CONTAINER FOR ADMINISTRATION, STORAGE, DELIVERY OR TRANSPORTATION OF PROTEIN HAVING LOW PROTEIN ADSORBABILITY OR PROTEIN-CONTAINING COMPOSITION, AND APPARATUS FOR PRODUCING PROTEIN OR PROTEIN COMPOSITION

Abstract

There is provided a container or an equipment having low-protein adsorption properties, to be used for administering, storing, conveying or transporting protein or a composition including protein, or for producing protein or a composition including protein. A container or an equipment for producing protein or a composition including protein, wherein the surface of the container or the equipment in contact with protein or a composition including protein is formed of a fluororesin which is at least one fluororesin selected from a tetrafluoroethylene-hexafluoropropylene-based copolymer and a tetrafluoroethylene-perfluoroalkylvinyl ether-based copolymer, which has a melting point of 320 C. or less and which has a total number of non-fluorinated group terminals and CF.sub.2H group terminals in the fluororesin of 70 or less per 110.sup.6 carbon atoms, has remarkable low-protein adsorption properties. Such a container or equipment can be used to thereby, for example, prevent, in a producing (culturing and purifying, and the like) step, a storing and delivering step and/or administration of a protein formulation such as an antibody pharmaceutical product, the protein formulation from being lost due to adsorption thereof to the equipment.

Claims

1. A container for administering, storing, conveying or transporting a protein or a composition including the protein, or an equipment for producing a protein or a composition including the protein, wherein a surface of the container or the equipment in contact with the protein or the composition including the protein is formed of a fluororesin which is at least one fluororesin selected from a tetrafluoroethylene-hexafluoropropylene-based copolymer and a tetrafluoroethylene-perfluoroalkylvinyl ether-based copolymer, which has a melting point of 320 C. or less and which has a total number of a non-fluorinated group terminal and a CF.sub.2H group terminal in the fluororesin of 70 or less per 110.sup.6 carbon atoms.

2. The container for administering, storing, conveying or transporting a protein or a composition including the protein, or the equipment for producing a protein or a composition including the protein according to claim 1, which is a container.

3. The container for administering, storing, conveying or transporting a protein or a composition including the protein, or the equipment for producing a protein or a composition including the protein according to claim 1, which is a bag.

4. The container for administering, storing, conveying or transporting a protein or a composition including the protein, or the equipment for producing a protein or a composition including the protein according to claim 1, wherein the protein or the composition including the protein is un antibody (immunoglobulin).

5. The container for administering, storing, conveying or transporting a protein or a composition including the protein, or the equipment for producing a protein or a composition including the protein according to claim 1, wherein the protein or the composition including the protein is albumin.

6. The container for administering, storing, conveying or transporting protein or a composition including the protein, or the equipment for producing u protein or a composition including the protein according to claim 1, which is an equipment for producing protein formulation.

Description

MODE CARRYING OUT THE INVENTION

[0032] The container for administering, storing, conveying or transporting protein or a composition including protein, or the equipment for producing protein or a composition including protein according to the present invention (hereinafter, referred to simply as the container or the equipment according to the present invention or the container or the equipment in some cases) is not especially limited as long as it is a container or an equipment to be used for administering, storing, conveying or transporting protein or a composition including protein, or to be used for producing protein or a composition including protein, wherein the surface of the container or the equipment in contact with protein or a composition including protein is formed OF a fluororesin which is at least one fluororesin selected from a tetrafluoroethylene-hexafluoropropylene-based copolymer and a tetrafluoroethylene-perfluoroalkylvinyl ether-based copolymer, which has a melting point of 320 C. or less and which has a total number of non-fluorinated group terminals and CF.sub.2H group terminals in the fluororesin of 70 or less per 110.sup.6 carbon atoms (hereinafter, these fluororesins are generically referred to as the present fluororesin in some cases); and the container or the equipment as a whole is optionally formed of the present fluororesin. The container or the equipment according to the present invention has a feature in that the container or equipment surface in contact with protein or a composition including protein is formed of the present fluororesin. A container or an equipment having such a feature can be used to administer, store, convey or transport protein (for example, antibody immunoglobulin)) or a composition including protein, thereby, for example, preventing, in a producing (culturing and purifying, and the like) step, a storing and delivering step and/or administration of a protein formulation such as an antibody pharmaceutical product, the protein formulation from being lost, due to adsorption thereof to the equipment, and expensive protein ingredients (for example, growth factors and cytokines necessary for cell growth, differentiation induction and the like) from being lost due to adsorption thereof to the equipment, leading to a decrease in cost.

