Multi-layer composite flexible membrane material for biopharmaceutical process bag and preparation method of multi-layer composite flexible membrane material

Abstract

The invention relates to the technical field of composite materials, in particular to a multi-layer composite flexible film material for a biopharmaceutical process bag and a preparation method thereof.The multi-layer composite flexible film material comprises an outermost layer, a first bonding layer, a first anti-impact layer, a blocking layer, a second anti-impact layer, a second bonding layer and an innermost layer, and the outermost layer has better impact strength, tensile property and optical transparency; the barrier layer has a shape memory effect, the first bonding layer and the second bonding layer realize the stability of a film co-extrusion multi-layer structure, and the first impact-resistant layer and the second impact-resistant layer enhance the impact resistance of the film, play roles in dispersing and buffering impact, reduce the chance that crazing develops into cracks due to stress, and solve the problems that a flexible soft film material is poor in impact resistance and poor in impact resistance. And the problem is solved.

Description

Technical Field

[0001] The invention relates to the technical field of composite materials, and in particular to a multi-layer composite flexible film material for a biopharmaceutical process bag and a preparation method thereof. Background Art

[0002] With the development of medical materials, drug containers made of plastics acceptable for drug packaging have been increasingly used in medical liquid storage bags. Plastic soft bag containers have extremely strict requirements on film materials, requiring high flexibility, mechanical strength and welding properties. Therefore, the development and application of container materials has become an important part of the development of the biotechnology field.

[0003] Disposable biopharmaceutical process liquid storage and reaction containers are disposable, ready-to-use containers. Small-capacity containers are generally made of rigid plastic tanks, while large-capacity disposable biopharmaceutical process liquid storage and reaction containers are generally made of flexible plastic bags made of film materials placed on a support device.

[0004] Disposable bioprocess liquid storage and reaction container membranes are usually made of polyethylene, ethylene vinyl acetate, polycarbonate, polystyrene, etc. However, flexible soft film materials usually choose to use non-PVC polyolefin materials. There are two types of commonly used polyolefin multilayer co-extrusion films: the first type is that the inner layer and the middle layer are mixed with polypropylene and elastic materials in different proportions. They are non-toxic, inert and have good heat sealing properties, and the outer layer is polypropylene or polyester materials with high mechanical strength; the second type is that the inner layer is a mixed material of polypropylene and styrene-ethylene-butylene-styrene (SEBS) copolymer, the middle layer is SEBS, and the outer layer is polypropylene. In addition to polypropylene materials, polyethylene materials also have advantages in biosafety and chemical stability, so they are also used in the production of non-PVC flexible packaging bags.

[0005] However, in the existing disclosed patent technologies and products, the flexible soft film materials have poor impact resistance and are easily damaged by pulling. Summary of the invention

[0006] The purpose of the present invention is to provide a multi-layer composite flexible film material for biopharmaceutical process bags and a preparation method thereof, aiming to solve the problem that the flexible soft film material has poor impact resistance and is easily damaged by pulling.

[0007] To achieve the above-mentioned objectives, in a first aspect, the present invention provides a multi-layer composite flexible film material for a biopharmaceutical process bag, comprising an outermost layer, a first adhesive layer, a first impact-resistant layer, a barrier layer, a second impact-resistant layer, a second adhesive layer and an innermost layer, wherein the first adhesive layer is arranged on one side of the outermost layer, the first impact-resistant layer is arranged on a side of the first adhesive layer away from the outermost layer, the barrier layer is arranged on a side of the first impact-resistant layer away from the first adhesive layer, the second adhesive layer is arranged on a side of the barrier layer away from the first impact-resistant layer, the second impact-resistant layer is arranged on a side of the second adhesive layer away from the barrier layer, and the innermost layer is arranged on a side of the second impact-resistant layer away from the second adhesive layer.

[0008] The outermost layer is made by blending metallocene linear polyethylene and low-density polyethylene, and the density of the metallocene polyethylene is 0.850-0.950 g / cm 3 The density of the low-density polyethylene is 0.910-0.925 g / cm 3 The blending mass percentage of the metallocene polyethylene and the low-density polyethylene is: 20%:80%-40%:60%, preferably 25%:75%, and is frosted or atomized, with a melting point of 110-140°C, preferably 120-130°C.

