Abstract:
The present invention provides a container and method for storing a solution containing a labile species comprising storing said solution in a flexible, optically transparent container comprised of an ethylene vinyl alcohol copolymer having an oxygen permeability of less than 0.2 cc/100 in 2 /24 hrs.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application is a continuation of U.S. patent application Ser. No. 10/188,706, filed Jul. 2, 2002, which is a continuation of U.S. patent application Ser. No. 10/097,200, filed Mar. 12, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 09/607,058, filed Jun. 29,2000 (now U.S. Pat. No. 6,361,843), which is a continuation of U.S. patent application Ser. No. 08/934,924, filed Sep. 22, 1997 (now U.S. Pat. No. 6,083,587). 
     
    
     BACKGROUND OF THE INVENTION  
       [0002]     The present invention relates to a system and method for delivering fluids. In particular, researchers are continually developing medical fluids to treat patients for a wide range of medical conditions. Such fluids can include intravenous solutions, nutritional solutions, drug solutions, blood, blood components, blood substitutes such as deoxygenated hemoglobins, dialysate fluids, cell culture media, bioprocessing fluids containers for therapeutic products such as Factor VIII, or other fluids that might be delivered to a patient.  
         [0003]     Medical and other fluid delivery systems typically include a container that holds the fluid, and tubing in communication with the container that delivers the fluid. The container is often a polymeric film bag or pouch designed to hold the particular fluid. The container may also be a glass bottle, or any other container suitable for holding the fluid.  
         [0004]     Numerous polymeric films have been developed for use in containers. Container films may be a monolayer structure or a multiple layer structure of polymeric materials formed as a pouch or bag. The monolayer structure can be made from a single polymer, or from a polymer blend. Multiple layer structures can be formed by co-extrusion, extrusion lamination, lamination, or any suitable means. The multiple layer structures can include layers such as a solution contact layer, a scratch resistant layer, a barrier layer for preventing ingress of oxygen or water vapor, tie layers, or other layers.  
         [0005]     The pouch can be formed by placing two polymeric film sheets in registration by their peripheral portions and sealing the outer periphery to form a fluid tight pouch. The sheets are typically sealed by heat sealing, radio frequency sealing, thermal transfer welding, adhesive sealing, solvent bonding, and ultrasonic or laser welding.  
         [0006]     Blow molding is another method used to make the pouch. Blow molding is a blown extrusion process that provides a moving tube of extrudate exiting an extrusion die. Air under pressure inflates the tube. Longitudinal ends of the tube are sealed to form the pouch. Blow molding only requires seals along two peripheral surfaces, where the registration method requires seals along four peripheral surfaces to form the pouch.  
         [0007]     Medical fluid containers commonly provide ports for access to medical fluid contained within them. For pouch or bag containers, access ports typically are a tube inserted between the sidewalls of the container, or attached to a sidewall of the container. A membrane tube is typically inserted into the access port tube. The membrane tube is often solvent bonded to the access port tube. In solvent bonding, the membrane tube is dipped into solvent, and then inserted into the port tube. Thus, the outer surface of the membrane tube becomes bonded to the inner surface of the access port tube.  
         [0008]     The membrane tube defines a passageway which permits fluid communication between the container and tubing which delivers the medical fluid to the patient. A membrane is typically disposed across the passageway to seal the medical fluid in the container until the fluid is to be delivered. The membrane also helps to preserve fluid that may be sensitive to the atmosphere. For example, the fluid may degrade in the presence of oxygen. To access fluid in the container, a hollow access spike is typically inserted into the access port. When inserted sufficiently into the access port, the access spike punctures the membrane thereby allowing fluid to flow from the container.  
         [0009]     Conventional solution containers employing access ports typically use access port materials of flexible polyvinyl chloride (PVC) or soft polyolefins such as low density polyethylene (LDPE). These materials have sufficient elasticity to grip the outside of the access spike to retain the spike during fluid delivery. The inner diameter of the end port is dimensioned slightly smaller than the outer diameter of the access spike. The elasticity of PVC or LDPE is sufficient to permit the end port to expand about the outside of the access spike forming an interference fit.  
         [0010]     Researchers are also continually developing medical and other therapeutic or nutritional solutions that have unusual and specific container requirements. These requirements can include providing a gas barrier to prevent contamination or degradation of the medical fluid within the container by contact with gases. For example, ethylene (vinyl alcohol) (EVOH) provides a high barrier to the ingress of oxygen. EVOH may be used as a barrier layer in a laminate of polymeric material or co-extruded with the polymeric material. The membrane which seals the container is often also made of a polymeric material combined with a barrier material layer such as EVOH. The inclusion of EVOH, however, in a film increases the film&#39;s rigidity. This may make the membrane containing EVOH difficult to puncture with the typical access spike.  
         [0011]     Moreover, some solutions require containers having increased reactive inertness with respect to the solution. For example, proteins, blood, blood components and biologically active substances can be denatured by contact with the polymer molecules of the container. Polymeric materials with increased inertness used to manufacture containers or membranes also typically have a higher modulus or elasticity, and are more difficult to puncture with an access spike than containers not requiring additional inertness.  
         [0012]     In the interest of safety, fluid delivery systems are also trending away from needles, to needleless systems. Needleless systems include blunt cannulas in increasing use in the medical field. Needleless systems eliminate, or at least lessen, the chance of a medical worker accidentally incurring a needle stick. Needleless systems, therefore, protect the medical worker from accidental exposure to blood-borne pathogens. They also help prevent contamination of the medical fluid. The trend to needleless systems, combined with the use of increasingly rigid materials in medical fluid packaging make the seals of the container difficult to puncture using typical access spikes. Difficulty in puncturing may result in the container, access port, membrane tube, or membrane being torn. It may also cause a break of the interference fit between the access port and the access spike. These conditions may cause the medical fluid to leak from the container. It may also result in contamination or degradation of the medical fluid because of contact with the atmosphere.  
         [0013]     For renal fluid applications, the delivery to the patient typically requires multiple fluids be delivered to the patent in succession. These fluids may consist of two or more different fluids that must be delivered to the patient during a treatment session, or two or more containers of the same fluid, or switching from one fluid to another, and back. Thus, for renal applications, a disconnectable and reconnectable fluid delivery system that prevents leakage from a renal fluid container is desirable. Moroever, frangible tubes used in renal systems must be snapped and then wiggled to remove the frangible.  
         [0014]     In the medical field, where beneficial agents are collected, processed and stored in containers, transported, and ultimately delivered through tubes by infusion to patients to achieve therapeutic effects, materials which are used to fabricate the containers must have a unique combination of properties. For example, in order to visually inspect solutions for particulate contaminants, the container must be optically transparent. To infuse a solution from a container by collapsing the container walls, without introducing air into the container, the material which forms the walls must be sufficiently flexible to collapse upon draining. The material must be functional over a wide range of temperatures. The material must be capable of withstanding radiation sterilization without degrading its physical properties. The material must function at low temperatures by maintaining its flexibility and toughness as some medical solutions, and blood products are stored and transported in containers at temperatures such as −25 to −30 degree C.  
         [0015]     A further requirement is to minimize the environmental impact upon the disposal of the article fabricated from the material after its intended use. For those articles that are disposed of in landfills, it is desirable to use as little material as possible and avoid the incorporation of low molecular weight leachable components to construct the article. Further benefits are realized by using a material which may be recycled by thermoplastically reprocessing the post-consumer article into other useful articles.  
         [0016]     For those containers that are disposed of through incineration, it is necessary to use a material that minimizes or eliminates entirely the formation of inorganic acids which are environmentally harmful, irritating, and corrosive, or other products which are harmful, irritating, or otherwise objectionable upon incineration.  