[0033] In the present invention, the protiein means a single polymer compound or multiple polymer compounds made by linearly linking (polymerizing) many L-amino acids via amide bonds (also referred to as peptide bonds), and is not limited with respect to the number of amino acids serving as constituent elements. Accordingly, so-called peptide is also encompassed in the protein in the present invention. Further, glycoprotein obtained by binding sugar and protein, and lipoprotein obtained by binding lipid and protein are also encompassed in the protein in the present invention. Examples of the protein to be used in the present invention include albumin, fibrinogen, globulin (1-globulin, 2-globulin, -globulin, -globulin), erythropoietin, collagen, elastin, keratin, lactoferrin, avidin, cadherin, proteoglycan, mucin, LDL (Low Density Lipoprotein), HDL (High Density Lipoprotein), VLDL (Very Low Density Lipoprotein), a cell proliferation factor such as insulin and transferrin, and cytokine and a growth factor such as activin A, a bone morphogenetic factor 4 (BMP-4), an epithelial cell growth factor (EGF), a stem cell factor (SCF) and interleukin, but are not limited thereto.

[0034] The composition including protein in the present invention means a mixture or a product of one or more proteins and one or more substances other than such proteins. Examples of the composition including protein, to be used in the present invention, include a protein formulation such as an antibody pharmaceutical product, a body fluid such as blood, a biological ingredient including protein such as serum and plasma, and a culture medium including a protein ingredient (particularly, a serum-free culture medium and a culture medium for differentiation induction), but are not limited thereto.

[0035] With respect to the container for administering, storing, conveying or transporting protein or a composition including protein in the present invention, the container for administering, container for storing, container for conveying, container for transporting, and equipment for producing and equipment mean the followings, respectively.

[0036] The container for administering means a container to be used in the case of administering protein or a composition including protein to a patient in a clinical setting.

[0037] The container for storing means a container to be used in the case of storing protein or a composition including protein for a certain period.

[0038] The container for conveying means a container to be used in the case of moving protein or a composition including protein by a human power, a machine (including a robot), or the like.

[0039] The container for transporting means a container to be used in the case of carrying protein or a composition including protein by transport means such as a car, a ship, and an airplane.

[0040] The equipment for producing means an equipment to be used in the case of producing protein or a composition including protein.

[0041] The equipment means a material for making tools (simple utensils), instruments (relatively compact and small-scale devices and utensils (instruments) to be directly operated by human beings), and tools and instruments. Examples include a pipe, a tube and a container of production facility for antibody pharmaceutical products, etc., and a purification equipment (for example, a filter and a column).

[0042] In the present fluororesin, the total number of non-fluorinated group terminals (for example, functional groups such as COF, COOH, COOH associated with water, CH.sub.2OH, CONH.sub.2 and COOCH.sub.3) and CF.sub.2H group terminals in the fluororesin is preferably 70 or less per 110.sup.6 carbon atoms, more preferably 35 or less per 110.sup.6 carbon atoms. Furthermore, the total number is more preferably 20 or less per 110.sup.6 carbon atoms, especially preferably 10 or less per 110.sup.6 carbon atoms. Any fluororesin including no CF.sub.2H group terminal is optionally adopted, and when no CF.sub.2H group terminal is included, the number of non-fluorinated group terminals in the fluororesin is preferably 70 or less per 110.sup.6 carbon atoms, more preferably 35 or less per 110.sup.6 carbon atoms. Further, the number is still more preferably 20 or less per 110.sup.6 carbon atoms, and especially preferably 10 or less per 110.sup.6 carbon atoms.

