Medical tubing and method of formation

Abstract

In one embodiment, a medical tubing (10) having a clear or transparent appearance adapted for in vivo transport of aqueous fluids to a subject and which is manually bendable, comprising an inner layer (3), a middle layer (2) and an outer layer (1), wherein the inner layer (3) comprises polypropylene, the outer layer (1) comprises a thermoplastic polyurethane or a cyclic olefin copolymer, and the middle layer (2) is selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

Description

[Technical field]

[0001] This invention relates to polymeric tubing for delivering medical fluids to a patient and to methods of forming such tubing having many layers of the same or different polymeric materials, each layer being subsequently bonded to one another, typically by a coextrusion process. [Background technology]

[0002]

[0002] Tubing constructed from polymeric materials is used in many industrial and commercial applications, including the medical field. A variety of FDA compliant plastic products are used depending on the desired properties and intended use. The choice of polymeric material can be a factor when the tubing is used to transport fluids for in vivo treatment of a human patient.

[0003]

[0003] Three-ply tubing has been used, with a polyethylene-based polymer as the innermost layer in contact with the medical fluid, and this innermost polyethylene layer is bonded to an outermost layer of polyurethane via a central or intermediate layer of adhesive as disclosed in U.S. Patent No. 10,646,704. While such tubing construction has several advantages, the polyethylene tubing layer in contact with typical aqueous medical treatment fluids can negatively interact with certain commonly useful medical fluids, such as aqueous compositions of insulin and other drugs.

[0004] Polyvinyl chloride (PVC) is one of the most widely used plastic products. Although structurally stable and easily formable into desired shapes, PVC is typically fabricated with plasticizers that can migrate out of the PVC matrix into bodily fluids and have other properties that make it less than ideally suited for medical treatment applications. Similarly, inherent attributes of plasticized PVC tubing result in the possibility that drugs and other components of aqueous fluids used in medical treatments can be absorbed into the sidewalls of the PVC tube. Polyurethane is a potential substitute for PVC. However, bi-layer tubing composed of polyurethane and polyethylene does not allow the two layers to remain adhered to each other under low to moderate stress, strain or mechanical operating conditions. U.S. Patent No. 4,627,844 to Schmitt, the disclosure of which is incorporated herein by reference as if set forth in its entirety, discloses a tri-layer tubing embodied in a commercial product sold under the trademark "SUREPATH 151" by the Natvar Division of Tekni-Plex, Inc. As disclosed in Schmitt, an outer layer of PVC and an inner, fluid-contacting layer of low density polyethylene (LDPE) are coextruded with an intermediate ethylene vinyl acetate copolymer (EVA) tie layer. However, while Schmitt's inner polyethylene layer may be inert or not interfere with some medical fluid components, polyethylene may adversely interact with other medical fluid components, such as many common fluid compositions that contain insulin. Summary of the Invention [Problem to be solved by the invention]

[0005] As mentioned above, tubing having a polyethylene lining may negatively interact with pharmaceutical ingredients over long periods of time.

[0006] According to the present invention, the selection of polypropylene as the inner layer polymeric material can prevent unwanted loss / absorption of pharmaceutical ingredients and protect the integrity of the formulation during normal use of the tubing to deliver aqueous fluids such as drug suspensions, chemotherapy drugs and insulin to or from human subjects.

[0006]

[0007] A two-ply tubing consisting of an inner polypropylene layer and an outer polyurethane layer does not allow the two layers to remain adhered to one another.

[0008] The present invention relates to an inner layer, an outer layer, and a middle intermediate layer that bonds the inner and outer layers together and prevents delamination of the multi-layer structure under moderate stress, strain or mechanical manipulation. [Means for solving the problem]

[0007]

[0009] Selection of an appropriate interlayer polymeric material prevents delamination of the multi-layer structure and protects the integrity of the tubing, the tubing and fitting bonds, and the delivered formulation.

[0010] The polymeric material of the intermediate layer is selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

[0008]

[0011] Thermoplastic polyurethane as an outer layer is beneficial for medical tubing where PVC is not desired due to the presence of plasticizers. TPU provides a secure bond to fittings during post tube manufacturing operations and assembly of medical devices. Alternatively, the TPU outer layer can be replaced with a cyclic olefin copolymer to provide the desired performance characteristics at a lower cost.

[0009]

[0012] In one embodiment of the present invention, there is provided a tube (10) adapted for in vivo transport of an aqueous fluid to a subject, comprising an inner layer (3), a middle layer (2) and an outer layer (1), formed by a coextrusion process, the inner layer (3), the middle layer (2) and the outer layer (1) being concentric, the inner layer (3) and the outer layer (1) being bonded to the middle layer (2) and to each other by being bonded to the middle layer (2); The inner layer (3) comprises polypropylene, The outer layer (1) comprises a thermoplastic polyurethane, The tube, wherein the middle layer (2) is selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

[0010]

[0013] In one embodiment of the invention, the intermediate layer (2) comprises an ethylene ethyl acrylate copolymer or an ethylene methyl acrylate copolymer or an anhydride grafted ethylene methyl acrylate copolymer, a copolymer of two or more of said acrylates or a mixture of two or more of the above.