         [0017]     For ease of manufacture into useful articles, it is desirable that the material be sealable using radio frequency (“RF”) sealing techniques generally at about 27.12 MHz. Therefore, the material should possess sufficient dielectric loss properties to convert the RF energy to thermal energy.  
         [0018]     It is also desirable that the material be free from or have a low content of low molecular weight additives such as plasticizers, slip agents, stabilizers and the like which could be released into the medications or biological fluids or tissues, contaminating such substances being stored or processed in such devices.  
         [0019]     In many medical product applications, it is desirable to provide a multilayered structure that provides a barrier to the passage of oxygen, carbon dioxide, and water. For medical solutions that are packaged having a desired concentration of a drug or solute, the barrier to water helps maintain this concentration by preventing water from escaping from the container. In solutions that have a buffer to prevent pH changes, such as a commonly used sodium bicarbonate buffer, the barrier to carbon dioxide helps maintain the buffer by preventing carbon dioxide from escaping from the container. For medical solutions containing labile species, the oxygen barrier helps prevent the ingress of oxygen which can oxidize proteins or amino acids rendering the solution ineffective for its intended purpose.  
         [0020]     Ethylene vinyl alcohol (EVOH) is known for use as an oxygen barrier in multilayer films. One commercially available EVOH layered structure is sold by Barrier Film Corporation under the product designation BF-405 for thermoforming into food packaging. It is believed that the BF-405 film has an outer layer of nylon, a core layer of EVOH and an inner layer of a metallocene-catalyzed ultra-low density polyethylene. These layers are formed into a layered structure or film by a blown film process. This film has an oxygen transmission rate, for a film 2.6 mils in thickness, of 0.05 cc/100 sq.in./24 hrs.  
         [0021]     The BF-405 film is unacceptable for medical applications as slip agents must be used during the processing of the film. Such slip agents include low molecular weight components that are soluble in water and are capable of leaching out into the medical solution which it contacts. Thus, if such film were constructed into a medical container and filled with a medical solution, it would likely lead to an unacceptably high extractable content in the contained medical solution.  
         [0022]     There are numerous U.S. patents that disclose EVOH barrier films. For example, U.S. Pat. No. 4,254,169 provides barrier films having layers of EVOH and polyolefins. The &#39;169 Patent discloses an adhesive for bonding the EVOH to polyolefins which includes a high density polyethylene grafted with a fused-ring carboxylic acid anhydride blended with an unmodified polyolefin. (Col. 2, line 65-col. 3, line 21). In many of the examples, the &#39;169 Patent discloses adding a slip agent to make the outer surface of the films more slippery. (See Tables I and II and col. 5, lines 35-37).  
         [0023]     U.S. Pat. No. 4,397,916 discloses multilayered EVOH structures in which the EVOH is attached to other layers such as polyolefins by a layer of a graft-modified ethylene resin grafted with a carboxylic acid or a functional derivative thereof. The &#39;916 Patent also provides for attaching nitrogen containing polymers such as nylons to polyolefins with the graft modified ethylene resins. The &#39;916 Patent does not discuss limiting low molecular weight additives to reduce the amount of extractables. In fact the &#39;916 encourages the use of slip agents, lubricants, pigments, dyes and fillers (Col. 6, lines 38-42) which could have a deleterious impact on the amount of extractables and on the optical transparency of the polymer blend.  
         [0024]     U.S. Pat. No. 5,164,258 discloses a multilayered structure containing EVOH as a barrier layer sandwiched between two layers of polyolefins. The polyolefin layers are intended to facilitate the escape of moisture which becomes absorbed in the barrier layer during a steam sterilization process. The polyolefin layers are attached to the EVOH layer with, for example, a maleic anhydride graft-modified polyethylene adhesive. The &#39;258 Patent discloses increasing the WVTR of one of the polyolefin layers by adding organic and inorganic fillers to the layer. (Col. 4, lines 22-59). These fillers are likely to render the multilayered structure optically opaque.  
         [0025]     The present invention addresses these and other problems.  
       SUMMARY OF THE INVENTION  
       [0026]     The present invention provides a container and method for storing a solution containing a labile species comprising storing said solution in a flexible, optically transparent container comprised of an ethylene vinyl alcohol copolymer having an oxygen permeability of less than 0.2 cc/100 in 2 /24 hrs.  
         [0027]     The present invention provides a system and method for delivering fluid. In one embodiment, the system and method include a container to hold the fluid, and a closed-end tube having a first end in communication with the container and a closed second end. The closed second end is contoured in a pattern to form a zone of weakness. The zone of weakness facilitates reduced spike force access, i.e., the force necessary for an access spike to puncture the closed second end.  
         [0028]     In another embodiment of the present invention, the system and method include a container for holding the fluid, a passageway in communication with the container, and a membrane disposed across the passageway to seal the passageway. The membrane is contoured in a pattern to define a zone of weakness. The zone of weakness again provides the advantage of reduced spike access force.  
         [0029]     In a further embodiment of the present invention, the system and method include a container for holding the fluid, and a tube defining a passageway in communication with the container. The tube has a membrane disposed across the passageway, and is contoured in a pattern to define a zone of weakness. There is an interface in the tube between the membrane and an end of the tube, and a connector inserted into the end of the tube. The connector is adapted to engage the interface, and to cause the interface to puncture the membrane thereby delivering the fluid through the passageway. The present invention, therefore, permits a low access force for use with in-line frangibles for renal applications.  
         [0030]     A further embodiment of the present invention includes a capsule having a body, the body having a first end and a second end, and at least one of the first end or second end contoured to define a zone of weakness. A still further embodiment includes a fluid mixing system having a capsule, the capsule having a first end and a second end, and at least one of the first end or second end contoured to define a zone of weakness, the capsule contained within a container, the capsule containing a first material, and the container containing a second material.  
         [0031]     In another aspect of the present invention, the contouring also permits resealing of the membrane after puncturing. Additional features and advantages of the present invention are described in, and will be apparent from, the following Detailed Description of the Invention and the figures. 
     
    
     BRIEF DESCRIPTION OF THE FIGURES  
       [0032]      FIG. 1  is a cross-sectional view of a molded closed end tube in accord with the present invention.  
         [0033]      FIG. 2  is a cross-sectional view of a series of extrusion molded closed end tubes in accord with the present invention.  
         [0034]      FIG. 3  is a cross-sectional view of an extruded tube and a sealed tube in accord with the present invention.  
         [0035]      FIG. 4  is a contouring pattern in accord with one embodiment of the present invention.  
         [0036]      FIG. 5  is a contouring pattern in accord with another embodiment of the present invention.  
         [0037]      FIG. 6  is a contouring pattern in accord with a further embodiment of the present invention.  
         [0038]      FIG. 7A  is side view of a contouring pattern in accord with an additional embodiment of the present invention.  
         [0039]      FIG. 7B  is an end view of the contouring pattern of  FIG. 7A .  
         [0040]      FIG. 8A  shows one method of contouring in accord with one embodiment of the present invention.  
         [0041]      FIG. 8B  shows a later step of the contouring method of  FIG. 8A .  
         [0042]      FIG. 8C  shows a later step of the contouring method of  FIG. 8B .  
         [0043]      FIG. 9A  is a cross-sectional view of an embodiment of the present invention.  
         [0044]      FIG. 9B  is a cross-sectional view of the embodiment of  FIG. 9A .  
         [0045]      FIG. 9C  is a cross-sectional view of the embodiment of  FIG. 9A .  
         [0046]      FIG. 10  is a cross-sectional view of another embodiment of the present invention.  
