Abstract:
The present invention provides a receptacle ( 30 ) for a therapeutic fluid susceptible to deterioration on exposure to a gas such as oxygen or carbon dioxide. The receptacle ( 30 ) has walls of sheet material each including at least one layer forming a barrier essentially impermeable to such gas, and a seal sealing the walls together in a region thereof. A transfer tube ( 40 ) is sealed in the seal having a proximal end in the receptacle ( 30 ), a distal end accessible from outside the receptacle ( 30 ), a flow passage ( 56 ) extending between said proximal and distal ends, and a closure ( 54 ) blocking flow through the flow passage ( 56 ) adapted to be pierced by a tubular needle for transfer of therapeutic through the needle. The transfer tube ( 40 ) and closure ( 54 ) are essentially impermeable to said gas.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of provisional application Ser. No. 60/284,277, filed Apr. 17, 2001, which is incorporated by reference and made a part hereof. 
     
    
     TECHNICAL FIELD 
       [0002]    The present invention relates to a high gas barrier primary receptacle system, and more particularly to a receptacle system for medical solutions. 
       BACKGROUND OF THE INVENTION 
       [0003]    There is an ever increasing number of therapeutic fluids being developed for delivery by a flexible receptacle. Many of these therapeutic fluids are sensitive as they degrade or react with gases such as oxygen and carbon dioxide. These therapeutic fluids must be protected from contact by such gases to maintain the efficacy of the therapeutic fluid. 
         [0004]    For example, hemoglobin solutions are known to lose their ability to function as blood substitutes during storage. A hemoglobin solution loses its ability to function as a blood substitute because of spontaneous transformation of oxyhemoglobin in the solution to methemoglobin, a physiologically inactive form of hemoglobin which does not function as a blood substitute by releasing oxygen into a patient&#39;s bloodstream. To improve shelf life, the blood substitutes industry delays loss of function by refrigerating or freezing the solutions, or controlling the oxygenation state of the hemoglobin within the solution. 
         [0005]    Therapeutic hemoglobin solutions are typically oxygenated, stored frozen in conventional oxygen-permeable, 200 ml plastic solution bags, and thawed to room temperature hours before use. 
         [0006]    WO 99/15289 describes a multiple layer structure for fabricating medical products. The layer structure has a core layer of an ethylene vinyl alcohol copolymer, a solution contact layer of a polyolefin positioned on a first side of the core layer, an outer layer positioned on a second side of the core layer opposite the solution contact layer, the outer layer being selected from the group consisting of polyamides, polyesters and polyolefins, and a tie layer on each side of the core layer. The tie layer is 0.2-1.2 mils in thickness, and is the only layer of the structure which may be composed of ethylene vinyl acetate. 
         [0007]    U.S. Pat. No. 6,271,351 describes a method of storing deoxyhemoglobin in a container which is said to exhibit low oxygen permeability. The container is composed of a layered structure including ethylene vinyl alcohol, but does not include ethylene vinyl acetate. 
         [0008]    There is a need for containers having minimal oxygen permeability which would enable deoxygenated hemoglobin solutions to be stored for weeks or months at room temperature and then used as a blood substitute. 
         [0009]    Receptacles used for the shipping, storing, and delivery of liquids, such as medical or therapeutic fluids, are often fabricated from single-ply or multiple-ply polymeric materials. Two sheets of these materials are placed in overlapping relationship and the overlapping sheets are bonded at their outer peripheries to define a chamber or pouch for containing liquids. It is also possible to extrude these materials as a tube and to seal longitudinally spaced portions of the tube to define chambers between two adjacent seals. Typically, the materials are joined along their inner surfaces using bonding techniques such as heat sealing, radio-frequency sealing, thermal transfer welding, adhesive sealing, solvent bonding, sonic sealing, and laser welding. 
