable flexible material such as metal or plastic and forming a loop around the outer peripheral surface of the drive roller 171. The drive roller 171 is connected to a drive motor such as a usual direct current motor or a progressive motor to convey the conveyor belt 176 through the separator in a predetermined stepwise manner. The belt 176 contains a series of discrete grooves 175 which are cut into the belt material perpendicular to the direction of belt travel. Each slot 175 is approximately 12.4 mm wide and thus can receive the feed barrel of the feed inlet tube of the vessel. The groove 175 has a width sufficient to receive the feed cylinder but is also thin enough to matingly engage the lower surface of the lowermost flange (103 in fig. 8 a) of the feed inlet tube.

There is a hole 173 in the middle of a pair of grooves and this hole is distributed all the way through the material of the belt 176. Each hole is approximately 11.0 mm in diameter and serves as a convenient receptacle for receiving the feed inlet tube cover (109 in figure 8 a) when the cover is opened from the feed inlet tube for containment. Although in the exemplary embodiment of fig. 15a the aperture 173 is shown at an equidistant position from both slots 175, it is apparent that the location of such aperture (or cover receptacle) 173 may be anywhere near the slots 175. If, for example, an automated up-down loader is used to open the closures from the feed inlet tubes, all that is required is that each closure receptacle 173 has a specific relationship to a slot 175 so that the position of the closure receptacle 173 can be programmed into the automated apparatus.

Referring back to fig. 14, the containers may be manually removed from the rack support and placed on the conveyor belt 176; the operator may reach into the insulation through a padded entry port by means of a half-cut or flexible arm guard, or the containers may be placed on a conveyor belt 176 by an automated up-and-down swinging boom 177 which grasps each container and rotates it approximately 90 degrees to fit the flange of the feed inlet pipe into the recess of the conveyor belt.

First, to obtain the empty weight for reference in subsequent weight measurements, the conveyor belt 176 transports each container to a tare scale 178 where each container is tared. Empty containers can be removed from the conveyor belt 176 and placed on a tare scale by hand or by means of an automated up and down loading and unloading mechanical boom 179. The containers are then replaced on a conveyor and transported to a sterile rotating in-line powder feeder 180. In the powder feeder 180, a mechanical arm 181 oscillates in an arc to engage a cover on the feed inlet tube (104 in fig. 8) of the medicament chamber. The closure can be opened by grasping the opening flange of the closure and applying a vertical upward force (as depicted in figure 8 a). After opening, the closure of the feed inlet tubes of the medicament chambers are placed in the closure receptacles (173 of fig. 15 a) located between the feed inlet tube slots on the conveyor belt. The cover of the inlet tube of the medicament chamber is now in a known position relative to the inlet tube of the medicament chamber so that the cover can be easily retrieved by an automated device for reinsertion into the inlet tube of the medicament chamber as will be described in more detail below. After the closure cap was opened, a jet of nitrogen or air filtered through a 0.2 micron microporous filter was passed through the feed cylinder of the feed inlet tube of the medicament chamber to open the medicament chamber.

Referring now to figure 15b, the feed inlet tube of the conveyor belt which then transports the containers to the medicament chambers is located under a conventional generally circular dosing wheel 182 which automatically dispenses a predetermined quantity of powdered medicament into the medicament chambers through the open inlet. The dosing wheel 182 is positioned in a direction perpendicular to the direction of transport of the conveyor belt 176 and the containers 10 suspended thereon. The reason for the medicament chamber inlet tube being higher than the diluent chamber inlet tube is therefore clear at this point. In order to allow the entire powder dose contained in the dosing wheel to be introduced into the dose chamber without excessive leakage, the length of the dose chamber inlet conduit should be such that its opening is at a distance of about 1.0 mm from the dosing wheel. In order to allow the inlet line of the diluent chamber, now still with the closure, to pass through the bottom edge of the applicator wheel after the filling is complete and during the transport of the container to the next device, the total height of the diluent chamber inlet line and the closure carried must not exceed the height of the medicament chamber inlet line with the closure opened, that is, the space between the conveyor belt 176 and the applicator wheel 182.