         [0047]      FIG. 11  is a cross-sectional view of a further embodiment of the present invention.  
         [0048]      FIG. 12  is a plan view of a center access spike.  
         [0049]      FIG. 13  is a plan view of a bevel access spike.  
         [0050]      FIG. 14  is a plan view of a typical medical fluid delivery system.  
         [0051]      FIG. 15  is a cross-sectional view of a three-layered tubing.  
         [0052]      FIG. 16  is a cross-sectional view of a two-layered tubing.  
         [0053]      FIG. 17  is a cross-sectional view of a two-layered membrane film.  
         [0054]      FIG. 18  is a cross-sectional view of a three-layered membrane film.  
         [0055]      FIG. 19  is a cross-sectional view of a five-layered membrane film.  
         [0056]      FIG. 20  is a side view of a spike holder.  
         [0057]      FIG. 21  is an end view taken along line A-A of  FIG. 20 .  
         [0058]      FIG. 22  is cross-sectional view of a spike holder assembly.  
         [0059]      FIG. 23  is a cross-section area of one embodiment of a membrane in accord with the present invention.  
         [0060]      FIG. 24  is a cross-sectional view of a further embodiment of the present invention.  
         [0061]      FIG. 25  is a plan view of a capsule embodiment of the present invention  FIG. 26  is a plan view of an embodiment incorporated the capsule of  FIG. 25 .  
         [0062]      FIG. 27  shows a cross-sectional view of a five layered film structure of the present invention.  
         [0063]      FIG. 28  shows another embodiment of the present invention.  
         [0064]      FIG. 29  shows yet another embodiment of the present invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0065]     It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims. For example, though described below with respect to a medical fluid delivery application, this invention may be used in other fluid delivery applications such as food or chemical industry packaging and delivery.  
         [0066]      FIG. 14  generally illustrates an intravenous medical delivery system  10  used in one embodiment of the present invention.  FIG. 14  shows a container  12  for holding medical fluids  14  for delivery to a patient (not shown). The medical fluids  14  may include intravenous solutions, nutritional solutions, drug solutions, blood, blood components, blood substitutes such as deoxygenated hemoglobins, renal fluids, cell culture, recombinant DNA fluids for forming therapeutic products such as Factor VIII, or other fluids that have a therapeutic effect.  
         [0067]     The container  12  may be made of any suitable material, but is typically made of polymeric film materials. Container  12  films may be a monolayer structure or a multiple layer structure of polymeric materials formed as a pouch or bag. The monolayer structure can be made from a single polymer, or from a polymer blend. The monolayer film can be formed by extrusion or other polymer processing techniques well-known to those skilled in the art. Multiple layer films can be formed by co-extrusion, extrusion lamination, lamination, or any suitable means. The multiple layer structure can include the monolayer structure with additional layers. The additional layers can include layers such as a solution contact layer, a scratch resistant layer, a barrier layer for preventing ingress or egress of oxygen, carbon dioxide, or water vapor, tie layers or other layers.  
         [0068]     The container  12  can be formed by placing two polymeric film sheets in registration by their peripheral portions and sealing the outer periphery  16  to form a fluid tight pouch. The sheets are sealed along their periphery  16  by heat sealing, radio frequency sealing, thermal transfer welding, adhesive sealing, solvent bonding, and ultrasonic or laser welding.  
         [0069]     Blow molding is another method that may be used to make the container  12 . Blow molding is a blown extrusion process that provides a moving tube of extrudate exiting an extrusion die. Air under pressure is used to inflate the tube. Longitudinal ends of the tube are sealed to form the pouch. Blow molding only requires seals along two peripheral surfaces, where the registration method requires seals along four peripheral surfaces  16  to form the pouch.  
         [0070]     Films typically used to make the container  12  include layers of polymeric materials selected from the following: high density polyethylene (HDPE), medium density polyethylene (MDPE), low density polyethylene (LDPE), very low density polyethylene (VLDPE), ultra low density polyethylene (ULDPE), linear low density polyethylene (LLDPE), polypropylene, polyolefins, modified polyolefins, polyvinyl chloride (PVC), nylon, ethylene vinyl acetate (EVA), polyester, polyamides, or any other suitable material. The particular polymeric material selected will depend on the application.  
         [0071]     For medical and other applications, it is also often desirable that films used to make container  12  include one or more layers of a barrier material. Barrier materials minimize the infiltration of gases such as oxygen, carbon dioxide, or water vapor, into the fluid  14  in the container  12 . Such gases may contaminate or degrade the fluid  14 , thereby decreasing or negating its usefulness. Typical barrier materials include ethylene (vinyl alcohol) (EVOH), which provides a high barrier to oxygen. Other barrier materials include polyvinylidene chloride (PVDC) and metal foils such as aluminum foil. Barrier materials may be laminated, blow molded, or co-extruded with other polymeric materials as described above. The barrier layers typically include EVOH with about 25% to about 45% ethylene content by mole percent.  
         [0072]     For medical applications where the containers  12  are disposed by incineration, it is also desirable to construct the container  12  and other components of the fluid delivery system  10  from non-halogen containing polymers. Halogen containing compounds potentially create inorganic acids upon incineration. For medical applications, it is also desirable to construct the delivery system  10  from as small amount as possible of low molecular weight additives. Low molecular weight components, such as plasticizers can potentially leach into the fluids contained in the container  12 , or transported through the delivery system  10 .  
         [0073]     The container  12  typically provides at least one access port  18  that permits access to the medical fluid  14  in the container  12 . The access port  18  is generally a tube. The access port  18  is typically inserted between the container sidewalls, and is in communication with the inside of the container  12 . A membrane tube  19  is inserted into the access port  18 . The outer surface of the membrane tube  19  is preferably solvent bonded to the interior surface of the access port  18 . The membrane tube  19  is generally sealed with a membrane (not shown) disposed across the membrane tube  19  that seals the medical fluid  14  in the container  12 . To access the fluid  14  from the container  12 , an access spike  20  is inserted into the membrane tube  19 . When inserted, the access spike  20  punctures the membrane. Tubing  22  attached to the access spike  20  delivers the medical fluid  14  to the patient.  
         [0074]     Typical access spikes  20  include a beveled spike  24  ( FIG. 13 ), and center point spike  25  ( FIG. 12 ). When a barrier material such as EVOH is used in the membrane of the fluid delivery system, it increases the force necessary to puncture the membrane using typical access spikes  24  or  25  because of EVOH&#39;s rigidity.  
         [0075]     In another embodiment, the container  12  may be rigid and may be pressurized or evacuated. Thus, when the access spike  20  is inserted, an audible indication of puncture is heard caused by the movement of air.  
         [0076]     In one preferred embodiment, the present invention includes a closed end membrane tube  26  ( FIG. 1 ). Like the typical membrane tube  19 , the closed end tube  26  is attached to the container  12  using any suitable process, but may be inserted between container sidewalls. The closed end tube  26  has a sidewall  28  substantially cylindrical in cross-section that defines a passageway  30 . The closed end tube  26  and passageway  30 , however, need not be cylindrical, but may be any suitable cross-sectional shape such as elliptical or polygonal. The passageway  30  communicates with the interior of the container  12  to permit fluid  14  to flow through the passageway  30 . The closed end tube  26  has a first end  32  and a second end  34 . The closed end tube  26  is closed at the second end  34 . The closed second end  34  has an inner surface  35  and an outer surface  37 .  