         [0010]    It is also common to provide such receptacles with access ports to provide access to the interior of the receptacle. Access ports typically take the form of one or more end ports (transfer tubes) inserted between the sidewalls of the receptacle or panel ports attached to a sidewall of the receptacle. The end ports typically have a fluid passageway with a closure wall positioned inside the passageway to form a fluid tight seal of the receptacle. The closure, typically in the form of a membrane, must be punctured by an access needle or “spike” to allow for delivery of the contents of the receptacle. 
         [0011]    Conventional flexible solution receptacles employing end port designs typically use flexible PVC or soft polyolefins such as LDPE to construct the port tubes. Such materials have sufficient elasticity to grip the outside of an access spike to retain the spike during fluid delivery. The inner diameter of the end ports are dimensioned to be smaller than the outer diameter of the access device. Due to the ductility of PVC or LDPE, the port tube can expand about the outside of the access spike to form an interference fit therewith. However, such receptacle and port closure systems are readily permeated by oxygen and other gases such as carbon dioxide. If such receptacles are to be utilized to house a gas sensitive liquid, such packages must utilize a gas barrier overwrap material. 
         [0012]    To provide a stand-alone gas barrier primary receptacle, all components of the receptacle system should be fabricated using barrier material. For medical applications where such receptacles are typically disposed of by incineration, it is desirable to construct the receptacle system components from non-halogen containing polymers. Halogen containing compounds have the potential for creating inorganic acids upon incineration. Further, for medical applications, it is also desirable to construct the receptacle system components from polymers having a low quantity of low molecular weight additives, such as plasticizers, as such low molecular weight components can potentially leach out into the fluids contained or transported therein. 
         [0013]    It is well known that certain materials provide a high resistance to the ingress of oxygen or other gases. For example, ethylene vinyl alcohol (EVOH) provides a high barrier to the ingress of oxygen. However, EVOH provides a significant design challenge for use in flexible receptacle systems as EVOH is also know to be a very rigid material. A port tube containing a significant quantity of EVOH will have insufficient elasticity to expand around an access device. Thus, such an EVOH containing port tube cannot be dimensioned to be smaller in diameter than an access device. 
         [0014]    Due to the variation in the outer diameter dimensions of access devices commercially, it is also difficult to design a single port tube to have an appropriate diameter to form an interference fit with all access devices commercially available. The spike holder or needle holder has sufficient elastomeric properties to form around an access device and form a grasping hold of the access device. The present invention is provided to solve these and other problems. 
       SUMMARY OF THE INVENTION 
       [0015]    The present invention provides a receptacle for a therapeutic fluid susceptible to deterioration on exposure to a gas such as oxygen or carbon dioxide. The receptacle has walls of sheet material each including at least one layer forming a barrier essentially impermeable to said gas, and a seal sealing the walls together in a region thereof. A transfer tube is sealed in the seal having a proximal end in the receptacle, a distal end accessible from outside the receptacle, a flow passage extending between said proximal and distal ends, and a closure blocking flow through said flow passage adapted to be pierced by a tubular needle for transfer of therapeutic through the needle. The transfer tube and closure are essentially impermeable to said gas. 
         [0016]    The present invention further provides a transfer tube for attachment to a receptacle adapted to hold a fluent therapeutic susceptible to deterioration on exposure to gas such as oxygen or carbon dioxide. The transfer tube has a tubular body having a proximal end, a distal end opposite the proximal end, a flow passage extending between said proximal and distal ends adapted to communicate with said receptacle, and a closure blocking flow through the flow passage and adapted to be pierced by a tubular needle for transfer of therapeutic through the needle. The tubular body and closure are essentially impermeable to said gas. 