[0011]

[0014] In one embodiment of the present invention, the intermediate layer (2) comprises ethylene vinyl acetate.

[0015] In one embodiment of the invention, the inner layer (3) comprises greater than 90% by weight of a polypropylene homopolymer or polypropylene copolymer, the outer layer (1) comprises greater than 90% by weight of an aromatic or aliphatic polyether-based polyurethane, and the middle layer (2) comprises greater than 90% by weight of one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

[0012]

[0016] In one embodiment of the present invention, the intermediate layer (2) comprises an ethylene ethyl acrylate copolymer with an ethyl acrylate content of at least 19.5 percent by weight.

[0017] In one embodiment of the present invention, the intermediate layer (2) comprises more than 90% by weight of ethylene methyl acrylate copolymer.

[0013]

[0018] In one embodiment of the present invention, the intermediate layer (2) comprises ethylene vinyl acetate with a vinyl acetate content of at least 19.5 percent by weight.

[0019] In one embodiment of the invention, the inner layer (3) comprises more than 90% by weight of a polypropylene homopolymer or polypropylene copolymer or a mixture of homopolymers and copolymers, and the outer layer (1) comprises more than 90% by weight of a polytetramethylene glycol-based polyurethane.

[0014]

[0020] In one embodiment of the invention, the outer polyurethane layer is 0.001 to 0.025 inches thick, the inner polypropylene layer is 0.001 to 0.025 inches thick, and the middle layer is 0.001 to 0.025 inches thick.

[0015]

[0021] In one embodiment of the invention, the inner layer (3) and the outer layer (1) do not visually delaminate from the middle layer (2) at a stress of 20 MPa or less and a strain of 400% or less.

[0022] In one embodiment of the present invention, the tube (10) does not visually delaminate when immersed in water at 60° C. for 72 hours.

[0016]

[0023] In one embodiment of the invention, the tube (10) has a central axial fluid flow passage, the central axial fluid flow passage being a path for passing an aqueous fluid, the inner layer (3) has a radially inward facing wall in contact with the aqueous fluid, the outer (1) and inner (3) layers resist delamination from the middle layer (2) at a stress of not more than 20 MPa and a strain of not more than 400%, and the tube (10) does not visibly delaminate after being immersed in water at 60° C. for 72 hours.

[0017]

[0024] In one embodiment of the invention, the inner layer (3) and the outer layer (1) do not visually delaminate from the middle layer (2) at a stress of 20 MPa or less and a strain of 400% or less, and the tube (10) does not visually delaminate after being immersed in water at 60° C. for 72 hours.

[0018]

[0025] In one embodiment of the present invention, the outer layer (1) comprises more than 90% by weight of aromatic polyether-based polyurethane, and the tube does not visually delaminate after being immersed in water at 60° C. for 72 hours.

[0019]

[0026] In one embodiment of the present invention, there is provided a method of delivering an aqueous fluid in vivo, comprising: selecting one or more aqueous compositions effective for treating a condition of a subject, the aqueous composition being selected from the group of an aqueous pharmaceutical suspension, an aqueous composition comprising a chemotherapeutic drug, and an aqueous composition comprising insulin; delivering one or more selected aqueous compositions to a subject via a tube by flow through the tube; A method comprising:

[0020]

[0027] In one embodiment of the present invention, there is provided a method for forming a medical tube for in vivo delivery of aqueous fluids that is clear or transparent in appearance and manually bendable, comprising the steps of: selecting a first polymeric material that is an aromatic or aliphatic polyether-based polyurethane material having a particular structural stability; selecting a second polymeric material that is a polypropylene material that is inert to aqueous fluids; selecting a third polymeric material having elastomeric properties, having visual clarity, and selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene; co-extruding the selected first, second and third polymeric materials to form respectively bonded outer, inner and intermediate layers of the medical tubing, the outer layer comprising at least 90% by weight of the first polymeric material, the inner layer comprising at least 90% by weight of the second polymeric material, and the intermediate layer comprising at least 90% by weight of the third polymeric material; Including, the material is selected to maintain the integrity of the tube against delamination and to maintain its clear or transparent appearance after being subjected to one or more of ethylene oxide and gamma radiation sterilization; A method in which a medical tubing has a central axial fluid flow passage defined by a radially inwardly facing wall surface of an inner layer, the central axial fluid flow passage transporting an aqueous fluid, and the tubing does not visibly delaminate after being immersed in water at 60°C for 72 hours and subsequently mechanically flattened by manually crushing from a normally round cross-sectional state to a crushed or oval cross-sectional shape or state.