         [0077]     While it is contemplated the closed end tube  26  can have any number of layers, in a preferred form of the invention the closed end tube  26  will include either a discrete layer of a barrier material or a blend layer including a barrier material. The barrier material will present a barrier to the passage of gases or water vapor transmission, and, in a preferred form of the invention, will reduce the passage rate of oxygen therethrough. It is also desirable that all materials in the solution contact layer, and more preferably all materials used in the tubing, be free of halogens, plasticizers or other low-molecular weight or water soluble components that can leach out into the solutions transferred through the tubing. Suitable barrier materials include ethylene (vinyl alcohol) copolymers having an ethylene content of from about 25% to about 45% by mole percent, more preferably from about 28% to about 36% by mole percent and most preferably from about 30% to about 34% by mole percent.  
         [0078]     In an even more preferred form of the invention the closed end tube  26  will have multiple layers.  FIG. 15  and  FIG. 16  show respectively a three-layered membrane tube and a two-layered membrane tube. The three-layered membrane tube  104  has an outside layer  106 , a core layer  108  and an inside solution contact layer  110 .  
         [0079]     Similarly, the two-layered port tube  112  has an outside layer  114  and an inside, solution contact layer  116 . The closed end  34  of the closed end tube  26  is preferably similarly constructed.  
         [0080]     In a preferred form of the invention, the multiple layered tubings  104  and  112  will have a discrete layer of a barrier material with the remaining layers being selected from polyolefins. The layers of the tubing can be positioned in any order, however, in a preferred form of the invention the barrier layer is not positioned as the outside layer  106  or  114 . Thus, the layers of a three layered tubing can be positioned in one of six orders selected from the group: first/second/third, first/third/second, second/first/third, second/third/first, third/first/second, and third/second/first. Further, in tubing embodiments having more than two layers, the tubing  104  can be symmetrical or asymmetrical from a material aspect and from a thickness of layers aspect. Suitable polyolefins include homopolymers, copolymers and terpolymers obtained using, at least in part, monomers selected from α-olefins having from 2 to 20 carbons. One particularly suitable polyolefin is an ethylene and α-olefin interpolymer (which sometimes shall be referred to as a copolymer). Suitable ethylene and α-olefin interpolymers preferably have a density, as measured by ASTM D-792 of less than about 0.915 g/cc and are commonly referred to as very low density polyethylene (VLDPE), ultra low density ethylene (ULDPE) and the like. The α-olefin should have from 3-17 carbons, more preferably from 4-12 and most preferably 4-8 carbons. In a preferred form of the invention, the ethylene and α-olefin copolymers are obtained using single site catalysts. Suitable single site catalyst systems, among others, are those disclosed in U.S. Pat. Nos. 5,783,638 and 5,272,236. Suitable ethylene and α-olefin copolymers include those sold by Dow Chemical Company under the AFFINITY tradename, Dupont-Dow under the ENGAGE tradename and Exxon under the EXACT and PLASTOMER tradenames.  
         [0081]     The polyolefins also include modified polyolefins and modified olefins blended with unmodified olefins. Suitable modified polyolefins are typically polyethylene or polyethylene copolymers. The polyethylenes can be ULDPE, low density (LDPE), linear low density (LLDPE), medium density polyethylene (MDPE), and high density polyethylenes (HDPE). The modified polyethylenes may have a density from 0.850-0.95 g/cc. The polyethylene may be modified by grafting or otherwise chemically, electronically or physically associating a group of carboxylic acids, and carboxylic acid anhydrides. Suitable modifying groups include, for example, maleic acid, fumaric acid, itaconic acid, citraconic acid, allylsuccinic acid, cyclohex-4-ene-1,2-dicarboxylic acid, 4-methylcyclohex-4-ene-1,2-dicarboxylic acid, bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, x-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, maleic anhydride, itaconic anhydride, citraconic anhyride, allylsuccinic anhydride, citraconic anhydride, allylsuccinic anhydride, cyclohex-4-ene-1,2-dicarboxylic anhydride, 4-methylcyclohex-4-ene-1,2-dicarboxylic anhydride, bicyclo[2.2.1]hept-5-ene2,3-dicarboxylic anhydride, and x-methylbicyclo[2.2.1]hept-5-ene-2,2-dicarboxylic anhydride.  
         [0082]     Examples of other modifying groups include C 1 -C 8  alkyl esters or glycidyl ester derivatives of unsaturated carboxylic acids such as methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, glycidyl acrylate, glycidal methacrylate, monoethyl maleate, diethyl maleate, monomethyl maleate, diethyl maleate, monomethyl fumarate, dimethyl fumarate, monomethyl itaconate, and diethylitaconate amide derivatives of unsaturated carboxylic acids such as acrylamide, methacrylamide, maleicmonoamide, maleic diamide, maleic N-monoethylamide, maleic N,N-dietylamide, maleic N-monobutylamide, maleic N,N dibutylamide, fumaric monoamide, fumaric diamide, fumaric N-monoethylamide, fumaric N,N-dietilylamide, fumaric N-monobutylamide and fumaric N,N-dibutylamide; amide derivatives of unsaturated carboxylic acids such as maleimide, N-butymaleimide and N-phenylmaleimide; and metal salts of unsaturated carboxylic acids such as sodium acrylate, sodium methacrylate, potassium acrylate and potassium methacrylate. More preferably, the polyolefin is modified by a fused ring carboxylic anhydride and most preferably a maleic anhydride.  
         [0083]     The polyolefins also include ethylene vinyl acetate copolymers, modified ethylene vinyl acetate copolymers and blends thereof. The modified EVA has an associated modifying group selected from the above listed modifying groups.  
         [0084]     In one preferred form of the invention, the tubing  104  has a solution contact layer  110  of a modified EVA copolymer sold by BYNEL under the trade designation CXA, a core layer  108  of an EVOH and an outside layer  106  of a modified EVA. Such a film is symmetrical from a materials standpoint. According to a preferred form of the invention, such tubing will have layers of the following thickness ranges: outside layer  106  from about 0.002 inches to about 0.042 inches, the core layer  108  from about 0.016 inches to about 0.056 inches, the solution contact layer  110  of from about 0.002 inches to about 0.042 inches.  
         [0085]     In another preferred form of the invention, the tubing  104  has a solution contact layer  110  of an EVOH, a core layer  108  of a modified EVA and preferably BYNEL CXA and an outside layer  106  of an ethylene and α-olefin copolymer. Such a film is symmetrical from a materials standpoint. The tubing layers can have various relative thicknesses. According to a preferred form of the invention, such tubing will have layers of the following thickness ranges: outside layer  106  from about 0.002 inches to about 0.042 inches, the core layer  108  from about 0.002 inches to about 0.042 inches, the solution contact layer  110  of from about 0.016 inches to about 0.056 inches.  
         [0086]     In a preferred form of the invention, the closed end tube  26 ,  104  or  112  shall have the following dimensions: inside diameter from about 0.100 inches to about 0.500 inches and the wall thickness shall be from about 0.020 inches to about 0.064 inches.  
         [0087]     The closed end tube  26  may be made using any suitable process, but preferably is extrusion molded as shown in  FIG. 2 .  FIG. 2  shows an extruded length  36 . The length  36  repeats at spaced intervals along the length of the extrudate. At each end  38  of the length  36  is an interval  40  which defines the successive lengths  36 . The lengths  36  are cut at the intervals  40  to leave a length  36  closed at each end  38 . The length  36  is then cut again along its center, thereby giving two closed end tubes. Any excess material at the closed second ends of the lengths  36  remaining after cutting may be trimmed using any suitable means. Alternatively, the closed end tube  26  may be extruded as an open end tube  42  as shown in  FIG. 3 , and then one end  44  sealed to provide a closed end tube  26 .  