         [0017]    The present invention is also directed to a needle holder for application to the distal end of a transfer tube of a receptacle particularly adapted to hold a fluent therapeutic  10  susceptible to deterioration on exposure to gas such as oxygen or carbon dioxide. The needle holder is adapted to hold in place the carrier of a transfer needle with the needle piercing the transfer tube. The holder has a body having a first annular wall defining a first cavity at a first end of the body, a second annular wall defining a second cavity at a second end of the body, and a flow passage extending between the two cavities, the first annular wall being sized for an interference fit with said transfer tube to releasably attach the needle holder to the transfer tube, and the second annular wall being sized for an interference fit with said needle carrier to releasably attach the needle carrier to the needle holder in a position in which needle is disposed in said flow passage. 
         [0018]    Additional features, advantages, and other aspects and attributes of the present invention will be discussed with reference to the following drawings and accompanying specification. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0019]      FIG. 1   a  is a plan view of a flowable materials receptacle and closure system; 
           [0020]      FIG. 1   b  is a cross-sectional view taken along line b-b of  FIG. 1   a;    
           [0021]      FIG. 1   c  is a plan view of a flowable materials receptacle having a fill port and an administration port; 
           [0022]      FIG. 2   a  is a cross-sectional view of a three-layer tubing; 
           [0023]      FIG. 2   b  is a cross-sectional view of a two-layer tubing; 
           [0024]      FIG. 3   a  is a cross-sectional view of a two-layer membrane film; 
           [0025]      FIG. 3   b  is a cross-sectional view of a three-layer membrane film; 
           [0026]      FIG. 3   c  is a cross-sectional view of a five-layer membrane film; 
           [0027]      FIG. 4  is a cross-sectional view of a membrane film and tube assembly; 
           [0028]      FIG. 5  is a side view of a needle or “spike” holder; 
           [0029]      FIG. 6  is cross-sectional view of the spike holder of  FIG. 6 ; 
           [0030]      FIG. 7  is an cross-sectional view taken along line A-A of  FIG. 6 ; 
           [0031]      FIG. 8  is an assembly of the membrane film and tube assembly with the spike holder or needle holder of  FIG. 5  with a spike being introduced therein; and 
           [0032]      FIG. 9  is a cross-sectional view of a four-layer membrane film. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0033]    While this invention is susceptible of embodiments in many different forms, there is shown in the drawings and will herein be described in detail preferred embodiments of the invention with the understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the broad aspect of the invention to the embodiments illustrated. 
         [0034]      FIG. 1   a  shows a flowable materials receptacle and closure system generally referred to as  10 . The system includes a flowable materials receptacle  30 , a port (transfer) tube and closure assembly  40 , and a needle or “spike” holder  50 . The relative size of the receptacle  30 , assembly  40 , and spike holder  50  are exaggerated for illustrative purposes. In a preferred form of the invention, the system  10  is useful for containing and delivering a fluent therapeutic susceptible to deterioration on exposure to a gas such as oxygen or carbon dioxide. The system is also particularly well suited for storage and delivery of a buffered solution. 
         [0035]    What is meant by “flowable material” is a material that will flow by the force of gravity. Flowable materials therefore include both liquid items and powdered or granular items and the like. Flowable materials receptacles find particular use for storage and delivery of medical or therapeutic fluids and include, but are not limited to, I.V. receptacles, peritoneal dialysis drain and fill receptacles, blood receptacles, blood product receptacles, blood substitute receptacles, nutritional receptacles, food receptacles and the like. 
         [0036]      FIGS. 1   a  and  8  illustrate the assembly  40  as including a port (transfer) tube  52  and a closure in the form of a wall or membrane  54 . The port tube  52  defines a fluid flow passage  56  and has an end surface  58 . The membrane  54  is shown attached to the port tube end surface  58 . It is contemplated by the present invention the membrane  54  could also be positioned inside the port tube flow passage  56  without departing from the scope of the present invention. 
         [0037]    While it is contemplated the port tube  52  can have any number of layers, in a preferred form of the invention the port tube  52  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 gasses 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. 
