Membrane for disposable biological container and preparation method thereof

Abstract

The invention belongs to the technical field of biological container films, and particularly relates to a disposable biological container film and a preparation method thereof.The biological container film is prepared through a continuous eleven-layer co-extrusion tape casting method, is provided with an eleven-layer co-extrusion film and comprises an outer layer, an inner layer and a barrier layer, the outer layer comprises 3-5 layers of linear low-density polyethylene resin and / or low-density polyethylene resin, and the inner layer comprises 3-5 layers of ultra-low-density polyethylene resin. By optimizing the hierarchical structure and the preparation process of the film, raw material components which have high performance requirements and are fused with one another are screened out, the biological container film with high heat sealing strength, high barrier property, high peel strength and high stability is obtained, and compared with a current Renolit 9101 or Lifemeta KA disposable film, the biological container film has the advantages that the thickness is smaller, and at least 4.61% of film materials can be saved.

Description

Technical Field

[0001] The present invention relates to the technical field of biocontainer membranes, and in particular to a disposable biocontainer membrane. Background Art

[0002] Disposable bioreactors have been gradually applied since the late 1990s and have become an important part of the biopharmaceutical field. This type of reactor is widely used in microbial culture and cell culture processes at experimental, clinical sample preparation, pilot scale and production scale. With the advancement of technology, disposable biological containers, such as disposable bioreactor bags, liquid storage bags, liquid preparation bags and feeding bags, have been widely used in biopharmaceuticals, especially in discontinuous or continuous culture processes. Compared with traditional stainless steel reactors, disposable bioreactors have obvious advantages in avoiding cleaning and sterilization validation and reducing the risk of cross contamination. However, despite the significant progress in the application of disposable bioreactors, biofilm technology is still a bottleneck in its development. As the core component of the reactor, the biofilm plays a vital role in ensuring the performance of the reactor.

[0003] High-quality biofilms need to meet a series of strict performance requirements, such as excellent barrier properties, solvent resistance, mechanical strength, peel strength and biocompatibility. For example, high barrier properties are one of the most basic and important properties of disposable biofilms, which can prevent external pollutants, oxygen and liquids from penetrating into the reactor, and prevent the contents in the reactor from leaking out, ensuring the stability of the culture in the reactor; specifically, it needs to meet the standard conditions of 23°C and 65% relative humidity, and the oxygen permeability should be <5m1 / m 2 ·Day or less, water vapor transmission <2g / m 2 ·d; During use, the reactor may experience environmental changes such as temperature changes, humidity fluctuations, and contact with chemical solvents or culture media. The peel strength directly affects the quality of the contents in the reactor. The delaminated biofilm is easily eroded, causing the contents to deteriorate faster. Therefore, a biofilm with a higher peel strength can better ensure the stability of the reactor during the entire use process in the face of these environmental changes. In addition, in order to control the thickness and uniformity of the membrane or enhance the adhesion between layers, some biofilms will add solvents to dissolve the resin during the production process; however, if the solvent residues are not completely removed, it may lead to an increase in the dissolution, which in turn affects the safety and stability of the contents. At present, biofilm products on the market mainly rely on imports and are expensive, resulting in higher usage costs for domestic users. Therefore, it is still a very challenging task to develop biofilms that meet strict technical requirements. Summary of the invention

[0004] An object of the present invention is to solve at least the above-mentioned problems and / or disadvantages and to provide a membrane for a disposable biocontainer and a method for preparing the same.