[0009] The first adhesive layer and the second adhesive layer are any one of anhydride-modified ethylene-vinyl acetate copolymer, anhydride-modified polyethylene polymer and anhydride-modified polypropylene polymer, the barrier layer is polylactic acid / ethylene-vinyl alcohol copolymer, the polylactic acid, ethylene-vinyl alcohol copolymer and stannous octoate of the barrier layer are in a mass ratio of 25:75:1, and the relative molecular weight of polylactic acid is 2.0×10 5 -4.0×10 5 , preferably 2.5×10 5 The ethylene content of the ethylene-vinyl alcohol copolymer is 35%-50%, preferably 45%. The innermost layer is an ultra-low density polyethylene film with a melting point between 90-125°C, preferably between 100-121°C, a density of 0.912g / cm3, a Vicat softening point of 105°C, and a welding sealing temperature of 101°C.

[0010] The first impact-resistant layer and the second impact-resistant layer are made by blending a polyolefin thermoplastic elastomer copolymer and polypropylene, wherein the polyolefin thermoplastic elastomer copolymer has an octene content greater than 20% and a density of 0.86-0.89 g / cm 3 The blending mass ratio of the polyolefin thermoplastic elastomer copolymer and the polypropylene is 10%:90%-25%:75%, preferably 15%:85%.

[0011] In a second aspect, the present invention also provides a method for preparing a multi-layer composite flexible film material for a biopharmaceutical process bag, comprising the following steps:

[0012] Seven extruders extrude molten plastic into seven film materials, and respectively transport the seven film materials to a compound die head;

[0013] The composite head shaping part combines the seven membrane materials to form a multi-layer composite flexible membrane material.

[0014] The invention discloses a multi-layer composite flexible film material for biopharmaceutical process bags. The outermost layer is formed by blending metallocene polyethylene mPE and low-density polyethylene LDPE. The polyethylene polymerized by metallocene catalyst has better impact strength, tensile properties and optical transparency than polyethylene polymerized by traditional catalysts. Through blending, while maintaining excellent processability, the impact strength, tensile properties and other indicators of the outer layer are improved. The film material can be well applied to the production of disposable bioprocess liquid storage and reaction containers. The barrier layer is cross-linked by adding stannous octoate to catalyze the ester exchange reaction between EVOH and PLA. Thereby, a certain degree of shape memory effect is obtained, and the composite flexible film material can better maintain its appearance after being made into a flexible liquid storage container. The first adhesive layer and the second adhesive layer realize the stability of the co-extruded multi-layer structure of the film. The first impact-resistant layer and the second impact-resistant layer enhance the impact resistance of the film, play a role in dispersing and buffering the impact, reduce the chance of silver streaks developing into cracks due to force, and give the disposable bioprocess liquid storage and reaction container better mechanical properties. The thickness of the multi-layer composite flexible film material is 50-600μm, which solves the problem that the flexible soft film material has poor impact resistance and is easily damaged by pulling. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0016] Figure 1 is a schematic structural diagram of a multi-layer composite flexible film material for a bioprocess bag according to an embodiment of the present invention,

[0017] Figure 2 Schematic diagram of a device for producing a composite flexible film material using a multi-layer co-extrusion technology according to an embodiment of the present invention.

[0018] Figure 3 3 is a thermogravimetric analysis (TGA) curve of the multilayer composite flexible film material described in Example 1 of the present invention.

[0019] Figure 4 It is a differential scanning calorimetry (DSC) test curve diagram of the multilayer composite flexible film material described in Example 1 of the present invention.

[0020] Figure 5 It is a schematic diagram of the multi-layer composite flexible film disposable operation bag described in Example 1 of the present invention.

[0021] Figure 6 It is a schematic diagram of the multi-layer composite flexible film material described in Example 1 of the present invention being applied to a 3D disposable square liquid preparation bag produced by Shanghai Si Rui Biotechnology Co., Ltd.

[0022] Figure 7 It is a schematic diagram of the multi-layer composite flexible film material described in Example 1 of the present invention being applied to a biopharmaceutical liquid storage bag.

[0023] In the figure: 1-outermost layer, 2-first adhesive layer, 3-first impact-resistant layer, 4-barrier layer, 5-second impact-resistant layer, 6-second adhesive layer, 7-innermost layer. DETAILED DESCRIPTION

[0024] Embodiments of the present invention are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to be used to explain the present invention, and should not be construed as limiting the present invention.