[0021]

[0028] In one embodiment of the present invention, there is provided a tube (10) adapted for in vivo transport of an aqueous fluid to a subject, comprising an inner layer (3), a middle layer (2) and an outer layer (1), formed by a coextrusion process, the inner layer (3), the middle layer (2) and the outer layer (1) being concentric, the inner layer (3) and the outer layer (1) being bonded to the middle layer (2) and to each other by being bonded to the middle layer (2); The inner layer (3) comprises polypropylene, The outer layer (1) comprises a cyclic olefin copolymer; The tube, wherein the middle layer (2) is selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

[0022]

[0029] In one embodiment of the invention, the inner layer (3) comprises greater than 90% by weight of a polypropylene homopolymer or polypropylene copolymer, the outer layer (1) comprises greater than 90% by weight of a cyclic olefin copolymer, and the middle layer (2) comprises greater than 90% by weight of one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

[0023]

[0030] In one embodiment of the invention, the inner layer (3) and the outer layer (1) do not visually delaminate from the middle layer (2) at a stress of 20 MPa or less and a strain of 400% or less, and the tube (10) does not visually delaminate after being immersed in water at 60° C. for 72 hours.

[0024]

[0031] In one embodiment of the invention, there is provided a method of delivering an aqueous fluid in vivo, comprising: selecting one or more aqueous compositions effective for treating a condition of a subject, the aqueous composition being selected from the group of an aqueous pharmaceutical suspension, an aqueous composition comprising a chemotherapeutic drug, and an aqueous composition comprising insulin; delivering one or more selected aqueous compositions through the tube to the subject via flow through the tube; A method comprising:

[0025]

[0032] In one embodiment of the present invention, there is provided a method for forming a medical tube for in vivo delivery of aqueous fluids that is clear or transparent in appearance and manually bendable, comprising the steps of: selecting a first polymeric material that is an aromatic or aliphatic polyether-based polyurethane material having a particular structural stability; selecting a second polymeric material that is a polypropylene material that is inert to aqueous fluids; selecting a third polymeric material having elastomeric properties, having visual clarity, and comprising an acrylate copolymer selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene; co-extruding the selected first, second and third polymeric materials to form respectively bonded outer, inner and intermediate layers of the medical tubing, the outer layer comprising at least 90% by weight of the first polymeric material, the inner layer comprising at least 90% by weight of the second polymeric material, and the intermediate layer comprising at least 90% by weight of the third polymeric material; Including, the material is selected to maintain the integrity of the tube against delamination and to maintain its clear or transparent appearance after being subjected to one or more of ethylene oxide and gamma radiation sterilization; A method in which a medical tubing has a central axial fluid flow passage defined by a radially inwardly facing wall surface of an inner layer, the central axial fluid flow passage transporting an aqueous fluid, and the tubing does not visibly delaminate after being immersed in water at 60°C for 72 hours and subsequently mechanically flattened by manually crushing from a normally round cross-sectional state to a crushed or oval cross-sectional shape or state.

[0026]

[0033] The drawings depict one or more embodiments of the invention, illustrated by way of example of the invention. [Brief description of the drawings]

[0027] [Figure 1]

[0034] FIG. 1 is a schematic perspective view of a three-layer tube showing the outer and middle layers broken away to better illustrate the construction and arrangement of the tubing; [Diagram 2]

[0035] FIG. 2 is a cross-sectional view of the tube 10 shown in FIG. 1 taken along line 2-2. [Diagram 3]

[0036] 3 is a photograph of a cross section of a tube having an inner layer, a middle layer and an outer layer that was subjected to a tensile test using a Lloyd tensile tester. The three layer tube was subjected to high tensile pulling or stretching of the tube to determine if one layer would pull past another layer under the applied high tension, thus indicating the relative degree of adhesion of the middle layer to the inner and outer layers. [Figure 4]

[0037] FIG. 4 is a matrix or chart showing the layer thicknesses and compositions of one example of 3M3L tubing with an EMAC intermediate layer according to the present invention (SR#2597), a comparative 2M2L example (SR#2604), and two further examples of 3M3L tubing with an EVA intermediate layer according to the present invention (SR#2605 and SR#2606). [Diagram 5]

[0038] FIG. 5 is a side view photograph of two sample tubes, 3M3L SR#2597 according to the invention on the left, and comparative 2M2L on the right, visually illustrating layer separation, measured under a microscope (L in 0.0254 mm=1 mil (n=5)) for each tube that was pinched and rotated 10 times and then aged for 3 days in distilled water at 60 degrees Celsius, where the inventive sample on the left had an L value of 4.350 mils, whereas the comparative tube on the right had a much larger L value of 51.656 mils (only larger layer separation for the 2M2L tube). [Figure 6]