There may be another design for the orientation of the container and the dosing wheel. For example, the containers may approach the applicator wheel in a direction perpendicular to the wheel face of the applicator wheel, rather than passing under the wheel in a line along their long axis, so that only the feed inlet tubes of the medicament chambers pass through the bottom edge of the arc of the applicator wheel. This particular orientation avoids the diluent inlet tube passing through a narrow space between the conveyor belt and the bottom edge of the circular arc of the applicator wheel, thus eliminating the need for a feed inlet tube of different height.

Referring back to fig. 13 and 14, after the dose is filled, nitrogen or air filtered through a 0.2 micron filter is introduced into the upper space of the dose chamber and the conveyor belt 176 transports the container to a heat seal 184. Although the present invention uses nitrogen or air filtered through a 0.2 micron filter, the choice of which gas between the two gases, or other filtered sterile gas (inert or other), will depend on the sensitivity of the particular agent entering the agent chamber. If the agent is particularly sensitive to oxidation, the upper space of the agent chamber is preferably filled with filter sterilized nitrogen or a similar inert gas. In the heat sealing means 184 opposing heat sealing tips act simultaneously on both sides of the container to seal off the passage (112 b in figure 8) between the feed inlet tube and the medicament chamber. This effectively extends the permanent heat seal between the wide edge seals 110e and 110f shown in figure 8, thereby sealing the medicament chamber.

The closure cap is then reinserted into the feed inlet tube of the medicament chamber and the containers containing the powdered medicament are transferred to a gross weight balance 186 where the gross weight is weighed to verify that the proper amount of powdered medicament is contained in each container. The gross weight measured on the device 186 is compared to the weight of the empty container measured on the tare device 178. If the gross weight balance 186 detects an improper amount of powder medicament contained in the medicament compartment of the container, the container is discarded and transported to a disposal guide bracket for subsequent removal from the powder containment spacer 174. If the gross weight balance detects that the amount of powdered medicament in the medicament chamber is correct, the container is considered to be correctly filled and transferred to the next device or devices, if there are other processing steps.

According to the invention, the further chamber of the container can be filled with further medicament or diluent in a subsequent separator device or in a plurality of subsequent separator devices (subsequent filling). Although the first loading step is described above in relation to the addition of powdered medicament to the medicament compartment, it will be appreciated that this is for a multi-compartment medicament container having separate powdered medicament and diluent compartments. However, a medicament container having a single chamber may contain a powdered medicament therein in the manner described above in connection with the present invention, or may contain a liquid diluent or medicament therein in the manner described below.

In fig. 14, the multi-compartment container of the exemplary embodiment of the present invention in a semi-filled state is delivered to a second liquid-containing separator device 190 for non-toxic containment of the diluent.

As shown in the exemplary process flow diagram of fig. 13, after the powder packing process is completed, the partially packed container is transferred from the powder packing separator 174 to the liquid packing separator 190 through a transfer passage 192 connecting the two separator devices. After the above-described powder filling step, the container is removed from the conveyor belt 176 of the powder filling separator 174 and placed on a conveyor belt 194 that extends through the conveyor path 192 and connects the two separator devices. Those skilled in the art will recognize that the conveyor channel 192 and conveyor belt 194 together provide an essential feature that may enhance the degree of patterning of the separator-based containment process of the present invention. It can be seen that joining together a plurality of separators by a transfer channel does increase the number of containment steps and the types of containable components in the process. The model nature of the container manufacturing process to produce single and multi-chamber containers is readily coupled with the model nature of the containment process. The same number of containment partitions as the desired number of chambers to be contained can be easily connected by the transfer channels, thus achieving a completely flexible manufacturing and containment line.

In the filling process and apparatus shown in fig. 13 and 14, the partially filled containers are conveyed into the liquid-filled barrier 190 through the conveying channel 192 and are again placed on a continuously rotating conveyor belt 196 that conveys the containers through the liquid filling step.