[0025] See also Figures 1 to 5 In a first aspect, the present invention provides a multi-layer composite flexible film material for a biopharmaceutical process bag, comprising an outermost layer 1, a first adhesive layer 2, a first impact-resistant layer 3, a barrier layer 4, a second impact-resistant layer 5, a second adhesive layer 6 and an innermost layer 7, wherein the first adhesive layer 2 is arranged on one side of the outermost layer 1, the first impact-resistant layer 3 is arranged on a side of the first adhesive layer 2 away from the outermost layer 1, the barrier layer 4 is arranged on a side of the first impact-resistant layer 3 away from the first adhesive layer 2, the second adhesive layer 6 is arranged on a side of the barrier layer 4 away from the first impact-resistant layer 3, the second impact-resistant layer 5 is arranged on a side of the second adhesive layer 6 away from the barrier layer 4, and the innermost layer 7 is arranged on a side of the second impact-resistant layer 5 away from the second adhesive layer 6.

[0026] In this embodiment, the outermost layer 1 is formed by blending metallocene polyethylene mPE and low-density polyethylene LDPE. The polyethylene polymerized by metallocene catalyst has better impact strength, tensile properties, and optical transparency than polyethylene polymerized by traditional catalysts. Through blending, while maintaining excellent processability, the impact strength, tensile properties and other indicators of the outer layer are improved, and it can be well applied to the preparation of disposable bioprocess liquid storage and reaction containers. The barrier layer 4 is cross-linked by adding stannous octoate to catalyze the ester exchange reaction between EVOH and PLA, thereby obtaining a certain degree of shape memory effect, and giving the composite flexible film material the ability to better maintain its appearance after being made into a flexible liquid storage container. The first adhesive layer 2 and the second adhesive layer 6 realize the stability of the co-extruded multilayer structure of the film. The first impact-resistant layer 3 and the second impact-resistant layer 5 enhance the impact resistance of the film, play a role in dispersing and buffering the impact, and reduce the chance of silver streaks developing into cracks due to force, giving the disposable bioprocess liquid storage and reaction container better mechanical properties, and solving the problem that the flexible soft film material has poor impact resistance and is easily damaged by pulling.

[0027] Furthermore, the outermost layer 1 is made by blending metallocene linear polyethylene and low-density polyethylene, and the density of the metallocene polyethylene is 0.850-0.950 g / cm 3 The density of the low-density polyethylene is 0.910-0.925 g / cm 3 The blending mass percentage of the metallocene polyethylene and the low-density polyethylene is: 20%:80%-40%:60%, preferably 25%:75%, and is frosted or atomized, with a melting point of 110-140°C, preferably 120-130°C.

[0028] In this embodiment, the outermost layer 1 uses metallocene polyethylene (m-PE) as a blend, which is blended with low-density polyethylene LDPE to form a film, and has more excellent optical properties, impact properties and heat sealing properties, and has higher tear strength and puncture strength.

[0029] Further, the first adhesive layer 2 and the second adhesive layer 6 are any one of anhydride-modified ethylene-vinyl acetate copolymer, anhydride-modified polyethylene polymer and anhydride-modified polypropylene polymer, the barrier layer 4 is polylactic acid / ethylene-vinyl alcohol copolymer, the polylactic acid, ethylene-vinyl alcohol copolymer and stannous octoate of the barrier layer 4 are in a mass ratio of 25:75:1, and the relative molecular weight of the polylactic acid is 2.0×10 5 -4.0×10 5 , preferably 2.5×10 5The ethylene content of the ethylene-vinyl alcohol copolymer is 35%-50%, preferably 45%, and the innermost layer 7 is an ultra-low density polyethylene film with a melting point between 90-125°C, preferably between 100-121°C, and a density of 0.912g / cm 3 , Vicat softening point is 105℃, and welding sealing temperature is 101℃.

[0030] In this embodiment, the barrier layer 4 is formed by a block copolymer of polylactic acid PLA and EVOH to enhance the performance of EVOH and improve the mechanical processing performance. Polylactic acid PLA has biodegradability, biocompatibility and environmental friendliness, and its barrier properties are not significantly reduced, but its impact resistance and co-extrusion process controllability are enhanced, and it also has the advantage of shape memory.