         [0088]     In another preferred form of the invention, membrane tube  19  inserted into the access port  18  to the container  12  may be an open end tube  46 . A membrane  48  is attached to the open end tube  46  as shown in  FIG. 10 . The membrane  48  has an inner surface  49  and an outer surface  51 . The open end tube  46  has a first end  50  in communication with the container  12 , and a second end  52 . A passageway  54  is defined by the first end  50  and second end  52 . The membrane  48  is attached to the second end  52  of the open tube  46 . The membrane  48  may be attached to the second end  52  using any suitable process, but preferably is attached by radio frequency welding. Alternatively, the membrane  48  may be disposed at a suitable point along the passageway  54  as in  FIG. 11 .  
         [0089]     The open tube  46  is preferably made in the manner described above with respect to the closed end tube  26 . The membrane  48  can have any number of layers, but in a preferred form of the invention has multiple layers.  FIG. 17  shows a two-layered structure  118  having an outside layer  120  and an inside layer  122 .  FIG. 18  shows a three-layered structure  124  having an outside layer  126 , an inside layer  128  and a core layer  130 .  FIG. 19  shows a five layered structure  132  having an outside layer  134 , an inside layer  136 , a core layer  138  and two tie layers  140 . In a preferred form of the invention one layer shall be of a barrier material defined above and the remaining layer or layers shall be selected from the polyolefins defined above, polyamides and polyesters. One of the inside layers or outside layer shall define a tubing contact layer or seal layer.  
         [0090]     Suitable polyamides include those obtained from a ring-opening reaction of lactams having from 4-12 carbons. This group of polyamides therefore includes, but is not limited to, nylon 6, nylon 10 and nylon 12.  
         [0091]     Acceptable polyamides also include aliphatic polyamides resulting from the condensation reaction of di-amines having a carbon number within a range of 2-13, aliphatic polyamides resulting from a condensation reaction of di-acids having a carbon number within a range of 2-13, polyamides resulting from the condensation reaction of dimer fatty acids, and amide containing copolymers. Thus, suitable aliphatic polyamides include, for example, nylon 66, nylon 6,10 and dimer fatty acid polyamides.  
         [0092]     Suitable polyesters include polycondensation products of di- or polycarboxylic acids and di or poly hydroxy alcohols or alkylene oxides. Preferably, the polyesters are a condensation product of ethylene glycol and a saturated carboxylic acid such as ortho or isophthalic acids and adipic acid. More preferably the polyesters include polyethyleneterphthalates produced by condensation of ethylene glycol and terephthalic acid; polybutyleneterephthalates produced by a condensations of 1,4-butanediol and terephthalic acid; and polyethyleneterephthalate copolymers and polybutyleneterephthalate copolymers which have a third component of an acid component such as phthalic acid, isophthalic acid, sebacic acid, adipic acid, azelaic acid, glutaric acid, succinic acid, oxalic acid, etc.; and a diol component such as 1,4-cyclohexanedimethanol, diethyleneglycol, propyleneglycol, etc. and blended mixtures thereof  
         [0093]     In a preferred form of the invention having a barrier layer, the membrane structure shall have five layers as shown in  FIG. 19  and is a variation of the film structure disclosed in commonly assigned U.S. Pat. No. 6,083,587 which is incorporated herein by reference and made a part hereof. The outside layer  134  is a polyamide and preferably nylon 12, the two tie layers  140  are a modified EVA copolymer, the core layer  138  is an EVOH and the inner layer  136  is a modified EVA. In a preferred form of the invention the inside layer  136  defines the tubing contact layer.  
         [0094]     Further, the structure shown in  FIG. 19  shall have the following layer thickness ranges: outside layer  134  from about 0.0005 inches to about 0.003 inches, the tie layers  140  from about 0.0005 inches to about 0.02 inches, the core layer  138  of from about 0.0005 inches to about 0.0015 inches and an inside layer  136  of from about 0.008 inches to about 0.012 inches.  
         [0095]     For membranes not using a barrier, the preferred membrane structure is a monolayer structure. The monolayer structure preferably comprises polypropylene and styrene ethylene butene styrene (SEBS), or kraton. The polypropylene and SEBS are preferably blended using 20-50% SEBS, and 50-80% polypropylene. Most preferably, the blend is about 30% SEBS and 70% polypropylene.  
         [0096]     Another preferred membrane monolayer structure includes a MARQ material. The MARQ material includes about 10% SEBS, 45% polypropylene, 35% ultra low density polyethylene (ULDPE), and 10% di-mer fatty acid polyamide as disclosed in U.S. Pat. No. 5,849,843, fully incorporated as though made a part hereof. In a further preferred embodiment, the membrane monolayer structres is made entirely of ULDPE.  
         [0097]      FIGS. 8A through 8C  show a preferred method by which the closed second end  34  of the closed end tube  26  is contoured with a selected pattern to define a zone of weakness in the closed second end  34  in accord with the present invention. The preferred method contemplates heating by radio frequency, ultrasonic or thermal conduction to form the contouring. The contouring may also be formed by injection molding the contour pattern, by cold coining, by coining while injection molding using core pins, laser etching, solvent etching, machine cutting using a spinning tool, forging or stamping methods, or any suitable method.  
         [0098]      FIG. 8A  illustrates the closed end tube  26  and a contour forming head  56 . The contour forming head  56  contains at its working end  58  the selected contouring pattern. The pattern may include those of the embodiments illustrated in  FIGS. 4 through 7 , discussed below. In  FIG. 8A , the contour forming head  56  is presented to the closed end tube  26 .  
         [0099]      FIG. 8B  shows the contour forming head  56  partially penetrating the outer surface  58  of the closed second end  34  of the closed end tube  26 . The contour forming head  56  thus forms the selected pattern in the outer surface  37  of the closed second end  34 .  
         [0100]     It should be understood that although the method has been described with respect to contouring the outer surface  37  of the closed second end  34 , the method may also be used to contour the inner surface  35  of the closed second end  34 . Moreover, while the preferred method has been described with respect to the embodiment employing the closed end tube  26 , it is contemplated that the same method can be used to contour the open end tube/membrane and renal application embodiments described herein. It is further contemplated that the closed end tube may also include a membrane disposed within it, or that the membrane tube may have more than one membrane.  
         [0101]      FIG. 8C  illustrates an elastomeric spike holder  60  overmolded onto the contoured closed end tube  26 . The elastomeric spike holder  60  engages the access spike and assists in holding the access spike in the tube during fluid delivery. The spike holder  60  may be of any type suitable for holding the access spike in place but is preferably as discussed below.  
         [0102]     As shown in  FIGS. 20-22 , the spike holder  60  preferably has a body  142  having a first chamber  144  at a first end a second chamber  146  at a second end and a passageway  148  connecting the first and second chambers.  FIGS. 20-22  illustrate the spike holder  60  in connection with the embodiment using a membrane  48  situated at the end of an open end tube  46  as described above. It will be understood that the spike holder  60  may be used with any embodiment described herein. The first chamber  144  is dimensioned to telescopically receive an end portion  150  of the tube  46 . It is contemplated by the present invention the chamber  144  could extend into the tube fluid passageway  148  and attach thereto without departing from the present invention. The second chamber  146  is dimensioned to form an interference fit with an access spike  20 . In a preferred form of the invention, the first chamber  144  and the second chamber  146  have a generally circular cross-sectional shape, the first chamber  144  having a first diameter and the second chamber  146  having a second diameter, the first diameter being larger than the second diameter.  