[0005] The object of the present invention is achieved as follows: The first aspect of the present invention is to provide a disposable biocontainer film, comprising eleven co-extruded films, wherein at least three types of layers are formed in these films, including an outer layer, an inner layer and a barrier layer between the outer layer and the inner layer; the outer layer comprises at least 3 to 5 layers of linear low-density polyethylene resin (LLDPE) and / or low-density polyethylene resin (LDPE), the inner layer comprises at least 3 to 5 layers of ultra-low-density polyethylene resin (ULDPE), and the barrier layer comprises at least ethylene-vinyl alcohol copolymer (EVOH); these films also have an adhesive layer or a structural layer, wherein the adhesive layer or the structural layer is bonded between the barrier layer and the outer layer and / or the inner layer; wherein, according to GB / T1037, the biocontainer film has a water vapor permeability of less than or equal to 1.41 g / ㎡-day at 90% RH and 38°C; according to GB / T1038, the biocontainer film has a water vapor permeability of less than or equal to 0.42 cm at 0% RH and 23°C. 2 / m 2 -Day-0.1Mpa oxygen permeability, meeting high barrier requirements.

[0006] As a preferred embodiment, the outer layer includes layer one serving as the outer surface of the biological container, wherein layer one includes linear low-density polyethylene resin (LLDPE); and layer two, layer three and layer four co-extruded with layer one, each including low-density polyethylene resin (LDPE) for improving the stretchability of the film.

[0007] As a preferred embodiment, the inner layer includes layer eleven as the inner surface of the biological container, the layer eleven includes ultra-low density polyethylene resin (ULDPE) and low-density polyethylene resin (LDPE), which are used to improve the heat sealing effect and ensure the sealing effect of the film; and layer eight, layer nine and layer ten co-extruded with layer eleven, the layer eight, layer nine and layer ten all include ultra-low density polyethylene resin (ULDPE), which are used to improve the flexibility, low temperature resistance, tear resistance and puncture resistance of the film, and there is no precipitation of additives, ensuring the cleanliness and safety of the inner layer.

[0008] As a preferred embodiment, the total thickness of the biocontainer membrane is controlled at 308-312µm, the thickness of the outer layer is controlled at 105-115µm, the thickness of the inner layer is controlled at 135-140µm, the thickness of the barrier layer is controlled at 28-32µm, and an adhesive layer 1 and an adhesive layer 2 are respectively provided between the barrier layer and the outer layer and the inner layer, and the thickness of the adhesive layer 1 and the adhesive layer 2 are both controlled at 15-17µm. More specifically, the outer layer includes layers 1 to 4, and the thicknesses thereof are controlled at 28-32µm, 21-25µm, 42-46µm, and 12-14µm, respectively; the inner layer includes layers 8 to 11, and the thicknesses thereof are controlled at 11-13µm, 46-50µm, 46-50µm, and 28-32µm, respectively.

[0009] As a preferred embodiment, the eleven-layer co-extruded film includes sequentially adjacent layers one to eleven, wherein layer one is a linear low-density polyethylene resin layer, serving as the outer surface of the biocontainer; layer two, layer three, and layer four are all low-density polyethylene resin layers; layer five includes a modified low-density polyethylene adhesive resin layer, serving as an adhesive layer for adjacent interlayers; layer six is ​​an ethylene-vinyl alcohol copolymer layer, serving as an intermediate barrier layer of the biocontainer film; layer seven is a modified low-density polyethylene adhesive resin layer, serving as an adhesive layer for adjacent interlayers; layer eight, layer nine, and layer ten are all ultra-low-density polyethylene resin layers; and layer eleven is an ultra-low-density polyethylene resin layer.

[0010] As a preferred embodiment, the raw materials of the low-density polyethylene resin layer are respectively / or all KF360T, or the low-density polyethylene resin layer contains at least 99wt% of the density of 0.895~0.9000g / cm 3 The outer layer is a low-density polyethylene resin layer made of 2036P, or a linear low-density polyethylene resin layer containing at least 99wt% of a density of 0.930-0.940g / cm 3 The raw materials of the ultra-low density polyethylene resin layer are respectively / or all 4404G, or these ultra-low density polyethylene resin layers contain at least 99wt% of the density of 0.900~0.910g / cm 3 An ultra-low density polyethylene resin or a mixture of multiple ultra-low density polyethylene resins within this density range.