[0031]

[0032] Furthermore, the first impact-resistant layer 3 and the second impact-resistant layer 5 are made by blending a polyolefin thermoplastic elastomer copolymer and polypropylene, wherein the polyolefin thermoplastic elastomer copolymer has an octene content greater than 20% and a density of 0.86-0.89 g / cm 3 The blending mass ratio of the polyolefin thermoplastic elastomer copolymer and the polypropylene is 10%:90%-25%:75%, preferably 15%:85%.

[0033] In this embodiment, the first impact-resistant layer 3 and the second impact-resistant layer 5 are toughened and modified by blending with polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE, which can significantly enhance the impact resistance of the film. This is because POE has a narrow molecular weight distribution, and the side octyl group in the molecular structure is longer than the side ethyl group, which can form a connection point in the molecular structure, and play a role in connecting and buffering between the components, so that the system can disperse and buffer the impact energy when it is impacted, reducing the chance of silver streaks developing into cracks due to force, thereby improving the impact strength of the system. When the system is subjected to tension, the network structure formed by these connection points can undergo a large deformation, and the elongation at break of the system is significantly increased.

[0034] In a second aspect, the present invention also provides a method for preparing a multi-layer composite flexible film material for a biopharmaceutical process bag, comprising the following steps:

[0035] S1 Seven extruders extrude the molten plastic into seven film materials, and respectively convey the seven film materials to the compound die head;

[0036] S2: the composite head shaping part combines the seven membrane materials to form a multi-layer composite flexible membrane material.

[0037] The seven-layer blown film extruder equipment consists of seven independent single-screw extruders and a die head. Each extruder conveys the molten plastic to the composite die head and converges at the die head shaping part. In addition, the device is equipped with advanced internal and external cooling systems and a film thickness distribution control module, which can automatically adjust the film thickness.

[0038] In order to better understand the present technical solution, the following embodiments are provided for further explanation:

[0039] Example 1 A multi-layer composite flexible film material for a bioprocess bag.

[0040] A multi-layer composite flexible film material for a bioprocess bag, the structure of which is:

[0041] The polymer of the first layer is a metallocene linear polyethylene mPE and a low-density polyethylene LDPE, which are blended to form the first layer, i.e., the outermost layer 1 of the composite flexible film material, and the thickness is 30% of the thickness of the entire film;

[0042] The polymer of the second layer is anhydride-modified ethylene-vinyl acetate copolymer, which is the first adhesive layer 2 of the composite flexible film material, and has a thickness of 5% of the thickness of the entire film;

[0043] The polymer of the third layer is a first impact-resistant layer 3 formed by blending polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, and the thickness is 10% of the thickness of the entire film;

[0044] The polymer of the fourth layer is polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH, which is the shape memory barrier layer 4, and the thickness is 10% of the thickness of the entire film;

[0045] The polymer of the fifth layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and a polypropylene PP, which are blended to form the second impact-resistant layer 5, and the thickness is 10% of the thickness of the entire film;

[0046] The sixth layer is an anhydride-modified ethylene-vinyl acetate copolymer, which is the second adhesive layer 6 of the composite flexible film material, and has a thickness of 5% of the entire film thickness;

[0047] The polymer of the seventh layer is an ultra-low density polyethylene (ULDPE) film, which is the innermost layer 7 of the composite flexible film material, and has a thickness of 30% of the thickness of the entire film;

[0048] The thickness of the multi-layer composite flexible film material in this embodiment is 50 μm.

[0049] The density of the metallocene polyethylene mPE in the first layer of the multi-layer composite flexible film is about 0.90 g / cm 3The density of the low-density polyethylene LDPE is about 0.92 g / cm 3 The blending weight percentage of the metallocene polyethylene mPE and the low-density polyethylene LDPE is 25%:75%;

[0050] The third and fifth layers of the multi-layer composite flexible film are a blend of polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP; the polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE has an octene content of 40% and a density of about 0.88 g / cm 3 The blending mass ratio of POE and PP is 15%:85%.

[0051] The fourth layer of the multi-layer composite flexible film material is polylactic acid / ethylene-vinyl alcohol copolymer.