         [0103]     In a preferred form of the invention, the spike holder  60  has an outwardly extending flange  154  at an intermediate portion thereof. The flange  14  is positioned generally at the intersection of the first chamber  144  and the second chamber  146 . The flange  154  has a first surface  156  wherein a plurality of buttresses  158  extend from the first surface of the body  142 . In a preferred form of the invention, the flange  154  is generally circular in cross-sectional shape and the buttresses  158  are circumferentially spaced about the first surface  156 . The buttresses  158  are shown having a generally tear-drop shape, however, could be of numerous different shapes without departing from the present invention. The buttresses  158  are provided to form a gripping surface for those handling the spike holder  60 .  
         [0104]     The spike holder  60  is formed from a polyolefin as defined above and more particularly is an ethylene and α-olefin copolymer. The spike holder  60  can also have a textured or matte finish on a portion or the entire outer surface  160  of the holder  60  for ease of handling. The spike holder  60  can be formed by any suitable polymer forming technique known to those skilled in the art and preferably the spike holder  50  is formed by injection molding. The spike holder  60  can also include a membrane film positioned in the passageway  148  in lieu of or in addition to the membrane  48 .  
         [0105]     In a preferred form of the invention, the spike holder  60  is formed directly over the end portion  150  of the open end tube  46 /membrane  48  assembly described above. Such a process shall be referred to as an overmolding process. The overmolding process includes the steps of: (1) providing a tubing as set forth above; providing a mold for forming a spike holder; inserting a portion of the tubing into the mold; and supplying polymeric material to the mold to form a spike holder on the tubing. While the preferred method has been described with respect to the embodiment employing the open end tube  46  and membrane  48 , it is contemplated that the same method can be used to contour the closed end tube and renal application embodiments described herein.  
         [0106]      FIG. 4  illustrates one preferred embodiment of the contouring pattern of the present invention.  FIG. 4  shows a radial contouring pattern  62 . The radial contouring pattern  62  preferably has a plurality of intersecting lines  64  that intersect at substantially the center point  66  of the closed second end  34  of the closed end tube  26 , or the membrane  48 . The radial contouring pattern  62  is preferably located on the outer surface  37  of the closed second end  34 , but alternatively may be on the inner surface  35 . The radial contouring pattern  62  due to the reduced thickness of the closed second end  34  along the pattern lines, creates a zone of weakness in the closed second end  34 . The zone of weakness can either be discrete or not, and can extend beyond the pattern or be entirely within the pattern, or extend along the pattern. The zone of weakness permits reduced spike access force to the closed second end  34 . The radial contouring pattern  62  favors use with a center point access spike  25 .  
         [0107]      FIG. 5  illustrates a concentric contouring pattern  68  representing another preferred embodiment of the present invention. The concentric contouring pattern  68  preferably includes a series of circles  70  arranged concentrically about a substantially center point  72  of the closed second end  34  of the closed end tube  26 , but may be a single circle. The concentric contouring pattern  68  is preferably located on the outer surface  37  of the closed second end  34 , but alternatively may be on the inner surface  35 . The concentric contouring pattern  68 , due to the reduced thickness of the closed second end  34  along the pattern lines, creates a zone of weakness in the closed second end  34 . The zone of weakness can either be discrete or not, and can extend beyond the pattern or be entirely within the pattern, or extend along the pattern. The zone of weakness permits reduced spike access force to the closed second end  34 . The concentric contouring pattern  68  favors use with a beveled access spike  24 .  
         [0108]      FIG. 6  illustrates a spiral contouring pattern  74  of a further preferred embodiment of the present invention. The spiral contouring pattern  74  preferably includes two intersecting spiral lines  76  that intersect a substantially the center point  78  of the closed second end  34  of the closed end tube  26 , but may be a single spiral line. The spiral contouring pattern  74  is preferably located on the outer surface  37  of the closed second end  34 , but alternatively may be on the inner surface  35 . The spiral contouring pattern  74  combines the features of the radial and concentric contouring patterns of  FIGS. 4 and 5 . Due to the reduced thickness of the closed second end  34  along the pattern lines, a zone of weakness is created in the closed second end  34 . The zone of weakness permits reduced spike access force to the closed second end  34 . The zone of weakness can either be discrete or not, and can extend beyond the pattern or be entirely within the pattern, or extend along the pattern. The spiral contouring pattern  74  may be used with either a center point access spike  25  or beveled access spike  24 .  
         [0109]      FIGS. 7A and 7B  illustrate a hinged valve contouring pattern  80  of a further embodiment of the present invention. The hinged valve contouring pattern  80  of  FIG. 7B  has a circular contoured portion  82  and a hinged section  84 . The circular portion  82  is preferably centrally located on the closed second end  34  of the closed end tube  26 . The hinged valve contouring pattern  80 , due to the reduced thickness of the closed second end  34  along the pattern lines, creates a zone of weakness in the closed second end  34 . The zone of weakness permits reduced spike access force to the closed second end  34 . The zone of weakness can either be discrete or not, and can extend beyond the pattern or be entirely within the pattern, or extend along the pattern.  
         [0110]     When an access spike punctures the closed second end  34 , the closed second end  34  breaks along the circular contoured portion  82  forming a flap  86 . ( FIG. 7A ) The hinged section  84  rotates the flap  86  about the hinged section  84 . When the access spike is removed, elastomeric properties of the hinged section  84  rotate the flap  86  back to its original position, thus resealing the closed second end of the closed second end  26 , and inhibiting flow of fluid from the container  12 . The zone of weakness can extend beyond the pattern or be entirely within the pattern, or extend along the pattern.  
         [0111]     Additional patterns are also contemplated that include combinations of the above patterns, such as use of radial lines of  FIG. 4  with concentric circles of  FIG. 5 . The pattern could also include a series of spaced perforations on the outer surface of the closed second end  26 . For each of these patterns, the zone of weakness can extend beyond the pattern or be entirely within the pattern, or extend along the pattern. The contour lines that form the above patterns are preferably v-shaped in cross-section.  
         [0112]     Also, it is contemplated that where multiple membranes are used, or where more than one membrane is also disposed within a closed end tube, the membranes and/or closed end of the closed end tube may have the same or differing patterns.  
         [0113]     Moreover, as shown in  FIG. 23 , the closed end  34  of the closed end tube  26  may be weakened by using a solvent to created create a zone of weakness  87 . Solvent weakening may be used by itself, or in conjunction with the patterns described above.  
         [0114]     A further embodiment is shown in  FIG. 24 . A tube  160  includes a bellows  162 . A tether  164  attached to the end  166  of the tube  160  extends through the tube  160  to a membrane  168  contoured or weakened as described above. When the bellows  162  is pulled in the direction of the arrow, the tether  164  pulls at least a portion of the membrane  168  from the sides of the tube  160  thereby permitting fluid flow. Alternatively, the tether  164  may extend out of the tube  160 .  
         [0115]      FIGS. 9A through 9C  illustrate a further preferred embodiment of the present invention contemplated for use with inline frangibles for delivery of renal fluids. In this embodiment, a tube  90  having an end  92  contains a membrane  94  disposed across the tube  90 . The membrane  94  is contoured with one of the patterns described above. A cannula interface  96  having a first end  98  and a second end  100  is placed in the tube  90  between the membrane  94  and the end  92 .  
         [0116]     A connector  102  is designed to engage with the second end  100  of the cannula interface  96  while in the tube  90  as shown in  FIG. 9B . When the connector  102  is inserted into the tube  90 , it engages the second end  100  of the cannula interface  96 . As shown in  FIG. 9C , further engagement of the connector  102  pushes the first end  98  of the cannula interface  96  through the contoured membrane  94  thereby enabling renal fluid delivery.  
         [0117]     While the contouring pattern embodiments of  FIGS. 4 through 7  have been described with respect to the embodiment employing the closed end tube  26 , it is contemplated that the same method can be used to contour the membrane and membrane renal application embodiments described herein. For the membrane embodiment described herein, substitute end tube  46  and membrane  48  for the closed end tube  26  and second end  34 , respectively. For the renal application embodiment, substitute tube  90  and membrane  94  for the closed end tube  26  and second end  34 , respectively.  