[0043] The number per 110.sup.6 carbon atoms of the COF, COOH, COOH associated with water, CH.sub.2OH, CONH.sub.2, COOCH.sub.3 and CF.sub.2H can be calculated by FT-IR.

[0044] In the present invention, the non-fluorinated group terminal means a terminal having some reactivity and usually called an unstable terminal, and specifically includes functional groups such as COF, COOH, COOH associated with water, CH.sub.2OH, CONH.sub.2 and COOCH.sub.3.

[0045] The melting point of the present fluororesin is 320 C. or less, and is 240 C. or more. Examples of a preferable range of the melting point include the range of 245 C. or more and 315 C. or less, and the range of 250 C. or more and 310 C. or less.

[0046] Specific examples of the present fluororesin include a tetrafluoroethylene (TFE) -hexafluoropropylene (HFP)-based copolymer (FEP) and a TFE-perfluoroalkylvinyl ether (PAVE)-based copolymer (PFA).

[0047] Among them, FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of 70 or less per 110.sup.6 carton atoms exhibits remarkable low-protein adsorption properties over FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms. That is, while FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms does not have sufficient low-protein adsorption properties, FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of 70 or less per 110.sup.6 carbon atoms exhibits remarkably more excellent low-protein adsorption properties than FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms. These properties are exhibited by only FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of 70 or less per 110.sup.6 carbon atoms.

[0048] The fluororesin in the present invention has the following properties (1) to (5) other than the above properties. [0049] (1) No elution of a plasticizer or the like. [0050] (2) Possibility of high-temperature vapor (autoclave) sterilization. [0051] (3) Insolubility in DMSO and DMF. [0052] (4) Excellent cryogenic properties (no embrittlement even at 200 C.). [0053] (5) High transparency.

[0054] The TFE-HFP-based copolymer means a copolymer containing at least TFE and HFP. That is, the TFE-HFP-based copolymer includes, in addition to a binary copolymer (TFE/HFP copolymer; FEP) of TFE and HFP, also a ternary copolymer such as a copolymer of TFE, HFP and vinyl fluoride (VF) (TFE/HFP/VF copolymer), a copolymer of TFE, HFP and vinylidene fluoride (VDF) (TFE/HFP/VDF copolymer) and a copolymer of TFE, HFP and a perfluoro(alkylvinyl ether) (PAVE) (TFE/HFP/PAVE copolymer), a quaternary copolymer such as a copolymer of TFE, HFP, VF and VDF (TFE/HFP/VF/VDF copolymer), a copolymer of TFE, HFP, VF and PAVE (TFE/HFP/VF/PAVE copolymer) and a copolymer of TFE, HFP, VDF and PAVE (TFE/HFP/VDF/PAVE copolymer), and a quinary copolymer such as a copolymer of TFE, HFP, VF, VDF and PAVE (TFE/HFP/VF/VDF/PAVE copolymer).

[0055] The melting point of the present fluororesin, especially FEP, is 300 C. or less, and is 240 C. or more. Examples of a preferable range of the melting point include the range of 245 C. or more and 290 C. or less and the range of 250 C. or more and 230 C. or less.

[0056] The TFE-HFP-based copolymer is preferably a TFE/HFP copolymer or a TFE/HFP/PAVE copolymer. The mass ratio of TFE and HFP in such a TFE/HFP copolymer is preferably 80 to 97/3 to 20, and more preferably 34 to 92/8 to 16. Further, the mass ratio of TFE, HFP and PAVE in the TFE/HFP/PAVE copolymer is preferably 70 to 97/3 to 20/0.1 to 10, and more preferably 81 to 92/5 to 16/0.3 to 5.