[0039] FIG. 6 is a matrix or chart showing side microscope measurements (L, in units of 0.0254 mm=1 mil) similar to FIG. 4, listing five samples for each of SR#2597 (invention, 3M3L, with EMAC interlayer), SR#2604 (2M2L, comparative), and SR#2605 and SR#2606 (invention, 3M3L, with EVA interlayer) and listing the average L value for each group of five samples, again showing that the 3M3L samples had much lower layer separation L values ​​versus the 2M2L samples. [Figure 7]

[0040] FIG. 7 is a 200X microscopic cross-section of two sample tubes, 3M3L SR#2597 according to the invention on the left, and comparative 2M2L SR#2604 on the right, visually illustrating the layer separation along with a visual assessment rating (1-5 rating) for each tube that was clamped and rotated 10 times and then aged for 3 days in distilled water at 60 degrees Celsius, where the inventive sample on the left had a rating of 2.5 and the comparative tube on the right had a much higher rating value of 4.75 (lower values ​​are desirable). [Figure 8]

[0041] FIG. 8 is a matrix or chart showing the cross-sectional visual evaluation ratings as in FIG. 6, listing five samples for each of SR#2597 (invention, 3M3L, with EMAC interlayer), SR#2604 (2M2L, comparative), and SR#2605 and SR#2606 (invention, 3M3L, with EVA interlayer) and giving the average rating value for each group of five samples, again showing that the 3M3L samples had much lower layer separation L values ​​versus the 2M2L samples. [Figure 9]

[0042] FIG. 9 is a graph showing tensile curves for one 2M2L (SR#2604) and various 3M3L tubes each with a different intermediate layer (EMAC SR#2597, EVA SR#2605 and EVA SR#2606) set up for delivery of insulin, where stress (psi) is the vertical axis and strain (%) is the horizontal axis, where the 3M3L tubes all showed much less layer separation (also known as sleeving) than the 2M2L samples. [Figure 10]

[0043] FIG. 10 is a matrix or chart showing the various tensile properties for the various tubes shown in FIG. 8, namely, 2M2L (SR#2604) and 3M3L tubes with different intermediate layers (EMAC SR#2597, EVA SR#2605 and EVA SR#2606) in the 3M3L tubes, all of which showed much better tensile properties and less layer separation (also called sleeving) than the 2M2L samples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028]

[0044] 1 shows one embodiment of a coextruded tri-layer tubing 10 according to the present invention that includes an outer layer 1 comprised of at least about 90% by weight of a polyurethane material, typically a polytetramethylene glycol-based polyurethane, one example of which is Lubrizol TPU Pellethane 2363-90AE. The outer layer could alternatively include a cyclic olefin copolymer material, such as Topas E-140.

[0029]

[0045] As shown in Figure 1, the tube typically includes an inner fluid contacting layer 3 comprised of at least about 90% by weight of a polypropylene material such as Ineos R01C, and an intermediate tie layer 2 comprised of at least about 90% by weight of an ethylene ethyl acrylate copolymer, an ethylene methyl acrylate copolymer, an anhydride grafted ethylene methyl acrylate copolymer, a copolymer of two or more of the foregoing acrylates, or a mixture of two or more of these acrylate-based compounds or compositions. One example of a suitable ethylene ethyl acrylate copolymer is Dow Amplify EA 103 (ethylene ethyl acrylate is about 19.5% by weight). Examples of suitable ethylene methyl acrylate copolymers are Westlake MA SP2268 (ethylene methyl acrylate is about 24% by weight), Westlake MA SP2220 (ethylene methyl acrylate is about 20% by weight). One example of a suitable anhydride grafted ethylene methyl acrylate copolymer is Westlake Tymax GA 7001 (anhydride grafted ethylene methyl acrylate).The intermediate layer may alternatively comprise an ethylene-vinyl acetate copolymer.

[0030]

[0046] As shown in Figure 1, outer layer 1 has a radially inwardly facing surface S1 that bonds and adheres to a radially outwardly facing surface S2 of middle layer 2. Similarly, inner layer 3 has a radially outwardly facing surface S4 that bonds and adheres to a radially inwardly facing surface S3 of middle layer 2. Middle layer 2 adheres to outer layer 1 and inner layer 3, such that layers 1 and 3 remain adhered to layer 2 and to each other when tube 10 is subjected to a stress of about 20 MPa or less and a strain of about 400% or less, where the break point of tube 10 is about 17-22 MPa and about 300-450%, as measured by pulling a length of tubing 10 along its axis A having an axial length L of about 2 inches using a Lloyd LR5K Plus mechanical testing machine at a pull rate of about 12 inches / minute at ambient environmental conditions of about 72°F and about 50% relative humidity. The layers 1, 2, 3 of such tubing 10 do not visibly delaminate after being subjected to immersion in water at 60° C. for 36 or 72 hours, followed by being mechanically flattened by manually crushing from a normally round cross-sectional state to a crushed or oval cross-sectional shape or state.