         [0038]    In an even more preferred form of the invention, the port tube  52  will have multiple layers.  FIG. 2   a  and  FIG. 2   b  show respectively a three-layer port tube  52  and a two-layer port tube. The three-layer port tube  52  has an outside or an outermost layer  60 , a core layer  62  and an inside solution contact layer  64 . Similarly, the two-layer port tube  52  has an outside layer  60  and an inside, solution contact layer  64 . 
         [0039]    In a preferred form of the invention, the multiple layer transfer tube or port tube  52  will have a discrete layer of a barrier material with the remaining layers being selected from polyolefins. The layers of the tube can be positioned in any order, however, in a preferred form of the invention, the barrier layer is not positioned as the outside layer  60 . Thus, the layers of a three layer tube 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 tube embodiments having more than two layers, the tube  52  can be symmetrical or asymmetrical from a material aspect and from a thickness of layers aspect. 
         [0040]    Suitable polyolefins include homopolymers, copolymers and terpolymers obtained using, at least in part, monomers selected from α-olefins having from 2 to 12 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 trademark, Dupont-Dow under the ENGAGE trademark and Exxon under the EXACT and PLASTOMER trademarks. 
         [0041]    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. 
         [0042]    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-diethylamide, 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; imide 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. 
         [0043]    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. 
         [0044]    In one preferred form of the invention, the tube  52  has a solution contact layer  64  of a modified EVA copolymer sold by DuPont Packaging under the trademark BYNEL® CXA, a core layer  62  of an EVOH and an outside layer  60  of a modified EVA, again preferably CXA. Such a structure 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  60  from about 0.002 inches to about 0.042 inches, preferably about 0.010 inches, the core layer  62  from about 0.016 inches to about 0.056 inches, preferably about 0.039 inches, and the solution contact layer  64  of from about 0.002 inches to about 0.042 inches, preferably about 0.010 inches. 
         [0045]    In another preferred form of the invention, the tube  52  has a solution contact layer  64  of an EVOH, a core layer  62  of a modified EVA and preferably BYNEL® CXA and an outside or outermost layer  60  of an ethylene and α-olefin copolymer. Such a structure is symmetrical from a materials standpoint. The tube layers can have various relative thicknesses. According to a preferred form of the invention, tube  52  will have layers of the following thickness ranges: outside layer  60  from about 0.002 inches to about 0.042 inches; the core layer  62  from about 0.002 inches to about 0.042 inches; and the solution contact layer  64  from about 0.016 inches to about 0.056 inches. The outermost layer  60  of EVA is well suited for bonding to the transfer tube, especially upon heat sealing. 
         [0046]    In a further preferred form, the tube  52  has a solution contact layer  64  of BYNEL® CXA, a core layer  62  of EVOH, and an outside layer  60  of a blend of 50% ULDPE and 50% CXA. Such tubing will have layers of the following thickness ranges: outside layer  60  from about 0.002 inches to about 0.042 inches, preferably about 0.010 inches; the core layer  62  from about 0.016 inches to about 0.056 inches, preferably about 0.039 inches; and the solution contact layer  64  of from about 0.002 inches to about 0.042 inches, preferably about 0.010 inches. 
         [0047]    In a preferred form of the invention, the port tube  52  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. The port tube  52  can be prepared by injection molding, extrusion, coextrusion or other polymer processing techniques well known in the art. 
         [0048]    Turning our attention now to the closure  54 , the membrane film forming the closure  54  can have any number of layers, but in a preferred form of the invention has multiple layers. The membrane film  54 , in a preferred form of the invention, shall have a barrier layer as defined above.  FIG. 3   a  shows a two-layer structure  54  having an outside layer  72  and an inside layer  70 .  FIG. 3   b  shows a three-layer structure  54  having an outside layer  72 , an inside layer  70  and a core layer  74 .  FIG. 3   c  shows a five-layer structure  54  having an outside layer  72 , an inside layer  70 , a core layer  74 , and two tie layers  76 . 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 layer  70  or outside layer  72  shall define a tubing contact layer or seal layer. 
         [0049]    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. 