[0052] The copolymerization process of polylactic acid / ethylene-vinyl alcohol (PLA-EVOH) is as follows: polylactic acid PLA, ethylene-vinyl alcohol copolymer EVOH, and stannous octoate Sn(Oct)2 are blended in a torque rheometer at a mass ratio of 25:75:1, the blending temperature is set at 200°C, the rotor speed is 100 r / min, and the banburying reaction is performed for 400 s to obtain the polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH; wherein the relative molecular weight of polylactic acid PLA is about 3.0×10 5 ; The ethylene content of ethylene-vinyl alcohol copolymer PLA-EVOH is about 40%.

[0053] The outer surface of the first layer of the multi-layer composite flexible film material is frosted; the seventh layer of the multi-layer composite flexible film material complies with the United States Pharmacopeia USP class VI certification requirements;

[0054] The melting point of the first layer of the multi-layer composite flexible film material is 135°C; the polymer of the seventh layer of the multi-layer composite flexible film material is an ultra-low density polyethylene ULDPE film with a density of 0.912 g / cm 3 , melting point is 120℃, Vicat softening point is 105℃, and welding sealing temperature is 101℃.

[0055] Example 2 A method for producing a multi-layer composite flexible film material for a bioprocess bag.

[0056] The composite flexible film material described in Example 1 is produced by multi-layer co-extrusion technology:

[0057] The equipment used is a seven-layer blown film extruder, which consists of seven independent single-screw extruders and a die head. Each extruder conveys the molten plastic to the composite die head and converges at the die head shaping part. In addition, the device is equipped with an advanced internal and external cooling system and a film thickness distribution control module, which can automatically adjust the film thickness.

[0058] Example 3 Parameters of the multilayer composite flexible film material for bioprocess bags of the present invention

[0059] Table 1. Comparison of oxygen permeability coefficients of various modified polymers of the multilayer composite flexible film material for bioprocess bags in Example 1 of the present invention

[0060]

[0061]

[0062] Table 2. Comparison of moisture vapor transmission rates of various modified polymers of the multilayer composite flexible film material for bioprocess bags in Example 1 of the present invention

[0063]

[0064] The thermogravimetric analysis (TGA) curve of the multilayer composite flexible film material described in Example 1 of the present invention is shown in the attached figure. Figure 3 shown.

[0065] The differential scanning calorimetry (DSC) curve of the multilayer composite flexible film material described in Example 1 of the present invention is shown in the attached figure. Figure 3 shown.

[0066] Example 4 A disposable operation bag made of a multi-layer composite flexible film material having the functions of sampling, inoculation, cultivation and disinfection.

[0067] The structure of the multi-layer composite flexible film material for the disposable operation bag is:

[0068] The polymer of the first layer is a metallocene linear polyethylene mPE and a low-density polyethylene LDPE, which are blended to form the first layer, and the thickness is 37% of the thickness of the entire film;

[0069] The polymer of the second layer is an anhydride-modified polypropylene polymer, which is the adhesive layer of the composite flexible film material, and its thickness is 6% of the thickness of the entire film;

[0070] The polymer of the third layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, which are blended to form an impact-resistant layer, and the thickness is 8% of the thickness of the entire film;

[0071] The polymer of the fourth layer is polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH, which is the shape memory barrier layer 4, and the thickness is 10% of the thickness of the entire film;

[0072] The polymer of the fifth layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, which are blended to form an impact-resistant layer, and the thickness is 8% of the thickness of the entire film;

[0073] The sixth layer is an anhydride-modified polypropylene polymer, which is the bonding layer of the composite flexible film material, and its thickness is 6% of the entire film thickness;

[0074] The polymer of the seventh layer is an ultra-low density polyethylene (ULDPE) film, which is the innermost layer 7 of the composite flexible film material, and has a thickness of 25% of the thickness of the entire film; it meets the United States Pharmacopoeia (USP) class VI certification requirements.

[0075] The thickness of the multi-layer composite flexible film material in this embodiment is 600 μm.

[0076] The density of the metallocene polyethylene mPE in the first layer of the multi-layer composite flexible film is about 0.95 g / cm 3 The density of the low-density polyethylene LDPE is about 0.91 g / cm 3 The blending weight percentage of the metallocene polyethylene mPE and the low-density polyethylene LDPE is: 40%:60%;

[0077] The third and fifth layers of the multi-layer composite flexible film are a blend of polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP; the polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE has an octene content of about 40% and a density of 0.89 g / cm 3 The blending mass ratio of POE and PP is 25%:75%.