As in the case of the powder containment step described previously, each container is transferred to a containment device 198 where an automated boom arm moving in an arc grasps the closure and removes it from the feed inlet tube of the diluent chamber and places it in a receptacle in the conveyor belt. The diluent chamber is then flushed away by a jet of nitrogen or air filtered through a 0.2 micron filter and conveyed forward so that the feed inlet pipe of the diluent chamber is located below the ingredient nozzle of the diluent holding device. A predetermined amount of diluent, such as saline or 5% dextrose injection, is injected into the container through the feed inlet tube. The diluent is typically pre-mixed in a separate mixing zone according to an acceptable process and injected into the holding device through the filtration conduit of the 0.2 micron filter. As is known to those skilled in the art, the diluent may be contained in the container in a single feed process, or a dual feed process or multiple feed processes may be employed for more precise control of metering and turbulence reduction.

After the diluent addition step, the container is transferred to a diluent chamber heat seal 200 where the headspace of the diluent chamber is first conditioned with nitrogen or air filtered through a 0.2 micron filter. The heat sealing device 200 comprises a heat sealing disc opposite a back plate which is pressed onto the container to sealingly close off the passage (112 a in figure 8) between the diluent chamber and its feed inlet tube. In effect, the heat sealing of the diluent chamber lengthens the permanent perimeter seal between zones 110d and 110e in fig. 8. Thus completely sealing off the filled container from the feed channel.

The contained container exits the liquid containment barrier 190 through the outlet port 202 and the outlet diverter 204. The container is cleaned and dried to remove any diluent and/or pharmaceutical agents remaining on its outer surface, and then trimmed to its final size by removing the wide edge region of the container including the feed inlet tube. During a possible trimming process, the peripheral seal along the rim of the container to be trimmed away may be enhanced to ensure sealing of the medicament and diluent chambers on the respective rim of the container. At this point, the container is completely manufactured and filled. The finished container is folded in half along the seal between the medicament and diluent chambers, bundled and packaged into a shipping container.

The production process for manufacturing and containing the containers is carried out with only one sterilisation process carried out after the manufacture of the original container. The construction of the container and the use of feed inlet tubes in communication with the diluent and medicament chambers, according to the present invention, allows for the subsequent aseptic containment of the diluent and medicament chambers and sealing without the need for any further sterilization steps. In fact, since the container of the present invention cannot be terminally sterilized with water vapor, the aseptic containment method described above is a necessary compensation for the manufacture of a sterile final product due to the highly moisture sensitive nature of the powdered medicament and the moisture barrier properties of the medicament chamber cover. The process of making and containing the container of the present invention thus allows the container to be made from materials that would not be sterilized by conventional steam sterilization, including high barrier laminates. Once subsequent sterilization is not required, the drug container may incorporate such a high barrier laminate structure in its structure, resulting in a drug container that is particularly suitable for long-term storage and can be efficiently manufactured at low manufacturing costs.

Furthermore, those skilled in the art will recognize that the structure and use of feed inlet tubes in communication with diluent and medicament chambers can provide a means for transporting, holding, positioning and manipulating the containers during the containment process. The size of the feed inlet opening is such that the container is adapted to suit the usual vial-containing instrument technology.

The feed inlet pipe is designed to include flanges to enable the container to be suspended by the conveyor, and each inlet includes two flanges to enable the container to be suspended by the automated handling equipment to a weighing device below the firing line or transported between insulated bodies. In addition, it can be seen that the use of the feed inlet tube and the manufacturing and containment process of the medicament container desirably enhances the modeling characteristics of the manufacturing and containment sequence.