[0011] As a preferred embodiment, the main raw material of the modified low-density polyethylene adhesive resin layer is 41E871, or the modified low-density polyethylene adhesive resin layer contains at least about 99wt% of a density of 0.905-0.925g / cm 3 The modified low-density polyethylene adhesive resin or a mixture of multiple modified low-density polyethylene adhesive resins within this density range; the material of the ethylene-vinyl alcohol copolymer layer is mainly BX6304B, or a mixture of two or more other types of ethylene-vinyl alcohol copolymers.

[0012] As a preferred embodiment, the biocontainer film is formed by co-extrusion casting, and the eleven layers of films contained therein do not contain solvents for dissolving resins, so as to avoid residual solvents from dissolving out.

[0013] The second aspect of the present invention is to provide a method for preparing a disposable biocontainer membrane, which is used to prepare the above-mentioned biocontainer membrane, specifically using a continuous eleven-layer co-extrusion casting process, including the following steps: feeding, melt extrusion: polyethylene, adhesive resin, and ethylene-vinyl alcohol copolymer are melted through a screw extruder, and the melt is extruded at a die; die mouth salivation: the melt is cast through a casting roller, and extruded through a casting die head to obtain a molten film, and the temperature of the casting roller is controlled to be; molding cooling: the molten film is cooled to a temperature lower than its melting point, and is cooled and shaped on a casting roller and a cooling roller to form a film; thickness detection: the obtained film is subjected to online thickness detection by a X-ray thickness gauge to obtain a film with a thickness deviation controlled within ±2%; corona treatment, and winding.

[0014] The third aspect of the present invention is to provide a biocontainer, which is constructed by the above-mentioned biocontainer film, forming at least one chamber for accommodating the contents, having an outer layer as the outer surface of the container, an inner layer in contact with the contents in the chamber, and a barrier layer between the outer layer and the inner layer for blocking gas and / or liquid, including (but not limited to) being used as a disposable bioreactor bag, a disposable liquid storage bag, a disposable liquid preparation bag and a disposable liquid injection bag, etc., for carrying out (but not limited to) biological reactions, cell culture, storage of culture medium, etc.

[0015] Compared with the prior art, the present invention has at least the following beneficial effects: The present invention provides a disposable biocontainer film having an eleven-layer co-extruded film structure, including an outer layer, an inner layer and a middle barrier layer. By optimizing the hierarchical structure and preparation process of the biofilm, the inner and outer layers are selected to have a combination of raw materials with excellent performance and are mutually integrated, so that the film has the characteristics of high barrier properties, high stability, high heat sealing strength and high peel strength, which can meet the strict requirements of disposable biocontainers, is suitable for packaging materials with high barrier requirements, and can be used for biological reactions, cell culture, and storage of culture media.

[0016] In a preferred embodiment of the present invention, when the thickness of the disposable biocontainer film is controlled at 310 μm, according to GB / T1037 and according to GB / T1038, under the corresponding test conditions, the biocontainer film has a water vapor permeability of less than or equal to 1.41 g / ㎡-day and a water vapor permeability of less than or equal to 0.42 cm 2 / m 2 -Day-0.1Mpa oxygen permeability, while ensuring high barrier performance, compared with the current Renolit 9101 or Lifemeta KA disposable biofilm, it has a thinner thickness and can save at least 4.61% of film materials.

[0017] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 A cross-sectional view of one embodiment of the disposable biocontainer membrane of the present invention; Figure 2 This is a flow chart of the method for preparing a membrane for a disposable biological container of the present invention; Figure 3 A cross-sectional view of one embodiment of a disposable biological container of the present invention; Markings in the figure: 1-membrane for disposable biological container; 2-chamber; 11-layer one; 12-layer two; 13-layer three; 14-layer four; 15-layer five; 16-layer six; 17-layer seven; 18-layer eight; 19-layer nine; 20-layer ten; 21-layer eleven. DETAILED DESCRIPTION

[0019] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0020] Reference to "embodiments" herein means that the specific features, structures, or characteristics described in conjunction with the embodiments may be included in multiple embodiments of the present application. The appearance of the phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0021] See also Figure 1 A disposable biocontainer film 1 has eleven co-extruded films, which are layer 1 11, layer 2 12, layer 3 13, layer 4 14, layer 5 15, layer 6 16, layer 7 17, layer 8 18, layer 9 19, layer 10 20 and layer 11 21, respectively. These films can be combined to form at least three types of layers, including (but not limited to) an outer layer, an inner layer and a barrier layer between the outer layer and the inner layer; the outer layer is used as the outer surface of the disposable biocontainer film 1, and the inner layer is used as the inner surface of the disposable biocontainer film 1.