[0078] The fourth layer of the multi-layer composite flexible film material is a polylactic acid / ethylene-vinyl alcohol copolymer, and the copolymerization process is as follows: polylactic acid PLA, ethylene-vinyl alcohol copolymer EVOH, and stannous octoate Sn(Oct)2 are mixed in a torque rheometer at a mass ratio of 25:75:1, the mixing temperature is set to 200°C, the rotor speed is 100r / min, and the banburying reaction is performed for 200s to obtain the polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH; wherein the relative molecular weight of polylactic acid PLA is about 2.0×10 5 ; The ethylene content of ethylene-vinyl alcohol copolymer PLA-EVOH is about 50%.

[0079] The melting point of the first layer of the multi-layer composite flexible film material is 120° C.; the melting point of the seventh layer is 100° C.

[0080] The disposable operation bag is prepared by co-extrusion of a multi-layer composite flexible film material in the manner described in Example 2.

[0081] The transparent sealed bag of Example 1 is welded into a plastic bag, which is used for a disposable operation bag device with sampling, inoculation, cultivation and disinfection functions, as shown in the attached Figure 5The transparent sealed bag made of the multi-layer composite flexible film has a culture dish stuck on the inner wall, the inoculation column, the sampling tube and the transfer tube all pass through the transparent sealed bag and are fixedly connected to the transparent sealed bag at the outside, and the body of the transparent sealed bag is provided with an operation port protruding to the outside of the transparent sealed bag.

[0082] The multi-layer composite flexible membrane material of the present invention is applied to bioprocess liquid storage and reaction containers, which can replace the use of imported membrane materials and further improve the production efficiency of bioengineering.

[0083] Example 5 is a 3D disposable square liquid preparation bag made of multi-layer composite flexible film material according to the product design of Shanghai Si Rui Bio-Pharmaceutical Co., Ltd.

[0084] The structure of the multi-layer composite flexible membrane material for the disposable bioreactor is:

[0085] The polymer of the first layer is a metallocene linear polyethylene mPE and a low-density polyethylene LDPE, which are blended to form the first layer, and the thickness is 37% of the thickness of the entire film;

[0086] The polymer of the second layer is an anhydride-modified polypropylene polymer, which is the adhesive layer of the composite flexible film material, and its thickness is 6% of the thickness of the entire film;

[0087] The polymer of the third layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, which are blended to form an impact-resistant layer, and the thickness is 8% of the thickness of the entire film;

[0088] The polymer of the fourth layer is polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH, which is the shape memory barrier layer 4, and the thickness is 10% of the thickness of the entire film;

[0089] The polymer of the fifth layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, which are blended to form an impact-resistant layer, and the thickness is 8% of the thickness of the entire film;

[0090] The sixth layer is an anhydride-modified polypropylene polymer, which is the bonding layer of the composite flexible film material, and its thickness is 6% of the entire film thickness;

[0091] The polymer of the seventh layer is an ultra-low density polyethylene (ULDPE) film, which is the innermost layer 7 of the composite flexible film material, and has a thickness of 25% of the thickness of the entire film; it meets the United States Pharmacopoeia (USP) class VI certification requirements.

[0092] The thickness of the multi-layer composite flexible film material in this embodiment is 200 μm.

[0093] The density of the metallocene polyethylene mPE in the first layer of the multi-layer composite flexible film is about 0.85 g / cm 3The density of the low-density polyethylene LDPE is about 0.925 g / cm 3 The blending weight percentage of the metallocene polyethylene mPE and the low-density polyethylene LDPE is: 20%:80%;

[0094] The third and fifth layers of the multi-layer composite flexible film are a blended polymer of polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP; the polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE has an octene content of about 25% and a density of 0.86 g / cm 3 The blending mass ratio of POE and PP is 10%:90%.

[0095] The fourth layer of the multi-layer composite flexible film material is a polylactic acid / ethylene-vinyl alcohol copolymer, and the copolymerization process is as follows: polylactic acid PLA, ethylene-vinyl alcohol copolymer EVOH, and stannous octoate Sn(Oct)2 are blended in a torque rheometer at a mass ratio of 25:75:1, the blending temperature is set to 200°C, the rotor speed is 100r / min, and the banburying reaction is performed for 400s to obtain the polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH; wherein the relative molecular weight of polylactic acid PLA is about 3.0×10 5 ; The ethylene content of ethylene-vinyl alcohol copolymer PLA-EVOH is about 40%.