[0057] The TFE-PAVE-based copolymer means a copolymer containing at least TFE and PAVE. That is, the TFE-PAVE-based copolymer includes, in addition to a binary copolymer of TFE and PAVE (TFE/PAVE copolymer; PFA), also a ternary copolymer such as a copolymer of TFE, PAVE and hexafluoropropylene (HFP) (TFE/PAVE/HFP copolymer), a copolymer of TFE, PAVE and vinylidene fluoride (VDF) (TFE/PAVE/VDF copolymer) and a copolymer of TFE, PAVE and chlorotrifluoroethylene (CTFE) (TFE/PAVB/CTFB copolymer), a quaternary copolymer such as a copolymer of TFE, PAVE, HFP and VDF (TFE/PAVE/HFP/VDF copolymer), a copolymer of TFE, PAVE, HFP and CTFE (TFE/PAVE/HFP/CTFE copolymer) and a copolymer of TFE, PAVE, VDF and CTFE (TFE/PAVE/VDF/CTFE copolymer), and a quinary copolymer such as a copolymer of TFE, PAVE, HFP, VDF and CTFE (TFE/PAVE/HFP/VDF/CTFE copolymer).

[0058] A PAVE constituting the PAVE unit is not especially limited, and examples thereof include perfluoro(methyl vinyl ether) [PMVE], perfluoro(ethyl vinyl ether) [PEVE], perfluoro(propyl vinyl ether) [PPVE], perfluoro(butyl vinyl ether), perfluoro(pentyl vinyl ether), perfluoro(hexyl vinyl ether) and perfluoro(heptyl vinyl ether).

[0059] The melting point of the present fluororesin, especially PFA, is 320 C. or less, and is 285 C. or more. Examples of a preferable range of the melting point include the range of 290 C. or more and 315 C. or less, the range of 295 C. or more and 315 C. or less, and the range of 300 C. or more and 310 C. or less.

[0060] The mass ratio of TFE and PAVE in the TFE-PAVE-based copolymer is preferably 90 to 98/2 to 10, and more preferably 92 to 97/3 to 8.

[0061] The present fluororesin can be fabricated by subjecting terminal groups of a fluororesin synthesized according to a usual method of suspension polymerization, emulsion polymerization or the like to a fluorination treatment by a known method such as a method in which before a fluororesin is melt extruded, the fluororesin and a fluorine-containing compound (for example, a fluorine radical source) are contacted with each other to carry out a stabilization treatment, and a method in which pellets of a fluororesin obtained after the fluororesin is melt extruded and a fluorine-containing compound are contacted with each other to carry out a fluorination treatment. Further, the present fluororesin can also be obtained by using a chain transfer agent and a polymerization catalyst capable of controlling terminal groups together with a fluorine monomer in production (polymerization reaction) of the fluororesin. Further, as the present fluororesin, commercially available products can be used. The fluorination treatment can also be carried out by contacting a fluorine-containing compound with moldings molded from fluororesins, like films molded by melting fluororesins, containers or equipments molded from the films and containers or equipments molded from fluororesins. Further, these treatment methods can also be combined.

[0062] That is, it is not needed that the total number of the non-fluorinated group terminals and the total number of the non-fluorinated group terminals and CF.sub.2 H group terminals are 70 or less per 110.sup.6 carbon atoms in each stage of fluororesins, pellets and films to become raw materials, and it suffices if on the surface of a final container or equipment in contact with protein, the total number thereof is 70 or less 110.sup.6 per carbon atoms. Further, in the case of a fluororesin having one or more CF.sub.3 terminal groups, it is not needed that the number of the CF.sub.3 terminal groups is one or more in each stage of fluororesins, pellets and films to become raw materials, and it suffices if on the surface of a final container or equipment in contact with protein, the fluororesin has one or more CF.sub.3 terminal groups.

[0063] The fluorine radical source is not especially limited, but examples thereof include a halogen fluoride such as IF.sub.5 and ClF.sub.3, F.sub.2 gas, CoF.sub.3, AgF.sub.2, UF.sub.6, OF.sub.2, N.sub.2F.sub.2 and CF.sub.3OF. The Ft gas is optionally of a concentration of 100%, but, from the safety aspect, is used by being mixed and diluted to 5 to 50% by mass, preferably 15 to 30% by mass, with an inert gas. The inert gas includes nitrogen gas, helium gas and argon gas, and from the viewpoint of the cost efficiency, nitrogen gas is preferable.