[0022] In the film structure with a total of eleven layers, the outer layer includes at least 3 to 5 layers of linear low-density polyethylene resin layers and / or low-density polyethylene resin layers in order to effectively resist physical damage during transportation and use, and the thickness of the outer layer is controlled at 105 to 115 µm; preferably, the outer layer includes 4 layers of linear low-density polyethylene resin layers and / or low-density polyethylene resin layers, namely, layer one 11, layer two 12, layer three 13 and layer four 14.

[0023] In the film structure with a total of eleven layers, the inner layer includes at least 3 to 5 layers of ultra-low density polyethylene resin layers in order to reduce the index of dissolution in the liquid phase material, and the thickness of the inner layer is controlled at 135 to 140 µm; preferably, the inner layer includes 4 layers of ultra-low density polyethylene resin layers, namely, layer eight 18, layer nine 19, layer ten 20 and layer eleven 21.

[0024] In the film structure with a total of eleven layers, in order to improve the barrier properties to water and gas, the barrier layer includes at least one layer of ethylene-vinyl alcohol copolymer, and the thickness of the barrier layer is controlled at 28~32µm; preferably, in order to better utilize the protective properties of the outer layer and the functions of the inner layer, the barrier layer is arranged in the middle position of the raw container film, that is, layer six 16.

[0025] In the film structure with a total of eleven layers, in order to reduce the dissolution amount of the film and further control the dissolution index, no solvent is used to dissolve the resin between the layers; and in order to enable the polar ethylene-vinyl alcohol copolymer layer to be combined with the non-polar polyethylene layer, an adhesive layer one and an adhesive layer two are respectively arranged between the barrier layer and the outer layer and the inner layer, that is, layer five 15 and layer seven 17 respectively, and the thickness of the adhesive layer one and the adhesive layer two is controlled at 15~17µm.

[0026] The present invention has no particular restrictions on the materials of the first and second adhesive layers, but preferably a modified low-density polyethylene adhesive resin is used. In addition, in some embodiments of the present invention, in the film structure with a total of eleven layers, a structural layer may be provided between the barrier layer and the inner layer or the outer layer to improve the tear resistance, toughness or low temperature resistance of the film.

[0027] On the basis of satisfying that the thickness of the outer layer is controlled within the range of 105-115µm, the outer layer includes 4 layers of linear low-density polyethylene resin layers and / or low-density polyethylene resin layers, which means that the outer layer can be 4 layers of linear low-density polyethylene resin layers, or 4 layers of low-density polyethylene resin layers, or a combination of linear low-density polyethylene resin layers and low-density polyethylene resin layers, for example, 1 layer of linear low-density polyethylene resin layer is combined with 3 layers of low-density polyethylene resin layers.

[0028] In the film structure of eleven layers in total, when the outer layer includes four layers, the thickness of the four layers is controlled to be 28-32µm, 21-25µm, 42-46µm, and 12-14µm, respectively; when the inner layer includes four layers, the thickness of the four layers is controlled to be 11-13µm, 46-50µm, 46-50µm, and 28-32µm, respectively. In particular, the thickness of the non-polar polyethylene resin layer (i.e., layer four 14 and layer eight 18) in contact with the adhesive layer is close to or slightly less than the thickness of the corresponding adhesive layer (i.e., layer five 15 and layer seven 17), so as to improve the interfacial bonding strength between the films and reduce the risk of interlayer delamination caused by temperature changes (such as low temperature) or mechanical stress.