[0096] The melting point of the first layer of the multi-layer composite flexible film material is 115° C.; the melting point of the seventh layer is 90° C.

[0097] The multi-layer composite flexible film is prepared by co-extrusion of the multi-layer composite flexible film in the manner described in Example 2.

[0098] The multi-layer composite flexible film material is passed through a heat sealing machine as shown in the attached Figure 6 The multi-layer composite flexible film material is folded in the shape shown, and a heat sealer is used to heat along the edge to fuse it into the main container of the 3D disposable square liquid bag. Then an opening is made on the wall of the main container to install the feeding port and stirring device.

[0099] The 3D disposable square liquid preparation bag made of the multi-layer composite flexible film material of the present invention has better impact strength, tensile properties and optical transparency than traditional polyethylene because the multi-layer composite structure, especially the outermost layer 1, is formed by blending metallocene polyethylene mPE and low-density polyethylene LDPE. Therefore, the 3D disposable square liquid preparation bag can maintain its three-dimensional internal space through its inherent support structure and is very suitable for the cultivation and preparation of bioprocess fluids. The maximum cell density of the 3D disposable square liquid preparation bag made by the present invention can reach 10 7 -10 8 / ml, which is significantly improved compared with traditional liquid preparation bags.

[0100] Example 6 A medical infusion bag is made of a multi-layer composite flexible film material.

[0101] The structure of the multi-layer composite flexible film material for medical infusion bag is:

[0102] The polymer of the first layer is a metallocene linear polyethylene mPE and a low-density polyethylene LDPE, which are blended to form the first layer, and the thickness is 10% of the thickness of the entire film;

[0103] The polymer of the second layer is an anhydride-modified polypropylene polymer, which is the adhesive layer of the composite flexible film material, and its thickness is 4% of the thickness of the entire film;

[0104] The polymer of the third layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, which are blended to form an impact-resistant layer, and the thickness is 15% of the thickness of the entire film;

[0105] The polymer of the fourth layer is polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH, which is the shape memory barrier layer 4, and the thickness is 5% of the thickness of the entire film;

[0106] The polymer of the fifth layer is a polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP, which are blended to form an impact-resistant layer, and the thickness is 15% of the thickness of the entire film;

[0107] The sixth layer is an anhydride-modified polypropylene polymer, which is the bonding layer of the composite flexible film material, and its thickness is 6% of the entire film thickness;

[0108] The polymer of the seventh layer is an ultra-low density polyethylene (ULDPE) film, which is the innermost layer 7 of the composite flexible film material, and has a thickness of 45% of the thickness of the entire film; it meets the United States Pharmacopoeia (USP) class VI certification requirements.

[0109] The thickness of the multi-layer composite flexible film material in this embodiment is 300 μm.

[0110] The density of the metallocene polyethylene mPE in the first layer of the multi-layer composite flexible film is about 0.90 g / cm 3 The density of the low-density polyethylene LDPE is about 0.915 g / cm 3 The blending weight percentage of the metallocene polyethylene mPE and the low-density polyethylene LDPE is: 30%:70%;

[0111] The third and fifth layers of the multi-layer composite flexible film are a blend of polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE and polypropylene PP; the polyolefin thermoplastic elastomer (ethylene / octene) copolymer POE has an octene content of about 30% and a density of 0.88 g / cm 3 The blending mass ratio of POE and PP is 20%:80%.

[0112] The fourth layer of the multi-layer composite flexible film material is a polylactic acid / ethylene-vinyl alcohol copolymer, and the copolymerization process is as follows: polylactic acid PLA, ethylene-vinyl alcohol copolymer EVOH, and stannous octoate Sn(Oct)2 are mixed in a torque rheometer at a mass ratio of 25:75:1, the mixing temperature is set to 200°C, the rotor speed is 100r / min, and the banburying reaction is performed for 500s to obtain the polylactic acid / ethylene-vinyl alcohol copolymer PLA-EVOH; wherein the relative molecular weight of polylactic acid PLA is about 4.0×10 5 ; The ethylene content of ethylene-vinyl alcohol copolymer PLA-EVOH is about 35%.