Use of the container

The use of the final container is essentially independent of the production technology used. A health care professional, typically a hospital pharmacy department, will receive the three-chamber container 10 and mixing system in the complete configuration shown in fig. 1 and 2. In fig. 16, in preparation for use of the container, the medicament chamber 20 containing the powdered medicament can be visually observed and the medicament therein can be observed by grasping the tab 62 on the aluminum-containing foil protective layer 55 and peeling the protective layer from the container. If the medicament appears dry and in a normal state, mixing of the liquid medicine can be performed by manually operating the container to apply pressure to the front and rear sheets at the diluent chamber 18 at the upper end as shown in fig. 17. The mechanical pressure created by the hydraulic force generated by the manually operated container breaks the peelable seal between the diluent and the medicament chamber (see 24' in the broken state). Further manual shaking may mix the liquid diluent with the powdered medicament. Whether the mixed liquid medicine was completely mixed was visually observed through the clear transparent front sheet. After mixing is complete, the seal between the medicament chamber and the lower protective chamber is broken (26' in a broken state), again by applying pressure to the front and rear tabs of the container to create hydraulic pressure in the container, as shown in fig. 18. The mixed medical fluid is then dispensed from the container through the outlet tube 30 using a standard intravenous delivery apparatus.

The design of the container 10 eliminates the possibility of unmixed diluent passing through the outlet tube 30. Further, the provision of the intermediate chamber 20 between the diluent chamber and the outlet tube increases the likelihood of complete mixing of the medicament and diluent and delivery of the medical fluid to the patient. For containers containing diluent and powdered medicament, it is substantially ensured that the first peelable seal between the diluent chamber 18 and the medicament chamber 20 has been broken before the second peelable seal between the medicament chamber 20 and the lower protective chamber 22 is broken, because the hydraulic pressure created in the diluent by manually operating the container is not transmitted through the powder in the medicament chamber until the first seal is broken and mixing of the diluent and medicament begins. In those cases where a liquid medicament is employed, the relative difference in size between the diluent chamber and the medicament chamber, and the provision of a smaller medicament chamber between the larger diluent chamber and the lower or guard chamber, care is taken only to ensure that the first seal between the diluent and medicament chamber will be broken before the second seal is broken.

In the exemplary embodiment of the container shown in fig. 16, 17 and 18, the peelable seal has a generally rectangular shape, the same shape as the seal described, for example, in U.S. patent No.5,176,634 (inventor Smith et al). This patent is specifically incorporated herein by reference in the present application. In accordance with the present invention, although generally shaped, the seals are formed in the manner previously described, they have a predictable response to manually generated pressure and are peeled apart at an applied pressure of about 4.0 ± 1.0 psi. In another embodiment of the invention, curvilinear peelable seals are provided which are capable of being completely peeled apart along their length under hydraulic pressure in substantially the same manner as the uniform peelable seals described above.

FIG. 19 is a schematic illustration of an exemplary embodiment of a curvilinear peelable seal 86 provided in accordance with the present invention. The curvilinear shape of the seal is intended to address the two conflicting performance requirements of peelable or breakable seals in binary medicament containers. A first performance requirement of peelable or breakable seals is that in order to avoid inadvertent breaking of the seal during normal operation, the container should have relatively strong resistance properties to the forces required to break or peel the seal by its user. A second performance requirement is that the seal should be substantially completely peeled off during activation by the user so that any subsequent restriction of the flow path between the communicating chambers is avoided. With respect to the typical linear type of peelable seal, it has been found that whether it is peelable or breakable, the seal may not completely peel during activation. So that a considerable amount of liquid diluent or mixed liquid medicine remains in the unopened sealed area. In addition, it has been found that with the typical straight peelable seal, as the force required for activation by the user increases, the likelihood of the seal not opening completely increases.

The handling of binary drug containers requires that the peelable seal have various impact properties over the shelf life of the container. When the container is folded in half along a seal, most of these impact resistances are ensured, and the peelable seal is therefore also better protected. However, after the container is no longer in a folded-over condition, it may exhibit significant impact behavior, and the peelable seal is now very sensitive to unintended activation by subsequent activation of the container. To reduce the risk of unintended activation, an effective binary medicament container should be employed that has a structure in which the peelable seal is strong enough to withstand most unintended impacts, but still yields to the pressures generated by conscious handling.