         [0118]     In a further embodiment of the present invention ( FIG. 25 ), a capsule  170  has a first end  172  and a second end  174 . The first end  172  and second end  174  preferably are contoured with a pattern  176  to define a zone of weakness as described above. The capsule  170  can be placed in a pouch or other squeezable container (not shown). For instance, the capsule  170  may contain soda syrup, and may be placed in a pouch containing carbonated water. By squeezing the pouch, the capsule  170  is also compress. The compression causes one or both of the first end  172  and second end  174  to fail at their zones of weakness. Upon shaking the pouch, the soda syrup inside the capsule  170  mixes with the carbonated water inside the pouch to create a soda drink.  
         [0119]     In a still further embodiment ( FIG. 26 ), a container  178  has within it a capsule  180  which may be constructed in accord with the embodiment of  FIG. 25 . The capsule  180  has a first end  182  and a second end  184  which preferably both contain patterns defining a zone of weakness as described above. A stick  186  is inserted into a leak-proof opening  188  in the container  178 . The stick  186  may be a straw or other suitable device. The capsule  180  is oriented such that when the stick  186  is inserted into the container  178 , it punctures at least on end  182  or  184  of the capsule  180 . As in the embodiment of  FIG. 25 , the container  178  may contain carbonated water, and the capsule  180  may contain soda syrup such that when the capsule  180  is punctured, the syrup mixes with the carbonated water to make soda. In addition to soda and syrup, the embodiments of  FIGS. 25 and 26  contemplate use with reconstituting drugs, for instance, the capsule  180  can contain a drug used to reconstitute that contained in container  178 .  
         [0120]      FIG. 27  shows a five layered film structure  190  having an outer layer  192 , a core layer  194 , an inner or solution contact layer  196  and two tie layers  198 . One of each of the tie layers  198  is located between the core layer  194  and the outer layer  192  and the inner layer  196  and the core layer  194 .  
         [0121]     The core layer  194  is an ethylene vinyl alcohol copolymer having an ethylene content of from about 25-45 mole percent (ethylene incorporated, as specified in EVALCA product literature). Kuraray Company, Ltd. produces EVOH copolymers under the tradename EVAL.RTM. which have about 25-45 mole percent of ethylene, and a melting point of about 150-195 degree C. Most preferably the EVOH has a ethylene content of 32 mole percent.  
         [0122]     The outer layer  192  preferably is a polyamide, polyester, polyolefin or other material that aids in the escape of water away from the core layer. Acceptable polyamides include those that result from a ring-opening reaction of lactams having from 4-12 carbons. This group of polyamides therefore includes nylon 6, nylon 10 and nylon 12. Most preferably, the outer layer  192  is a nylon 12.  
         [0123]     Acceptable polyamides also include aliphatic polyamides resulting from the condensation reaction of di-amines having a carbon number within a range of 2-13, aliphatic polyamides resulting from a condensation reaction of di-acids having a carbon number within a range of 2-13, polyamides resulting from the condensation reaction of dimer fatty acids, and amide containing copolymers. Thus, suitable aliphatic polyamides include, for example, nylon 66, nylon 6,10 and dimer fatty acid polyamides.  
         [0124]     Suitable polyesters for the outer layer  192  include polycondensation products of di- or polycarboxylic acids and di or poly hydroxy alcohols or alkylene oxides. Preferably, the polyesters are a condensation product of ethylene glycol and a saturated carboxylic acid such as ortho or isophthalic acids and adipic acid. More preferably the polyesters include polyethyleneterphthalates produced by condensation of ethylene glycol and terephthalic acid; polybutyleneterephthalates produced by a condensations of 1,4-butanediol and terephthalic acid; and polyethyleneterephthalate copolymers and polybutyleneterephthalate copolymers which have a third component of an acid component such as phthalic acid, isophthalic acid, sebacic acid, adipic acid, azelaic acid, glutaric acid, succinic acid, oxalic acid, etc.; and a diol component such as 1,4-cyclohexanedimethanol, diethyleneglycol, propyleneglycol, etc. and blended mixtures thereof.  
         [0125]     Suitable polyolefins for the outer layer  192  are the same as those specified for the inner layer  196  set forth below. Preferably a polypropylene is used.  
         [0126]     It is well known that the oxygen barrier properties of EVOH are adversely impacted upon exposure to water. Thus, it is important to keep the core layer  194  dry. To this end, the outer layer  192  should assist in the removal of water that makes its way to the core layer  194  through the inner layer  196  or otherwise to maintain the oxygen barrier properties of the core layer  194 .  
         [0127]     The inner layer  196  is preferably selected from homopolymers and copolymers of polyolefins. Suitable polyolefins are selected from the group consisting of homopolymers and copolymers of alpha-olefins containing from 2 to about 20 carbon atoms, and more preferably from 2 to about 10 carbons. Therefore, suitable polyolefins include polymers and copolymers of propylene, ethylene, butene-1, pentene-1, hexene-1, heptene-1, octene-1, nonene-1 and decene-1. Suitable polyolefins further include lower alkyl and lower alkene acrylates and acetates and ionomers thereof. The term “lower alkyl” means alkyl groups having 1-5 carbon atoms such as ethyl, methyl, butyl and pentyl. The term “ionomer” is used herein to refer to metal salts of the acrylic acid copolymers having pendent carboxylate groups associated with monovalent or divalent cations such as zinc or sodium.  
         [0128]     Most preferably, the inner layer  196  is selected from ethylene .alpha.-olefin copolymers especially ethylene-butene-1 copolymers which are commonly referred to as ultra-low density polyethylenes (ULDPE). Preferably the ethylene .alpha.-olefin copolymers are produced using metallocene catalyst systems. Such catalysts are said to be “single site” catalysts because they have a single, sterically and electronically equivalent catalyst position as opposed to the Ziegler-Natta type catalysts which are known to have a mixture of catalysts sites. Such metallocene catalyzed ethylene .alpha.-olefins are sold by Dow under the tradename AFFINITY, and by Exxon under the tradename EXACT. The ethylene .alpha.-olefins preferably have a density from 0.880-0.910 g/cc.  
         [0129]     Suitable tie layers  198  include modified polyolefins blended with unmodified polyolefins. The modified polyolefins are typically polyethylene or polyethylene copolymers. The polyethylenes can be ULDPE, low density (LDPE), linear low density (LLDPE), medium density polyethylene (MDPE), and high density polyethylenes (HDPE). The modified polyethylenes may have a density from 0.850-0.95 g/cc.  
         [0130]     The polyethylene may be modified by grafting with carboxylic acids, and carboxylic anhydrides. Suitable grafting monomers include, for example, maleic acid, fumaric acid, itaconic acid, citraconic acid, allylsuccinic acid, cyclohex-4-ene-1,2-dicarboxylic acid, 4-methylcyclohex-4-ene-1,2-dicarboxylic acid, bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, x-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, maleic anhydride, itaconic anhydride, citraconic anhyride, allylsuccinic anhydride, citraconic anhydride, allylsuccinic anhydride, cyclohex-4-ene-1,2-dicarboxylic anhydride, 4-methylcyclohex-4-ene-1,2-dicarboxylic anhydride, bicyclo[2.2.1]hept-5-ene2,3-dicarboxylic anhydride, and x-methylbicyclo[2.2.1]hept-5-ene-2,2-dicarboxylic anhydride.  