         [0050]    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. 
         [0051]    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 polyethyleneterephthalates 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. 
         [0052]    In a preferred form of the invention, the membrane structure shall have five layers as shown in  FIG. 3   c  and is described in detail in commonly assigned U.S. Pat. No. 6,083,587 which is incorporated herein by reference and made a part hereof. The outside layer  72  is a polyamide and preferably nylon 12, the two tie layers  76  are a modified EVA copolymer, the core layer  74  is an EVOH and the inner layer  70  is a modified EVA. In a preferred form of the invention the inside layer  70  defines the tubing contact layer. 
         [0053]    Further, the structure shown in  FIG. 3   c  has the following layer thickness ranges: outside layer  72  from about 0.0005 inches to about 0.003 inches; the tie layers  76  from about 0.0005 inches to about 0.02 inches; the core layer  74  of from about 0.0005 inches to about 0.0015 inches; and an inside layer  70  of from about 0.008 inches to about 0.012 inches. 
         [0054]    In another preferred form, the membrane structure has four layers as shown in  FIG. 9 .  FIG. 9  shows a membrane  126  having an outer layer  128  of a polyamide, preferably nylon and more preferably a nylon 12, a third layer  130  of a modified ethylene vinyl acetate, preferably CXA, a second layer  132  of a barrier material, preferably EVOH, and an inner solution contact layer  134  of a modified ethylene vinyl acetate, preferably CXA. 
         [0055]    The outer layer  128  has a thickness of a range of about 0.0003 to 0.0007 inches, and preferably about 0.0005 inches. The third layer  130  has a thickness range of between 0.0003 to 0.0007 inches, and preferably about 0.0005 inches. The second layer  132  has a thickness range of between 0.0007 to 0.0013 inches, and preferably about 0.001 inches. The inner layer  134  has a thickness of between 0.006 and 0.01 inches, and preferably about 0.008 inches. The membrane film can be formed by extrusion, coextrusion, lamination, extrusion coating, or other polymer processing technique well known in the art. 
         [0056]    Turning our attention now to the receptacle  30  ( FIGS. 1   a ,  1   b  and  1   c ). In a preferred form of the invention the receptacle  30  is of a polymeric material or structure and more preferably includes a barrier material as an additive to a layer or as a discrete barrier layer as defined above. In a preferred form of the invention, the receptacle has sidewalls  80  which are positioned in registration and sealed along a peripheral seam  82 . The sealing can be carried out by conductive heat sealing or inductive heat sealing such as through radio frequency sealing or can be sealed by other methods well known in the art. The peripheral seam  82 , preferably, has an outer seal  84 , an inner seal  86  and a material depot  88  positioned therebetween. One or more access or administration ports  89  can be provided as is well known in the art. In a preferred form of the invention the receptacle can have a fill port  89 ′ on one end of the container and a administration port  89  on an opposite end of the container. The administration port can be the closure assembly  40  described above. The fill port  89 ′ can have the same structure as the administration port or, in a more preferred form of the invention, will be of a polyolefin material, a polyolefin blend or one of the other materials set forth above but will not include the gas barrier material of the administration port. The fill port  89 ′ can be removed after filling the container by a hot knife or during a step of sealing the container after filling. The material depot  88  defines an unsealed portion where material from the seals  84  and  86  can flow. The sidewalls  80  define a fluid containing chamber  90 . The fluid chamber is capable of storing flowable materials and more preferably is capable of forming a fluid tight seal. The receptable and closure assembly will preferably have an oxygen permeability of less than 0.10 cc/day, more preferably less than 0.075 cc/day and most preferably less than 0.04 cc/day, or any range or combination of ranges therein. 