[0064] The fluorination treatment is carried out at a temperature of preferably 20 to 220 C., and more preferably 100 to 200 C. The fluorination treatment is carried out preferably for 5 to 30 hours, and more preferably for 10 to 20 hours.

[0065] The container or the equipment obtained by the present invention is optionally one in which the arithmetic mean roughness (Ra) of the surface roughness, the root-mean-square roughness (RMS) of the surface roughness, and the surface free energy have been regulated. Examples of the container or the equipment include one having its container inner surface or its equipment inner surface having an Ra of the surface roughness of 3.5 to 6.5 nm, an RMS of the surface roughness of 4.5 to 8.0 nm, and a surface free energy of 16.5 to 18.5 (mJ/m.sup.2).

[0066] FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of 70 or less per 110.sup.6 carbon atoms has extremely excellent properties as compared with FEP.PFA having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms, as described above, and especially has the following advantages. [0067] (1) In a producing (culturing and purifying, and the like) step, a storing and delivering step and/or administration of a protein formulation such as an antibody pharmaceutical product, the protein formulation is prevented from being lost due to adsorption thereof to the equipment. [0068] (2) In a cell culturing step (including a differentiation induction step) in a regenerative medicine application and the like, expensive protein ingredients (growth factors and cytokines necessary for cell proliferation, differentiation induction and the like) contained in a culture medium (particularly, a serum-free culture medium or a culture medium for differentiation induction) are prevented from being lost due to adsorption thereof to the equipment during culturing (leading to a decrease in cost).

[0069] The fluororesin in the present invention can be used for various containers having a surface in contact with protein or a composition including protein, and equipments such as a member of production facility, a purification equipment and an experimental tool.

[0070] Examples of forms of the container or the equipment according to the present invention include a bag, a bottle, a centrifugal tube, a vial, a syringe and a tube; in the case where the container according to the present invention is a container for administering protein, preferable are a syringe, a bag (for drip), a bottle (for drip) and a tube; in the case where the container according to the present invention is a container for storing protein, preferable are a bag, a bottle, a centrifugal tube and a vial; and in the case where the container according to the present invention is a container for conveying and transporting protein, preferable are a bag, a bottle, a vial and a tube. Particularly, the container according to the present invention having a bag shape, since it can be applied to every application for administering, storing, conveying and transporting protein, can be suitably exemplified. Examples of specific applications of the equipment for producing according to the present invention include the following. [0071] (1) A relevant application for a protein formulation such as an antibody pharmaceutical product:

[0072] a culturing container (bag and the like), a pipe of production facility, a reaction or storage tank, etc., a purification equipment (filter, column and the like), a container for storing and delivering, a container for administering (syringe, administering bag and the like) [0073] (2) A relevant application for culturing cells including a protein ingredient in a regenerative medicine application and the like:

[0074] a culturing container (bag and the like) (particularly, for culturing iPS cells in large amounts and for differentiation induction), a container for a culture medium (also including a container for a protein ingredient such as proliferation and growth factors, and cytokine)

[0075] The bag, bottle, centrifugal tube, vial, syringe, tube and the like can be produced by molding methods including compression molding, extrusion, transfer molding, inflation molding, blow molding, injection molding, rotation molding, lining molding, foam extrusion and film molding, as required in combination with sealing means such as heat sealing, high-frequency fusion and ultrasonic fusion. The case of production by these methods has the advantage of saving the trouble of coating as compared with the case of coating with a coating agent.

[0076] The bag can be produced specifically by overlapping films (sheets) of the present fluororesin material and heat sealing edge portions by using an impulse sealer.

[0077] The film to be used for molding of the bag may be a single-layer film or a laminated film consisting of a multilayer of two or more layers; and in the case of the laminated film consisting of a multilayer, it suffices if the bag is so molded that at least the inner surface in contact with mammal cells is a layer film of the present fluororesin material, and the other layer films are each allowed to be even a layer film of a material (for example, a polyolefinic resin material) different from the present fluororesin. The lamination of the films is carried out by using a method such as a heat lamination method, a heat compression method, a high-frequency heating method, a solvent casting method and an extrusion lamination method.