         [0131]     Examples of other grafting monomers include C.sub.1-C.sub.8 alkyl esters or glycidyl ester derivatives of unsaturated carboxylic acids such as methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, glycidyl acrylate, glycidal methacrylate, monoethyl maleate, diethyl maleate, monomethyl maleate, diethyl maleate, monomethyl fumarate, dimethyl fumarate, monomethyl itaconate, and diethylitaconate; amide derivatives of unsaturated carboxylic acids such as acrylamide, methacrylamide, maleicmonoamide, maleic diamide, maleic N-monoethylamide, maleic N,N-dietylamide, maleic N-monobutylamide, maleic N,N dibutylamide, fumaric monoamide, fumaric diamide, fumaric N-monoethylamide, fumaric N,N-diethylamide, fumaric N-monobutylamide and fumaric N,N-dibutylamide; amide derivatives of unsaturated carboxylic acids such as maleimide, N-butymaleimide and N-phenylnialeimide; and metal salts of unsaturated carboxylic acids such as sodium acrylate, sodium methacrylate, potassium acrylate and potassium methacrylate. More preferably, the polyolefin is modified by a fused ring carboxylic anhydride and most preferably a maleic anhydride.  
         [0132]     The unmodified polyolefins can be selected from the group consisting of ULDPE, LLDPE, MDPE, HDPE and polyethylene copolymers with vinyl acetate and acrylic acid. Suitable modified polyolefin blends are sold, for example, by DuPont under the tradename BYNEL.RTM., by Chemplex Company under the tradename PLEXAR.RTM., and by Quantum Chemical Co. under the tradename PREXAR.  
         [0133]     As can be seen in  FIG. 27 , the preferred multilayered structure  190  is asymmetrical about the core layer  194 . That is to say, the solution contact layer  196  is thicker than the outer layer  192 . It is well known that EVOH is hygroscopic. As the EVOH absorbs water its oxygen barrier properties are significantly reduced. The preferred structure  190  provides a relatively thin outer layer  192  of a polyamide that assists in the escape of water away from the core layer  194 . The solution contact layer  196  is a relatively thick layer of a polyolefin which has good water vapor barrier properties and  
         [0000]     serves to protect the core layer  194  from the ingress of water.  
         [0134]     The relative thicknesses of the layers of the structure  190  is as follows: the core layer  194  should have a thickness from 0.2-2.5 mil, more preferably from 0.7-1.3 mil or any range or combination of ranges therein. The outer layer  192  preferably has a thickness from 0.2-2.0 mil and more preferably 0.4-0.8 mil, or any range or combination of ranges therein. The inner layer  196  has a thickness from 3-8 mil and more preferably from 5-7 mil or any range or combination of ranges therein. The tie layers  198  preferably have a thickness from 0.2-1.2 mils and more preferably 0.6-0.8 mils. Thus, the overall thickness of the layered structure  190  will be from 3.8 mils-14.9 mils.  
         [0135]      FIG. 28  shows an alternative embodiment having seven layers. This embodiment is the same as that in  FIG. 27  with the exception that the solution contact layer  196  is divided into three sublayers  196   a , b and c. Preferably the centrally disposed sublayer  196   b  of the solution contact  196  has a lower WVTR than its flanking sublayers  196   a  and  196   c . Most preferably sublayers  196   a  and  196   c  are metallocene-catalyzed ULDPE and the central sublayer  196   b  is a metallocene-catalyzed low-density polyethylene. Preferably the flanking solution contact sublayers  196   a  and  196   c  have thicknesses of about 1 to 7 times, more preferably 2-6 times and most preferably 5 times thicker than the central sublayer  196   b . Preferably the flanking solution contact sublayers  196   a  and  196   c  will have a thickness of from about 1-5 mils and most preferably 2.5 mils and the central solution contact layer  196   b  will have a thickness of about 0.2-1 mils and most preferably 0.5 mils.  
         [0136]      FIG. 29  shows another alternative embodiment that is the same in all respects to the multilayered structure of  FIG. 27  with the exception that the core layer  194  comprises a plurality of thin core sublayers. Preferably there are anywhere from 2-10 core sublayers. It may also be desirable to incorporate tie sublayers in between each of the core sublayers. The tie sublayers may be selected from those set forth above for bonding the inner and outer layers to the core layer.  
         [0137]     The layered structures of the present invention are well suited for fabricating medical containers as they can be fabricated into containers and store medical solutions for extended periods of time without having large quantities of low molecular weight components migrating from the layered structure to the contained solution. For a 450 cm.sup.2 surface area container containing 250 ml of saline for seven days, preferably, the quantity of low molecular weight additives, as measured by total organic carbon (TOC), will be less than 1.0 ppt, more preferably less than 100 ppm and most preferably less than 10 ppm.  
         [0138]     The above layers may be processed into a layered structure by standard techniques well known to those of ordinary skill in the art and including cast coextrusion, coextrusion coating, or other acceptable process. For ease of manufacture into useful articles, it is desirable that the layered structure can be welded using radio frequency (“RF”) welding techniques generally at about 27.12 MHz. Therefore, the material should possess sufficient dielectric loss properties to convert the RF energy to thermal energy. Preferably, the outer layer  192  of the layered structure will have a dielectric loss of greater than 0.05 at frequencies within the range of 1-60 MHz within a temperature range of ambient to 250 degree. C.  
         [0139]     Preferably, the layered structure is fabricated into films using a cast coextrusion process. The process should be essentially free of slip agents and other low molecular weight additives that may increase the extractables to an unacceptable level.  
         [0140]     It is also preferred that the multilayered structure have the following physical properties: a mechanical modulus as measured by ASTM D 638 of less than 50,000 psi, more preferably less than 40,000 psi and most preferably from 35,000-40,000 or any range or combination of ranges therein. When fabricated into containers and used to store medical liquids, the total organic carbon that leaches out from the layered structure to the solution is less than 1.0 ppt, more preferably less than 100 ppm and most preferably less than 10 ppm. Preferably the layered structure has an oxygen permeability of less than 0.2 cc/100 sq.in./24 hrs.  
         [0141]     An illustrative, non-limiting example of the present multilayered structures is set out below. Numerous other examples can readily be envisioned in light of the guiding principles and teachings contained herein. The example given herein is intended to illustrate the invention and not in any sense to limit the manner in which the invention can be practiced.  
       EXAMPLE  
       [0142]     A five-layered structure was coextruded in accordance with the teachings of the present invention. The five-layered structure had an outer layer of nylon 12 (EMS America Grilon-Grilamid L20) having a thickness of 0.6 mil, a tie layer (BYNEL.RTM.4206 (DuPont)) having a thickness of 0.7 mil, a core layer of EVOH (EVAL.RTM. EVOH LC-F101AZ) having a thickness of 1.0 mil, and a ULDPE (Dow AFFINITY.RTM. PL1880) having a thickness of 6.0 mil. The structure was radiation sterilized using a cobalt source at a dosage of 40-45 kGys.  
         [0143]     The table below shows how the oxygen permeability of the structure depends on temperature. The oxygen permeability was measured using a MoCon tester (Modem Controls, Minneapolis, Minn.). The test chamber had a relative humidity of 75% on the O.sub.2 side and a 90% relative humidity on the N.sub.2 side to replicate a solution filled container in a high humidity environment.  
                                                                 TEMPERATURE   O.sub.2 PERMEABILITY           .degree. C.   cc/100 in. sup. 2/day                                        8   0.002           15   0.003           22   0.018           30   0.046           40   0.156                      
 
         [0144]     The water vapor transmission rate was also measured at 23.degree. C. and at a humidity gradient of 90% yielding a WVTR of 0.035 g H.sub.2 O/100 in.sup.2/day.