[0029] It should be noted that the above-mentioned linear low-density polyethylene resin layer, low-density polyethylene resin layer, ultra-low-density polyethylene resin layer, ethylene-vinyl alcohol copolymer layer and modified low-density polyethylene adhesive resin layer only refer to the linear low-density polyethylene resin, low-density polyethylene resin, ultra-low-density polyethylene resin, ethylene-vinyl alcohol copolymer and modified low-density polyethylene adhesive resin as the main materials of the corresponding film layers in these film layers, for example, accounting for more than 80wt% or 90wt% or 99wt%, but does not exclude the presence of other ingredients. For example, they are used together with other resins or fillers to improve certain properties of the film, such as toughness, puncture resistance, etc.

[0030] In order to further illustrate the present invention, the disposable biocontainer membrane 1 and the preparation method thereof are further described below in conjunction with the examples. In the following examples, the materials used, such as linear low-density polyethylene resin (LLDPE), low-density polyethylene resin (LDPE), ultra-low-density polyethylene resin (ULDPE), ethylene-vinyl alcohol copolymer (EVOH), modified low-density polyethylene adhesive resin (TIE), etc., are all conventional commercial products, and their corresponding models and performance parameters are shown in Table 1 below; Table 1 shows the raw materials and performance parameters of various embodiments of the present invention;

[0031] Embodiment 1, a disposable biocontainer film 1, with a total thickness of 310µm, includes sequentially adjacent layers 11 to 11, wherein: the raw material used for layer 11 is linear low-density polyethylene resin (LLDPE), with a thickness of 30µm; the raw materials used for layers 2 12 to 4 14 are all low-density polyethylene resin (LDPE), with thicknesses of 23µm, 44µm, and 13µm, respectively; the raw material used for layer 5 15 is modified low-density polyethylene adhesive resin (TIE), with a thickness of 16µm; the raw material used for layer 6 16 is ethylene-vinyl alcohol copolymer (EVOH), with a thickness of 30µm, and the raw material used for layer 7 17 is modified low-density polyethylene adhesive resin (TIE), with a thickness of 16µm; the raw materials used for layers 8 18 to 11 21 are all ultra-low-density polyethylene resin (ULDPE), with thicknesses of 12µm, 48µm, 48µm, and 30µm, respectively.

[0032] Embodiment 2, a disposable biocontainer film 1, with a total thickness of 310µm, includes sequentially adjacent layers 11 to 11, wherein: the raw materials used in layers 11 to 14 are all low-density polyethylene (LDPE), with thicknesses of 30µm, 23µm, 44µm, and 13µm, respectively; the raw material used in layer 5 15 is modified low-density polyethylene adhesive resin (TIE), with a thickness of 16µm; the raw material used in layer 6 16 is ethylene-vinyl alcohol copolymer (EVOH), with a thickness of 30µm, and the raw material used in layer 7 17 is modified low-density polyethylene adhesive resin (TIE), with a thickness of 16µm; the raw materials used in layers 8 18 to 11 21 are all ultra-low density polyethylene (ULDPE), with thicknesses of 12µm, 48µm, 48µm, and 30µm, respectively.

[0033] Embodiment 3, a disposable biocontainer film 1, with a total thickness of 310µm, includes sequentially adjacent layers 11 to 11, wherein: wherein: wherein: the raw material used for layer 11 is linear low-density polyethylene resin (LLDPE), with a thickness of 30µm, the raw materials used for layers 2 12 to 4 14 are all low-density polyethylene resin (LDPE), with thicknesses of 23µm, 44µm, and 13µm, respectively; the raw material used for layer 5 15 is modified low-density polyethylene adhesive resin (TIE), with a thickness of 16µm; the raw material used for layer 6 16 is ethylene-vinyl alcohol copolymer (EVOH), with a thickness of 30µm, the raw material used for layer 7 17 is modified low-density polyethylene adhesive resin (TIE), with a thickness of 16µm; the raw materials used for layers 8 18 to 10 20 are all ultra-low density polyethylene (ULDPE), with thicknesses of 12µm, 48µm, and 48µm, respectively, and layer 11 21 is low-density polyethylene resin (LDPE). In the embodiments 1 to 3 of the present invention, the raw materials and thicknesses of the eleven layers of film are shown in Table 2 below: Table 2 shows the corresponding raw materials and thicknesses of each layer of the biocontainer film in each embodiment of the present invention;