Thus, the curvilinear peelable seal 86 solves two conflicting performance requirements by having a shape that is mirror-symmetrical to the shape of a conventional linear peelable seal when it is initially peeled. As previously described in fig. 1 and 2 and now fig. 19, the peelable seal spans horizontally across the container and has a width 88 sufficient to join the permanent seals on both sides of the container, thereby dividing the container into multiple chambers. Each seal 86 has a first generally rectangular region 90 that defines the minimum width of the peelable seal 86 at its intersection with the permanent seal at the container edge. The rectangular area 90 is sized in the height direction (short side) from about 1/10 to 1/4 inches, preferably 1/8(0.125) inches. The rectangular area 90 is thus of the same shape as a typical rectangular (straight) seal. The peelable seal 86 further includes a curvilinear second region 92 having an arcuate portion overlying the rectangular region 90. The chord edge of the arcuate portion shares an edge with the rectangular area, and the arcuate portion extends into the chamber to form a source of the sealing opening pressure. The arcuate rim 94 is generally radial with a maximum radial depth of at least about one-half the width of the rectangular region 90 of the seal 86. The particular shape, radius of curvature, and radial depth of the curvilinear region 92 will vary depending on the length of the seal and the particular application of the binary container including the expected strength of any inadvertent impact. However, one skilled in the art can calculate the shape of a particular seal based on beam theory (beam theory) and can also determine the cracking pressure required for the seal.

In practice, the convex edge 94 of the peelable seal 86 has a composite resistance characteristic to the hydraulic pressure of the diluent or medicament that is created when its respective chamber is squeezed. As shown in fig. 20, the peel characteristics of typical peelable seals form a curved peel front when the seal is viewed after being partially peeled apart. This curved peel front indicates that the hydraulic pressure driving the seal apart is greatest at about the middle of the seal and decreases uniformly in a power law along the seal toward its outer edge. A partially peeled-off conventional seal thus forms a pattern of discrete depressions, the deepest part of which is located approximately in the centre of the seal. It can thus be readily seen that the usual seal tends to peel naturally at the earliest possible time in the central region of the seal, tending to remain initially closed along both sides of the seal, particularly where the peelable seal is in contact with a permanent edge seal.

In accordance with the present invention, the curvilinear peelable seal 86 of FIG. 19 includes a lip 94 shaped to mirror the peel characteristics of the normally sealed depressions. As shown in fig. 21, the resistive characteristics of the curvilinear seal match the curvilinear pressure gradient of the diluent or mixed drug solution attempting to peel the seal apart. The resistive characteristics of the curvilinear seal 86 are strongest at the center where the pressure is also greatest and decreases in a non-linear manner toward the edges of the seal in concert with the decrease in pressure. In this manner, the seal is peeled off evenly along its entire length.

While the curvilinear peelable seal 86 has been described as being capable of providing a non-linear resistance to pressure by having a curvilinear width, it will be apparent to those skilled in the art that such non-linear resistance may be provided by other means. For example, a curvilinear resistance characteristic may also be achieved on a rectangular linear peelable seal by varying the temperature or pressure of the sealing bar at which the seal is formed. The heat seal temperature may be highest in the center and decrease non-linearly towards the ends of the seal, thus providing a peelable seal that is strongest in the center because the seal is more permanent in the center. Alternatively, a curved sealing bar having a convex contact surface that is pressed against the binary medicament container during the formation of the heat seal may be used to achieve the same effect. While such a seal may have a generally linear shape, its middle portion must be pressed more tightly together during the sealing process. The application of pressure must maximize the strength of the seal in the middle, with the seal strength decreasing in a non-linear (curvilinear) manner towards the ends. All that is required is that the peelable seal have a non-linear resistance characteristic that substantially matches the non-linear pressure characteristic of the diluent or mixed drug solution when the respective chamber is squeezed.