[0113] The outer surface of the first layer of the multi-layer composite flexible film material is atomized; the melting point of the first layer of the multi-layer composite flexible film material is 115° C.; and the melting point of the seventh layer is 90° C.

[0114] The multi-layer composite flexible film is prepared by co-extrusion in the manner described in Example 2.

[0115] The multi-layer composite flexible film material is heat-sealed by a machine according to the specifications of medical infusion bags, such as the attached Figure 7 The style shown is formed by welding and processing using a heat sealer. The lower part of the medical infusion bag is welded with a tube port for discharging the infusion from the bag body.

[0116] The medical infusion bag made of the multi-layer composite flexible film material of the present invention can be safely sterilized under conventional sterilization conditions, with a peel strength of ≥28N / 5mm and excellent quality.

[0117] The above disclosure is only a preferred embodiment of a multi-layer composite flexible film material for a biopharmaceutical process bag and a preparation method thereof of the present invention. Of course, this cannot be used to limit the scope of rights of the present invention. Ordinary technicians in this field can understand that all or part of the processes of the above embodiments and equivalent changes made according to the claims of the present invention still fall within the scope of the invention.

Claims

1. A multi-layer composite flexible film material for biopharmaceutical process bags, characterized in that: The invention comprises an outermost layer, a first adhesive layer, a first impact-resistant layer, a barrier layer, a second impact-resistant layer, a second adhesive layer and an innermost layer, wherein the first adhesive layer is arranged on one side of the outermost layer, the first impact-resistant layer is arranged on a side of the first adhesive layer away from the outermost layer, the barrier layer is arranged on a side of the first impact-resistant layer away from the first adhesive layer, the second adhesive layer is arranged on a side of the barrier layer away from the first impact-resistant layer, the second impact-resistant layer is arranged on a side of the second adhesive layer away from the barrier layer, and the innermost layer is arranged on a side of the second impact-resistant layer away from the second adhesive layer.

2. The multi-layer composite flexible film material for biopharmaceutical process bags according to claim 1, characterized in that: The outermost layer is made by blending metallocene linear polyethylene and low-density polyethylene, and the density of the metallocene polyethylene is 0.850-0.950 g / cm 3 The density of the low-density polyethylene is 0.910-0.925 g / cm 3 The blending mass percentage of the metallocene polyethylene and the low-density polyethylene is: 20%:80%-40%:60%, preferably 25%:75%, and is frosted or atomized, with a melting point of 110-140°C, preferably 120-130°C.

3. The multi-layer composite flexible film material for biopharmaceutical process bags according to claim 1, characterized in that: The first adhesive layer and the second adhesive layer are any one of anhydride-modified ethylene-vinyl acetate copolymer, anhydride-modified polyethylene polymer and anhydride-modified polypropylene polymer. The barrier layer is polylactic acid / ethylene-vinyl alcohol copolymer. The polylactic acid, ethylene-vinyl alcohol copolymer and stannous octoate of the barrier layer are in a mass ratio of 25:75:

1. The relative molecular weight of polylactic acid is 2.0×10 5 -4.0×10 5 , preferably 2.5×10 5 The ethylene content of the ethylene-vinyl alcohol copolymer is 35%-50%, preferably 45%. The innermost layer is an ultra-low density polyethylene film with a melting point between 90-125°C, preferably between 100-121°C, a density of 0.912g / cm3, a Vicat softening point of 105°C, and a welding sealing temperature of 101°C.

4. The multi-layer composite flexible film material for biopharmaceutical process bags according to claim 1, characterized in that: The first impact-resistant layer and the second impact-resistant layer are made by blending a polyolefin thermoplastic elastomer copolymer and polypropylene. The polyolefin thermoplastic elastomer copolymer has an octene content greater than 20% and a density of 0.86-0.89 g / cm 3 The blending mass ratio of the polyolefin thermoplastic elastomer copolymer and the polypropylene is 10%:90%-25%:75%, preferably 15%:85%.

5. A method for preparing a multi-layer composite flexible film material for a biopharmaceutical process bag, the multi-layer composite flexible film material for a biopharmaceutical process bag as claimed in claim 1, characterized in that: The following steps are involved: Seven extruders extrude molten plastic into seven film materials, and respectively transport the seven film materials to a compound die head; The composite head shaping part combines the seven membrane materials to form a multi-layer composite flexible membrane material.

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