[0034]

[0035] Example 4, see Figure 2 A method for preparing a disposable biocontainer membrane can be used for preparing the disposable biocontainer membrane described in the first to third embodiments above. The preparation process is carried out using an eleven-layer casting production line equipment produced by W&H of Germany. The whole process is carried out in a 10,000-class clean workshop, and the resin raw materials used do not contain solvents for dissolving the resin between layers. Specifically, the method comprises the following steps: S1. Feeding: Put the polyethylene, adhesive resin and ethylene-vinyl alcohol copolymer corresponding to each layer of the above-mentioned film into the corresponding barrel: S2, melt extrusion: melt through a screw extruder, control the screw extruder to extrude low-density polyethylene material, the screw temperature is set to 240°C; the temperature of extruding vinyl alcohol-ethylene copolymer is set to 215°C, the die temperature is 250°C, and the melt is extruded at the die; S3, die casting: casting the melt through a casting roller, and extruding through a casting die to obtain a molten film, wherein the temperature of the casting roller is 45°C; S4, molding cooling: The molten film is cooled to a temperature below its melting point, cooled and shaped at 35°C on the casting roll and cooling roll to form a film; S5. Thickness detection: The cast film thickness detection system detects the film thickness by scanning back and forth with rays, and feeds back to the die head thickness adjustment bolt to automatically adjust the thickness, so as to obtain a film with a thickness deviation controlled within ±2%; S6, corona treatment, winding.

[0036] Example 5, see Figure 3 A disposable biocontainer is constructed using the disposable biocontainer film 1 disclosed in Examples 1 to 3 or the disposable biocontainer film 1 obtained by the method described in Example 4, and is heat-sealed using a sealing machine to form at least one chamber 2 as a space for accommodating contents, and includes an outer layer as the outer surface of the container, an inner layer in contact with the contents in the chamber 2, and a barrier layer between the outer layer and the inner layer for blocking gas and / or liquid. The biocontainer can be used as a disposable bioreactor bag, a disposable liquid storage bag, a disposable liquid preparation bag, a disposable liquid injection bag, and other bags that require transparent high barrier properties, and is used for biological reactions, cell culture, or storage of culture media.

[0037] In order to make the beneficial effects of the technical solution of the present application more clear to those skilled in the art, the disposable biocontainer membrane disclosed in Example 1 of the present invention was tested according to GB / T28117-2011, and the results are shown in Table 3 below; Table 3 is the performance test results of the disposable biocontainer membrane provided in Example 1 of the present invention;

[0038] As can be seen from Table 3, the inner layer and the outer layer of Example 1 of the present invention obtain a biofilm with high heat sealing strength, high barrier properties and high peel strength by screening out raw material components with high performance requirements and fusion with each other. Under the premise of ensuring high barrier properties, it has a thinner thickness than the current Renolit 9101 (325µm) or Lifemeta KA (400µm) disposable biofilm, and can save at least 4.61% of film materials.

[0039] In order to make the beneficial effects of the technical solution of the present application more clear to those skilled in the art, the present invention also conducted the following tests on the disposable biocontainer membrane provided in Example 1 (hereinafter referred to as the sample): According to USP43 <87> Mouse fibroblast L-929 cells were used to detect the cytotoxicity of the test samples. Under the test conditions, the toxicity of the extract of the test sample to L-929 cells was graded as level 0, indicating that it had no potential cytotoxicity.