[0031]

[0047] 1 and 2, layers 1, 2, 3 are formed into a structurally stable wall that surrounds and encloses a central hollow channel 20 through which aqueous solution flows in the axial direction A while contacting the radially inward surface S5 of inner layer 3. Middle layer 2 bonds to inner layer 3 and outer layer 1, holding them together.

[0032]

[0048] Inner layer 3 provides a radially inward fluid contacting surface S5 and typically has a cross-sectional thickness T1 ranging from about 0.001 inch to about 0.025 inch. Middle layer 2 typically has a cross-sectional thickness T2 ranging from about 0.001 inch to about 0.025 inch. Outer layer 1 typically has a cross-sectional thickness T3 ranging from about 0.001 inch to about 0.025 inch.

[0033]

[0049] The polypropylene material is preferably a homopolymer or copolymer of propene and ethene or a mixture thereof. An exemplary polypropylene material is Ineos R01C.

[0034]

[0050] Polyurethane elastomers (TPUs) are typically the reaction product of polyols and isocyanates and usually contain a combination of hard and soft segment domains. Aromatic polyether-based TPUs or aliphatic polyether-based TPUs, such as polytetramethylene glycol-based polyurethanes, can be used. Preferred TPUs include the Pellethane 2363-80AE series available from Lubrizol Corporation, such as Lubrizol TPU Pellethane 2363-90AE and BASF 1190A.

[0035]

[0051] The respective thicknesses of each layer of tubing 10 can be controlled by the extrusion equipment utilized, such as the "Tri Die" extrusion equipment manufactured by Genca Division of General Cable Company, Clearwater, Fla. The extrusion equipment is selected to provide uniform thicknesses of layers 1, 2, 3 along substantially the entire axial length L of all three layers 1, 2, 3.

[0036]

[0052] The polymeric material from which layers 1, 2, 3 are constructed is selected to be clear or transparent in appearance and to be manually bent along and about the tubing's axis A. The polymeric material is also selected to maintain the integrity of the tubing 10 (i.e., no delamination) and its transparency or clarity after being subjected to ethylene oxide (EtO) and gamma radiation sterilization processes.

[0037]

[0053] FIG. 3 is a photograph of a cross section of a tube having a polypropylene inner layer, an EMAC middle layer, and one of TPU or COC on the outer layer. The photograph of the tube on the left has an outer layer of polyurethane material, an EMAC middle layer, and an inner layer of polypropylene material. As can be seen from the cross section of the tube subjected to high tension pulling with the Lloyd instrument, the three layers remain substantially adhered to each other. As further shown in FIG. 3, the tube on the right has the same polypropylene inner layer material and the same EMAC middle layer material, but has an outer layer composed of a cyclic olefin copolymer (COC) material. As shown, the three layers of this tube remain substantially adhered to each other as the tube on the left.

[0038]

[0054] Further testing of various embodiments of the invention is described below and illustrated in Figures 4-10. Various materials and layer structures were used for two-material, two-layer (2M2L) tubes of samples according to the invention and comparative samples versus three-material, three-layer (3M3L) tubes as described below: material: ·PP Flint Hills 23R2 EMAC EMAC SP2268 EVA Celanese 2604A EVA Celanese 2803A TPU Texin RXT90A sample: SR2604 (2M2L) comparison PP Flint Hills 23R2 TPU Texin RXT90A SR2597(3M3L) PP Flint Hills 23R2 EMAC SP2268 TPU Texin RXT90A SR2605(3M3L) PP Flint Hills 23R2 EVA Celanese 2604A TPU Texin RXT90A SR2606(3M3L) PP Flint Hills 23R2 EVA Celanese 2803A TPU Texin RXT90A

[0055] FIG. 4 is a matrix or chart showing the layer thicknesses and compositions of one example of 3M3L tubing with an EMAC intermediate layer in accordance with the present invention (SR #2597), a comparative 2M2L example (SR #2604), and two additional examples of 3M3L tubing with an EVA intermediate layer in accordance with the present invention (SR #2605 and SR #2606).

[0039]

[0056] FIG. 5 is a side view photograph of two sample tubes, 3M3L SR#2597 according to the invention on the left, and comparative 2M2L on the right, visually showing the layer separation measured under a microscope (L, in units of 0.0254 mm=1 mil (n=5)) for each tube that was clamped and rotated 10 times and then aged for 3 days in distilled water at 60 degrees Celsius, where the inventive sample on the left had an L value of 4.350 mils, while the comparative tube on the right had a much larger L value of 51.656 mils (significantly larger layer separation for the 2M2L tube).