         [0057]    In a preferred form of the invention, the sidewalls  80  are of a multiple layer structure and can include the material structures as shown in  FIGS. 3   a  to  3   c  and the description set forth above for these structures. In a preferred form of the invention, the sidewall  80  has five layers. The structure is the same as that disclosed in  FIG. 3   c  but includes an additional layer outward from inside layer  70 . The inner layer is preferably a polyolefin and more preferably an ethylene and α-olefin copolymer. The relative thicknesses of the layers is fully set forth in U.S. Pat. No. 6,083,587 at column 5, line 64 through column 6, line 8. 
         [0058]    The receptacle  30  shall have the following physical properties: modulus of elasticity of the sidewall of the receptacle is less than 60,000 psi and more preferably less than 40,000 psi; is suitable of storing an oxygen sensitive composition for at least about 6 months, more preferably at least about 1 year, more preferably at least about 2 years and even more preferably at least about 3 years; is capable of achieving these storage periods at temperatures of about room temperature and more preferably from 5° C. to about 45° C. 
         [0059]    Turning our attention now to  FIG. 4  showing a port tube/closure assembly  40 . The assembly  40  preferably is constructed without the use of solvents or adhesives. The assembly  40  has one of the closure  54  described above formed into a disk shape and attached to the port tube end surface  58 . The closure can also be attached inside the port tube flow passage  56 . The closure  54  can be placed in contact with the end surface  58  of the port tube and attached thereto using conductive heat sealing, inductive heat sealing (such as using radio frequency energies), ultrasonic welding, vibration welding, or other techniques well known in the art. 
         [0060]    It should be understood that a port tube  52  having any of the constructions described above can be combined with a closure  54  having any of the constructions described above. Thus, an assembly of a port tube  52  having any number of layers and a closure  54  having two layers, three layers or more is contemplated by the present invention. It is also contemplated that a port tube  52  having two layers, three layers or more could be combined with a membrane film  54  having any number of layers. 
         [0061]    The spike holder  50  (which also may be referred to as a needle holder) is shown in  FIGS. 1   a , and  5 - 8 . The spike holder  50  has a body  100  having a first annular wall defining a first cavity or chamber  110  at a first end of the body, a second annular wall defining a second cavity or a second chamber  112  at a second end of the body, and a flow passage  114  connecting the first and second chambers. The first chamber  110  is dimensioned to telescopically receive an end portion  116  of the port tube  52 . In a preferred form of the invention the spike holder is fixedly attached to the port tube but could be releasably attached without departing from the scope of the present invention. It is contemplated by the present invention the annular wall could extend into the port tube flow passage  56  and attach thereto without departing from the present invention. The second chamber  112  is dimensioned to have an interference fit with an access spike or transfer needle  117  described below. As noted herein, the term interference fit means that the second chamber  112  has an identical or smaller dimension than the spike holders inserted therein but is capable of deforming (e.g., elastically) around the insert to hold the inserted device by friction. It is contemplated the second chamber  112  will fixedly attach to the insert or releasably attach to the insert. In a preferred form of the invention, the first chamber  110  and the second chamber  112  have a generally circular cross-sectional shape, the first chamber  110  having a first diameter and the second chamber  112  having a second diameter, the first diameter being larger than the second diameter. 
         [0062]    In a preferred form of the invention, the spike holder  50  has an outwardly extending flange  118  at an intermediate portion thereof. The flange  118  is positioned generally at the intersection of the first chamber  110  and the second chamber  112 . The flange  118  has a first surface  120  which is textured to facilitate handling and manipulation of the holder. In one embodiment, this texture is provided by a plurality of buttresses  122  around the first annular wall of the body  100 . In a preferred form of the invention, the flange  118  is generally circular in cross-sectional shape and the buttresses  122  are circumferentially spaced about the first surface  120 . The buttresses are shown having a generally tear-drop shape, however, they could be of numerous different shapes without departing from the present invention. The buttresses are provided to form a gripping surface for those handling the spike holder  50 . It may also be desirable to add an internal shoulder or other feature to the spike holder  50  to limit the extent the transfer tube can be inserted into the flow passage. 