The thorough mixing of the diluent and medicament, and the complete delivery of the mixed drug solution through the outlet tube to a standard intravenous delivery device, may be further enhanced by the sealed, non-linear peel-off feature of the present invention. As mentioned above, the non-linear resistance characteristic of the peelable seal to hydraulic pressure ensures that the seal is peeled away substantially completely along its length and thus also ensures that substantially all of the liquid diluent is able to enter the medicament chamber and mix with the medicament contained therein. The non-linear peel characteristic of the second seal ensures that the seal is substantially completely peeled along its length after mixing, allowing the mixed medical fluid to completely enter the outlet tube and intravenous delivery system.

It will be appreciated by those skilled in the art that the foregoing discussion of embodiments containing a diluent and a single powder medicament does not limit the scope of the invention. The use of liquid medicaments in the intermediate chamber or the mixing of liquid or powder medicaments with diluents in the various chambers can also be carried out with the process of the invention. A plurality of feed inlet tubes and communicating channels between the feed inlet tubes and the respective chambers may also be provided by carrying out the process of the present invention. Further, depending on the susceptibility of any of the components making up the contents of the multiple chambers to attack by moisture or oxygen, the chambers may be formed by further employing clear transparent SiO-containing_xIs covered over the front sheet of the container in the area of these chambers and protected. The high barrier laminate may or may not contain a high barrier peelable laminate cover layer containing an aluminum foil.

The foregoing description of the exemplary embodiment of the flexible, sterile container has been presented for the purposes of illustration. Various modifications may be made by those skilled in the art, and the invention should not be limited to the specific embodiments described above. These variations and other modifications are intended to be included within the scope and intent of the present invention as set forth in the following claims.

Claims (10)

1. A transport carrier suitable for sterilization by electron beam irradiation, the transport carrier comprising:

a container tray enclosing a space and including an outwardly curved upper perimeter forming a horizontally oriented perimeter;

a rail bracket comprising a plurality of discrete, elongated elements defining a plurality of slots for supporting a plurality of containers in an elevated position, and having a shape receivable within the tray space; and

is adhered to the horizontally oriented periphery thereby covering the tray to form a sealable cover film for transfer and sterilization of the empty container, a transferable sterile container separator.

2. The transport carrier of claim 1, wherein the container tray is rectangular.

3. The delivery vehicle of claim 1 or 2 wherein the sealable lidding film is sized such that the lidding film can be overlaid on the perimeter with the edge of the lidding film indented around the entire perimeter into the outer edge of the perimeter.

4. The transfer carrier of claim 3 wherein the sealable lidding film is heat sealed to the periphery of the tray.

5. The transport carrier of claim 4, wherein the heat seal of the lidding film extends beyond the edge of the lidding film and overlaps the edge of the lidding film with the perimeter of the tray such that the entire perimeter of the lidding film is heat sealed to the perimeter of the container.

6. The transport carrier of claim 1, wherein the container tray further has opposed first and second recessed areas formed in the middle of the opposed short sides of the tray and extending outwardly from the plane of the short sides, the recessed areas extending downwardly from the periphery to form opposed first and second recesses for receiving the rail brackets.

7. The transport carrier of claim 6, wherein the guideway support comprises means for engaging the feed inlet tubes of empty drug containers, whereby the guideway support can engage and carry a plurality of empty containers.

8. The transport carrier according to claim 7, wherein the feed inlet tube engaging means comprises a plurality of discrete rails defining slots therebetween into which the feed inlet tubes of the medicament containers are inserted, the slots having horizontally oriented flanges along the length of each slot which engage mating flanges on the feed inlet tubes and thereby support those feed inlet tubes.

9. The transport carrier of claim 8, wherein the rail bracket further comprises a pad that engages the plurality of discrete rails, the pad comprising means for grasping and manipulating the rail bracket without contacting a medication container carried thereon.

10. The transport carrier of claim 9, the rail bracket having a shape insertable into the container tray, having first and second ends adapted to be received in opposing recessed areas of the container tray.