[0040]

[0057] FIG. 6 is a matrix or chart showing side view microscope measurements (L, in units of 0.0254 mm=1 mil) similar to FIG. 4, listing five samples for each of SR#2597 (invention, 3M3L, with EMAC interlayer), SR#2604 (2M2L, comparative), and SR#2605 and SR#2606 (invention, 3M3L, with EVA interlayer) and listing the average L value of the five samples for each group, again showing that the 3M3L samples have much lower layer separation L values ​​than the 2M2L samples.

[0041]

[0058] FIG. 7 is a 200X microscopic cross-section of two sample tubes, 3M3L SR#2597 according to the invention on the left, and comparative 2M2L SR#2604 on the right, visually illustrating the layer separation along with a visual assessment rating (1-5 rating) for each tube that was clamped and rotated 10 times and then aged in distilled water at 60 degrees Celsius for three days, with the inventive sample on the left having a rating of 2.5 and the comparative tube on the right having a much higher rating value of 4.75 (lower values ​​are desirable).

[0042]

[0059] FIG. 8 is a matrix or chart showing cross-sectional visual evaluation ratings similar to FIG. 6, listing five samples for each of SR#2597 (invention, 3M3L, with EMAC interlayer), SR#2604 (2M2L, comparative), and SR#2605 and SR#2606 (invention, 3M3L, with EVA interlayer) and the average rating value for each group of five samples, again showing that the 3M3L samples have much lower layer separation L values ​​than the 2M2L samples.

[0043]

[0060] FIG. 9 is a graph showing tensile curves for one 2M2L (SR#2604) and various 3M3L tubes (EMAC SR#2597, EVA SR#2605 and EVA SR#2606) each with a different middle layer, the tubes were set up for delivery of insulin, stress (psi) is the vertical axis and strain (%) is the horizontal axis, the 3M3L tubes all showed much less layer separation (also known as sleeving) than the 2M2L samples.

[0044]

[0061] FIG. 10 is a matrix or chart showing the various tensile properties for the various tubes shown in FIG. 8, namely 2M2L (SR#2604) and 3M3L tubes with different intermediate layers within the 3M3L tubes (EMAC SR#2597, EVA SR#2605 and EVA SR#2606), with the 3M3L tubes all exhibiting much better tensile properties and less layer separation (also known as sleeving) than the 2M2L samples.

[0045]

[0062] In various embodiments, the intermediate layer typically serves as a barrier to migration of mobile components between or from the layers and the central channel, where mobile components include monomers, short chain polymers, ions, water, small organic molecules, metals, plasticizers, and catalysts.

[0046]

[0063] In various embodiments, layers of polymeric material are coextruded together to form a tubing such that the outer and inner layers are adhered to an intermediate layer and are adhered to one another by being adhered to the intermediate layer. The tubing is formed with a central hollow channel, hole or passageway radially surrounded and defined by the polymeric layers which act as the walls of the tubing.

[0047]

[0064] 1 and 2, preferably outer layer 1 has a thickness T3 of about 0.001" to about 0.025"; inner layer 3 has a thickness T1 of about 0.001" to about 0.025"; and middle layer 2 has a thickness T2 of about 0.001" to about 0.025"). Layers 1, 2, and 3 together form a tubular wall surrounding and defining a central fluid flow passage 20.

[0048]

[0065] The polymeric material is preferably "contaminant free", i.e., does not contain more than an insignificant amount of potentially undesirable substances (typically less than about out 0.5% by weight, preferably less than about 0.2%), and / or prevents unwanted substances, such as plasticizers, catalysts, monomers, metals, salts, ions, or other potentially undesirable substances to humans, from leaching or leaking into aqueous solutions or media with which one or other of the three layers may come into contact during normal use of the tubing to deliver aqueous fluids, such as insulin, chemotherapy drugs, and other potentially unstable aqueous pharmaceutical suspensions, to or from human subjects. In addition to acting as an adhesive between and adhering to the outer and inner layers, the intermediate layer prevents delamination of the outer and inner layers from the intermediate layer under conditions of relatively low to moderate stress or strain. Additionally, the intermediate layer functions as a barrier against leaching or leaking of contaminants from the outer layer into the inner layer, or through the inner layer into the hollow central hole or passageway of the tube.

[0049]

[0066] The polypropylene material typically includes one or more of a polypropylene homopolymer and a polypropylene copolymer.

[0067] Ethylene vinyl acetate (EVA), ethylene ethyl acrylate copolymer (EEA), ethylene methyl acrylate (EMA) copolymer and anhydride grated ethylene methyl acrylate (AEMA) copolymer have elastomeric properties and have excellent visual clarity. In a typical 3M3L coextrusion process, TPU, EVA, EEA or EMA or AEMA and PP are melt extruded through a die head to form a tubular shaped extrudate, which is then cooled through a conventional water bath or water vacuum tank, and then wound up or cut into specific lengths for use. The level of elasticity and softness of EVA, EEA, EMA AEMA or their copolymers is controlled by the amount of vinyl acetate, ethyl acrylate or methyl acrylate comonomer utilized with ethylene in the copolymerization process. Tri-layer tubes produced by such coextrusion processes behave monolithically in that they return to near their original shape and dimensions after being pulled or stretched in tension along the longitudinal axis of the tube at stresses of up to about 20 MPa and strains of up to about 400%, and are free of any visible delamination between any of the layers after being immersed in water at about 60° C. for about 36 hours.