[0040] According to USP43 <88> , the test samples were subjected to intradermal reaction test, and the test samples were extracted with sodium chloride injection, ethanol sodium chloride mixture (1:20), polyethylene glycol 400 and sesame oil respectively. The test sample extract and the corresponding control solution were injected intradermally on both sides of the back of the rabbit, and the skin reaction of all animals was observed 24, 48 and 72 hours after injection; during the 72-hour observation period, the reaction of the animals in the test sample extract group was the same as that of the animals in the negative control group; under this test condition, the test sample extract did not cause intradermal irritation reaction; According to USP43 <88> , the test samples were subjected to subcutaneous implantation test to evaluate the irritation and toxicity reaction of the test sample after implantation into rats. The prepared test samples and negative controls were implanted into the subcutaneous part of the rats' backs under sterile conditions, and the health status of the animals and the clinical observation of the implantation sites were observed. After 1 week, the animals were painlessly killed and the size of the cysts was observed and recorded. The difference in the final average score of cysts between the test group and the control group was no more than 1.0. Under the conditions of this test, the test samples did not cause irritation reaction in the subcutaneous tissue of rats, which met the test requirements; According to USP43 <88> , a systemic toxicity test was conducted on the test samples. The test samples were extracted with sodium chloride injection, ethanol sodium chloride mixture (1:20), polyethylene glycol 400 and sesame oil. The mice were injected with four test sample extracts and corresponding control samples from the tail vein or abdominal cavity. After the injection, the immediate reaction of the mice was observed, and the general state, toxicity manifestations and number of dead animals of the test group and the control group were observed and recorded at 4h, 24h, 48h and 72h, and the body weight of the animals was weighed at 72h; during the 72h observation period, the reactions of the animals in the test sample extract group were the same as those of the animals in the negative control group; under this experimental condition, the extract of the test sample did not cause systemic toxic reactions; According to YBB00272004-2015, a disposable biocontainer prepared by the disposable biocontainer membrane disclosed in Example 1 of the present invention was tested for particle contamination. The test results are shown in Table 4 below: Table 4 shows the particle contamination detection results of the embodiment of the present invention;

[0041] It can be seen from Table 4 that under this test condition, the test sample 50cm 3 (Eluent volume: 75ml) The number of particles >5.1um is 9.5 particles / ml, the number of particles >10um is 1.7 particles / ml, and the number of particles >25μm is 0.0 particles / m1, which meets the requirements for insoluble particles in medical device packaging materials; The above results show that the disposable biocontainer film material provided by the present invention has the characteristics of high heat sealing strength, high barrier properties and high peel strength, and also has excellent biocompatibility, safety and stability, proving that the film provided by the present invention can be used as a film material for disposable biocontainers such as disposable bioreactor bags, disposable liquid storage bags, disposable liquid preparation bags and disposable liquid injection bags, and is used for operations such as biological reactions, cell culture or storage of culture medium.

Claims

1. A disposable biocontainer membrane, characterized in that: The total thickness of the disposable biocontainer film is controlled to be 305-315 μm, and the film has eleven layers of co-extruded film, which are combined to form an outer layer, an inner layer, and a barrier layer between the outer layer and the inner layer; The outer layer comprises 3 to 5 layers of linear low-density polyethylene resin and / or low-density polyethylene resin, and the density of the linear low-density polyethylene resin is controlled at 0.930 to 0.940 g / cm 3 The density of the low-density polyethylene resin is controlled at 0.895-0.9000 g / cm 3 ; The inner layer comprises 3 to 5 layers of ultra-low density polyethylene resin, the barrier layer comprises at least one layer of ethylene-vinyl alcohol copolymer, and the density of the ultra-low density polyethylene resin is controlled at 0.900 to 0.910 g / cm 3 These films also have an adhesive layer or a structural layer, which is combined between the barrier layer and the outer layer and / or the inner layer.

2. The disposable biocontainer membrane according to claim 1, characterized in that: The outer layer includes a first layer as the outer surface of the biocontainer film, the first layer includes a linear low-density polyethylene resin; and a second layer, a third layer and a fourth layer adjacent thereto, the second layer, the third layer and the fourth layer include a low-density polyethylene resin.