[0078] Further, the container or equipment according to the present invention can also be obtained by subjecting a base material, such as a bag, a bottle, a centrifugal tube, a vial, a syringe and a tube, produced of a glass, a metal, a resin or the like, to a coating treatment with a coating agent consisting of the present fluororesin. Any methods can be employed according to the form of the base material. Such a coating treatment includes spin coating, spray coating, bar coating, roll coating, dipping, brush coating, rotolining and electrostatic coating. The base material is coated with the fluororesin coating agent, and thereafter subjected to a drying treatment and a high-temperature heating treatment to thereby form a coating layer. Further, the coating layer is allowed to be made to be thick to any thickness by further double-coating a coating agent containing the present fluororesin.

[0079] Hereinafter, the present invention will be described more specifically by way of Examples, but the technical scope of the present invention is not limited to those Examples.

EXAMPLE 1

[0080] 1. Production of Container

[0081] Each of 5 kinds of films of 10 cm4 cm in size and 100 m in thickness was stacked for two films, and heat sealed by using an impulse sealer under the conditions of a sealing time of 50 sec, a sealing pressure of 0.2 MPa and a sealing width of 4 mm to thereby produce each of 5 kinds of perfluoropolymer bags (containers A to E).

[0082] Here, a polyethylene bag (container F) used was a commercially available bag of 70500.04 mm in size (Unipac(R) A-4 manufactured by Seisannipponsha Ltd), and a glass container (container G) used was a commercially available screw pipe bottle having a size of 21 mm in barrel diameter45 mm in total length (TS Screw tube bottle (9 mL) manufactured by Maruemu Corporation).

[0083] 2. Measurement of the number of non-fluorinated group terminals and the number of CF.sub.2H terminals Samples of corresponding resins of about 250 to 300 m in thickness were fabricated, and analyzed by using an FT-IR Spectrometer 1760X (manufactured by PerkinElmer, Inc.).

[0084] The samples of corresponding resins of about 250 to 300 m in thickness were fabricated, and subjected to measurement by using the films (fabricated from the pellets by melt molding) constituting the bags as they were, and in the case where the thickness was insufficient, by overlapping the films.

[0085] Difference spectra from standard samples (samples fluorinated enough until substantially no difference was any more observed in spectra) were acquired; absorbances of each peak were read; and the number of non-fluorinated group terminals and the number of CF.sub.2H terminals per 110.sup.6 carbon atoms were calculated for each sample according to the following equation. The number of non-fluorinated group terminals and the number of CF.sub.2H terminals in each of the bags are shown in Table 2.

[0086] The numbers of non-fluorinated group terminals and CF.sub.2H terminals (per 110.sup.6 carbon atoms)=l.Math.k/t

[0087] l: absorbance

[0088] k: correction factor (see Table 1)

[0089] t: sample thickness (mm)

TABLE-US-00001 TABLE 1 Absorption Wave Number and Correction Factor of each Non-Fluorinated Group Terminal Group and CF.sub.2H Terminal Absorption Wave Correction Terminal Group Number (cm.sup.1) Factor COF 1884 405 COOH(free) 1813 455 COOH(bonded) 1775 455 1790 COOCH.sub.3 1795 355 CONH.sub.2 3438 480 CH.sub.2OH 3648 2325 CF.sub.2H 3006 26485

TABLE-US-00002 TABLE 2 The Number of Non-Fluorinated Group Terminals and the Number of CF.sub.2H Group Terminals in the Container The Number of The Number Container Material of Non-Fluorinated of CF.sub.2H Name Container Group Terminals Terminals A FEP 21 424 B FEP 13 0 C FEP 68 0 D PFA 201 159 E PFA 25 0 F Polyethylene G Glass

EXAMPLE 2

[0090] (Non-adhesiveness to protein) [0091] (1) Preparation of coloring liquid and protein solution

[0092] The coloring liquid used was obtained by mixing 50 mL of a peroxidase coloring liquid (3,3,5,5-tetramethylbenzidine (TMBZ), manufactured by KPL) and 50 mL of TMB Peroxidase Substrate (manufactured by KPL).