[0050]

[0068] Cyclic olefin copolymers are typically: Chain copolymerization of cyclic monomers with ethene, or Ring-opening metathesis polymerization of cyclic monomers followed by hydrogenation Produced by.

[0051]

[0069] Cyclic olefin copolymers are: Chain copolymerization of cyclic monomers consisting of one or more of 8,9,10-trinorborn-2-ene and 1,2,3,4,4a,5,8,8a-octahydro-1,4:5,8-dimethanonaphthalene with ethene, or Ring-opening metathesis polymerization of cyclic monomers followed by hydrogenation It can be produced by

[0052]

[0070] The foregoing description is illustrative and is not intended to limit the scope of the present invention; those skilled in the art will appreciate that equivalents thereof are contemplated by the above description, and that changes and modifications may be made without departing from the present invention, and all such equivalents, changes and modifications are intended to fall within the scope of the following claims.

Claims

1. A tube (10) adapted for in vivo delivery of an aqueous fluid to a subject, comprising an inner layer (3), a middle layer (2) and an outer layer (1), It is formed by a co-extrusion process, the inner layer (3), the middle layer (2) and the outer layer (1) being concentric, the inner layer (3) and the outer layer (1) being bonded to the middle layer (2) and to each other by being bonded to the middle layer (2); The inner layer (3) comprises polypropylene, The outer layer (1) comprises a thermoplastic polyurethane, and The tube, wherein the middle layer (2) is selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

2. 2. The tube of claim 1, wherein the intermediate layer (2) comprises an ethylene ethyl acrylate copolymer or an ethylene methyl acrylate copolymer or an anhydride grafted ethylene methyl acrylate copolymer, copolymers of two or more of said acrylates or a mixture of two or more thereof.

3. 2. The tube of claim 1, wherein the intermediate layer (2) comprises ethylene vinyl acetate.

4. 2. The tube (10) of claim 1, wherein the inner layer (3) comprises more than 90% by weight of a polypropylene homopolymer or polypropylene copolymer, the outer layer (1) comprises more than 90% by weight of an aromatic or aliphatic polyether-based polyurethane, and the middle layer (2) comprises more than 90% by weight of one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylic acid terpolymer, and maleic anhydride grafted polypropylene.

5. 5. The tubing of claim 4, wherein the intermediate layer (2) comprises an ethylene ethyl acrylate copolymer having an ethyl acrylate content of at least 19.5 weight percent.

6. 5. The tube of claim 4, wherein the intermediate layer (2) comprises more than 90% by weight of ethylene methyl acrylate copolymer.

7. 5. The tubing of claim 4, wherein the intermediate layer (2) comprises ethylene vinyl acetate having a vinyl acetate content of at least 19.5 weight percent.

8. 2. The tube of claim 1, wherein the inner layer (3) comprises more than 90% by weight of a polypropylene homopolymer or a polypropylene copolymer or a mixture of said polypropylene homopolymers and copolymers, and the outer layer (1) comprises more than 90% by weight of a polytetramethylene glycol-based polyurethane.

9. 10. The tubing of claim 1, wherein the outer polyurethane layer is 0.001-0.025 inch thick, the inner polypropylene layer is 0.001-0.025 inch thick, and the middle layer is 0.001-0.025 inch thick.

10. 2. The tube of claim 1, wherein the inner layer (3) and the outer layer (1) do not visually delaminate from the intermediate layer (2) at a stress of up to 20 MPa and a strain of up to 400%.

11. 10. The tubing of claim 1 which does not visually delaminate when immersed in water at 60°C for 72 hours.

12. 10. The tube of claim 1, wherein the tube (10) has a central axial fluid flow passage, the central axial fluid flow passage being a path for passing an aqueous fluid, the inner layer (3) having a radially inward facing wall in contact with the aqueous fluid, the outer layer (1) and the inner layer (3) resist delamination from the intermediate layer (2) at a stress of 20 MPa or less and a strain of 400% or less, and the tube (10) does not visibly delaminate after being immersed in water at 60°C for 72 hours.

13. 2. The tube of claim 1, wherein the inner layer (3) and the outer layer (1) do not visually delaminate from the middle layer (2) at a stress of 20 MPa or less and a strain of 400% or less, and do not visually delaminate after immersion in water at 60° C. for 72 hours.

14. 2. The tube of claim 1, wherein the outer layer (1) comprises more than 90% by weight of aromatic polyether-based polyurethane and does not visually delaminate after immersion in water at 60°C for 72 hours.