3. The disposable biocontainer membrane according to claim 2, characterized in that: The inner layer includes layer eleven as the inner surface of the biocontainer membrane, wherein layer eleven includes ultra-low density polyethylene resin and / or low-density polyethylene resin; and layer eight, layer nine and layer ten adjacent in sequence, wherein layer eight, layer nine and layer ten include ultra-low density polyethylene resin.

4. The method for preparing a disposable biocontainer membrane according to claim 3, characterized in that: The melting point of the low-density polyethylene resin is controlled at 88-92°C, and the melt index is controlled at 3.4-3.6 g / 10min; the melting point of the linear low-density polyethylene resin is controlled at 123-127°C, and the melt index is controlled at 2.4-2.6 g / 10min; the melting point of the ultra-low-density polyethylene resin is controlled at 122-126°C, and the melt index is controlled at 3.9-4.1 g / 10min.

5. The disposable biocontainer membrane according to any one of claims 1 to 4, characterized in that: The thickness of the outer layer is controlled at 105-115 µm; the thickness of the inner layer is controlled at 135-140 µm; the thickness of the barrier layer is controlled at 28-32 µm; an adhesive layer 1 and an adhesive layer 2 are respectively arranged between the barrier layer and the outer layer and the inner layer, and the thickness of the adhesive layer 1 and the adhesive layer 2 are both controlled at 15-17 µm.

6. The disposable biocontainer membrane according to claim 5, characterized in that: The outer layer includes layer one, layer two, layer three and layer four, and the thicknesses thereof are controlled at 28~32µm, 21~25µm, 42~46µm and 12~14µm respectively; the inner layer includes layer eight, layer nine, layer ten and layer eleven, and the thicknesses thereof are controlled at 11~13µm, 46~50µm, 46~50µm and 28~32µm respectively.

7. The disposable biocontainer membrane according to claim 6, characterized in that: It comprises layers one to eleven which are adjacent to each other in sequence, wherein layer one is a linear low-density polyethylene resin layer; layer two, layer three and layer four are all low-density polyethylene resin layers; layer five is a modified low-density polyethylene adhesive resin layer; layer six is ​​an ethylene-vinyl alcohol copolymer layer; layer seven is a modified low-density polyethylene adhesive resin layer; layer eight, layer nine, layer ten and layer eleven are all ultra-low-density polyethylene resin layers.

8. A method for preparing a disposable biocontainer membrane, for preparing the biocontainer membrane according to claim 1, characterized in that: The continuous eleven-layer co-extrusion casting process is adopted, which includes the following steps: S1, feeding, melt extrusion: feeding the corresponding materials of each layer into the barrel, melting them through the screw extruder, and extruding the melt at the die; S2, die mouth drooling: casting the melt through a casting roller, and extruding through a casting die to obtain a molten film; S3, molding cooling: the molten film is cooled to a temperature below its melting point, cooled and shaped on the casting roll and cooling roll, and a film is formed; S4. Thickness detection: The obtained film is tested online by a X-ray thickness gauge, and the thickness deviation is controlled within ±2%; S5, corona treatment and rolling to obtain the biocontainer film.

9. The method for preparing a disposable biocontainer membrane according to claim 8, characterized in that: The entire process of preparing the disposable biocontainer membrane is carried out in a Class 10,000 clean environment; the screw temperature of the screw extruder for extruding the low-density polyethylene material is set to 240°C; the temperature for extruding the vinyl alcohol-ethylene copolymer is set to 215°C, the temperature of the die head is 250°C, the temperature of the casting roller is 45°C, and the cooling and shaping temperature is 35°C.

10. A disposable biological container, characterized in that: A biocontainer film prepared by the biocontainer film according to claim 1 or the method for preparing a disposable biocontainer film according to claim 8, forming at least one chamber for accommodating a content, and having an outer layer as an outer surface, an inner layer for contacting the content in the chamber, and a barrier layer between the outer layer and the inner layer for blocking gas and / or liquid.

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