         [0063]    The spike holder  50  is formed from a polyolefin as defined above and more particularly is an ethylene and α-olefin copolymer. The spike holder  50  can also have a textured or matte finish on a portion or the entire outer surface  124  of the holder  50  for ease of handling. The spike holder  50  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  50  can also include a membrane film  54 ′ positioned in the passageway  114  in lieu of or in addition to the membrane  54 . 
         [0064]    In a preferred form of the invention, the spike holder  50  is formed directly over the end portion  116  of the port tube/membrane film assemblies  40  described above. Such a process is conventional and 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  116  of the tubing  52  into the mold; and supplying polymeric material to the mold to form a spike holder on the tubing. 
         [0065]    In an embodiment of the invention, the tubing, closure, and/or container sidewalls are comprised of a multilayer polymeric structure which includes a first layer of an ethylene vinyl alcohol copolymer having first and second sides, and a second layer of a modified ethylene vinyl acetate copolymer attached to the first side of the first layer. The second layer has a thickness of greater than 1.2 mils, preferably at least 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mils. The polymeric structure optionally includes a third layer attached to the second side of the first layer. Preferably, the third layer comprises a polyamide or polyester as described herein. In one embodiment, the sidewalls of a container include a core layer, outside layer, or solution contact layer comprising a modified ethylene vinyl acetate copolymer as described herein. In another embodiment, the polymeric structure comprises an outside layer of a polyamide or polyester, a core layer of an ethylene vinyl alcohol copolymer, and a sealing layer of a modified ethylene vinyl acetate copolymer, wherein the core layer is between the outside and sealing layers. This polymeric structure optionally includes one or more tie layers attached to the core layer. 
         [0066]    The receptacles of the present invention are used to store deoxyhemoglobin solutions or other therapeutic fluids which react with oxygen. The receptacles are filled with the solution in a low oxygen or oxygen free environment, sealed, and then stored at about 5 to 45° C. for weeks or months prior to use. Conventional methods of filling and sealing containers in a low oxygen or oxygen free environment are suitable for the invention. After storage, the deoxyhemoglobin solution contains less than 15% methemoglobin and is physiologically acceptable for administration to a patient. In a preferred embodiment, the deoxyhemoglobin solutions are stored at room temperature and ambient conditions. 
         [0067]    The following is an example of the present invention and is not intended to limit the claims of the present invention. 
       EXAMPLE 
       [0068]    Several 250 ml volume receptacles were fabricated as shown in  FIG. 1   c  with a fill port and an administration port. Each receptacles had a total nominal surface area of approximately 450 cm 2 . The administration port had a core layer of an EVOH and an outside layer of a modified EVA (CXA) and a solution contact layer of a modified EVA (CXA). A membrane film was sealed to a distal end of the administration port. The membrane had an outer layer  134  of nylon 12, a third layer  130  of a modified ethylene vinyl acetate (CXA), a second layer  132  of EVOH, and an inner solution contact layer  128  of a modified ethylene vinyl acetate (CXA) (see  FIG. 9 ). The fill port was injection molded of ethylene vinyl acetate (EVA). The receptacle sidewalls were fabricated from a five-layer structure as shown in  FIG. 3   c . An outside layer  72  was nylon 12, two tie layers  76  were a modified EVA copolymer (CXA), a core layer  74  was an EVOH and the inner layer  70  was a metallocene catalyzed ultra low density polyethylene. The empty containers were sterilized by exposure to gamma radiation. The sterile containers were aseptically filled with an oxygen sensitive indicator solution through the fill port and the fill port was sealed and removed by a heated bar. The oxygen permeability of the containers were measured at 70% relative humidity at temperatures of 4° C., 23° C. and 40° C. and found to be 0.0008, 0.0041, and 0.0396 cc/day/package, respectively. 
         [0069]    It is understood that, given the above description of the embodiments of the invention, various modifications may be made by one skilled in the art. Such modifications are intended to be encompassed by the claims below.