15. 1. A method of delivering an aqueous fluid in vivo, comprising: selecting one or more aqueous compositions effective for treating a condition of a subject, the aqueous composition being selected from the group of an aqueous pharmaceutical suspension, an aqueous composition comprising a chemotherapeutic drug, and an aqueous composition comprising insulin; Delivering one or more selected aqueous compositions through a tube to a subject via flow through the tube of claim 1; A method comprising:

16. 1. A method of forming a medical tube having a clear or transparent appearance and which is manually bendable for in vivo delivery of aqueous fluids, comprising: selecting a first polymeric material that is an aromatic or aliphatic polyether-based polyurethane material having a particular structural stability; selecting a second polymeric material that is a polypropylene material that is inert to aqueous fluids; selecting a third polymeric material having elastomeric properties, a clear appearance, and selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene; co-extruding the selected first, second and third polymeric materials to form respectively bonded outer, inner and intermediate layers of the medical tubing, the outer layer comprising at least 90% by weight of the first polymeric material, the inner layer comprising at least 90% by weight of the second polymeric material, and the intermediate layer comprising at least 90% by weight of the third polymeric material; Including, the material is selected to maintain the integrity of the tube against delamination and maintain a clear or transparent appearance after being subjected to one or more of ethylene oxide and gamma radiation sterilization; A method in which a medical tubing has a central axial fluid flow passage defined by a radially inward wall surface of an inner layer, the central axial fluid flow passage transporting an aqueous fluid, and the tubing does not visibly delaminate after being immersed in water at 60°C for 72 hours and subsequently mechanically flattened by manually crushing from a normally round cross-sectional state to a crushed or oval cross-sectional shape or state.

17. A tube (10) adapted for in vivo delivery of an aqueous fluid to a subject, comprising an inner layer (3), a middle layer (2) and an outer layer (1), The tube is formed by a co-extrusion process, the inner layer (3), the middle layer (2) and the outer layer (1) being concentric, the inner layer (3) and the outer layer (1) being bonded to the middle layer (2) and to each other by being bonded to the middle layer (2); The inner layer (3) comprises polypropylene, The outer layer (1) comprises a cyclic olefin copolymer, The tube (10), wherein the middle layer (2) is selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene.

18. 18. The tube (10) of claim 17, wherein the inner layer (3) comprises more than 90% by weight of a polypropylene homopolymer or polypropylene copolymer, the outer layer (1) comprises more than 90% by weight of a cyclic olefin copolymer, and the intermediate layer (2) comprises more than 90% by weight of one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylic acid terpolymer, and maleic anhydride grafted polypropylene.

19. 18. The tube of claim 17, wherein the inner layer (3) and the outer layer (1) do not visually delaminate from the middle layer (2) at a stress of 20 MPa or less and a strain of 400% or less, and do not visually delaminate after immersion in water at 60° C. for 72 hours.

20. 1. A method of delivering an aqueous fluid in vivo, comprising: selecting one or more aqueous compositions effective for treating a condition of a subject, the aqueous composition being selected from the group of an aqueous pharmaceutical suspension, an aqueous composition comprising a chemotherapeutic drug, and an aqueous composition comprising insulin; Delivering one or more selected aqueous compositions through a tube to a subject via flow through the tube of claim 17. and

21. 1. A method of forming a medical tube having a clear or transparent appearance and which is manually bendable for in vivo delivery of aqueous fluids, comprising: selecting a first polymeric material that is an aromatic or aliphatic polyether-based polyurethane material having a particular structural stability; selecting a second polymeric material that is a polypropylene material that is inert to aqueous fluids; selecting a third polymeric material having elastomeric properties, a clear appearance, and comprising an acrylate copolymer selected from one or more of ethylene vinyl acetate copolymer, ethylene acrylate copolymer, ethylene-acrylate maleic anhydride terpolymer, ethylene-acrylate glycidyl methacrylate terpolymer, and maleic anhydride grafted polypropylene; co-extruding the selected first, second and third polymeric materials to form respectively bonded outer, inner and intermediate layers of the medical tubing, the outer layer comprising at least 90% by weight of the first polymeric material, the inner layer comprising at least 90% by weight of the second polymeric material, and the intermediate layer comprising at least 90% by weight of the third polymeric material; Including, the material is selected to maintain the integrity of the tube against delamination and maintain its clear or transparent appearance after being subjected to one or more of ethylene oxide and gamma radiation sterilization; A method in which a medical tubing has a central axial fluid flow passage defined by a radially inward wall surface of an inner layer, the central axial fluid flow passage transporting an aqueous fluid, and the tubing does not visibly delaminate after being immersed in water at 60°C for 72 hours and subsequently mechanically flattened by manually crushing from a normally round cross-sectional state to a crushed or oval cross-sectional shape or state.

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