[0093] The protein solution used was obtained by diluting protein (POD-goat anti mouse IgG, manufactured by Bio-Bad Laboratories, Inc.) with a phosphate buffer solution (D-PBS, manufactured by Wako Pure Chemical Industries, Ltd.) by 16,000-fold. [0094] (2) Protein adsorption

[0095] To each of containers A to G was dispensed 2 mL of the protein solution by a micropipette (used at 2 mL with respect to each of the containers), and left to stand at room temperature for 1 hour. Each reaction was performed at N=3. [0096] (3) Washing of container

[0097] Then, the protein solution was drained off from each of the containers, and thereafter each of the containers was washed with 4 mL of a phosphate buffer solution including 0.05% by mass of a surfactant (Tween 20, manufactured by Wako Pure Chemical Industries, Ltd.) four times (used at 4 mL with respect to each of the containers four times). [0098] (4) Dispensing of coloring liquid

[0099] Then, 2 mL of the coloring liquid was dispensed to each of the containers washed (used at 2 mL with respect to each of the containers), and a coloring reaction was performed for 7 min. The coloring reaction was terminated by addition of 1 mL of a 1 M phosphoric acid solution (used at 1 mL with respect to each of the containers).

[0100] In a blank, 2 mL or the coloring liquid was dispensed to each of 3 glass containers (used at 2 mL with respect to each of the glass containers), and thereafter 40 L of the protein solution was dispensed thereto. A coloring reaction was performed for 7 min, and terminated by addition of 1 mL of a 1 M phosphoric acid solution (used at 1 mL with respect to each of the glass containers). [0101] (5) Preparation of absorbance measurement

[0102] Then, 3 mL of the liquid was taken out from each of the containers, and transferred to a cell for spectrophotometer. [0103] (6) Absorbance measurement and protein adsorption rate Q

[0104] The absorbance was measured as the absorbance at 450 nm by an ultraviolet spectrophotometer U-3310 (manufactured by Hitachi Ltd.). Here, the average of the absorbance (N=3) of the blank was designated as A0. The absorbance of the liquid moved from each of the bags was designated as A1.

[0105] The protein adsorption rate Q1 was determined according to the following equation, and the protein adsorption rate Q was determined as the average.

Q1=A1/{A0(2000/Amount of dispensing of protein solution of blank)}100

=A1/{A0(2000/40)}100[%]

TABLE-US-00003 TABLE 3 Liquid Protein Protein Contact Adsorption Container Adsorption Area Rate/cm.sup.2 Name Rate Q (%) (cm.sup.2) (%) Comparative A 1.12 13.2 0.085 Example 1 Example 1 B 0.24 13.2 0.018 Example 2 C 0.46 13.2 0.035 Comparative D 1.03 13.2 0.078 Example 2 Example 3 E 0.14 13.2 0.011 Comparative F 2.10 12.0 0.175 Example 3 Comparative G 0.95 9.4 0.101 Example 4

[0106] As shown in Table 3, it was revealed that protein remarkably hardly adsorbed to the surface of each of containers B, C and E each using a perfluoropolymer having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of 70 or less per 110.sup.6 carbon atoms as compared with not only the surfaces of container F made of polyethylene and glass container G, but also the surfaces of containers A and D each using a perfluoropolymer having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms. In other words, the low-protein adsorption properties exhibited by a perfluoropolymer having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms were about 1/7 to about those exhibited by a perfluoropolymer having a total number of fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms.

EXAMPLE 3

[0107] 1. Production of container H

[0108] There was used, as container H, cover glass (manufactured by Matsunami Glass Ind., Ltd., C025251, 2525 No. 1) where a frame border of 1010 mm was written on the surface by PAP Pen Super-Liquid Blocker (manufactured by Daido Sangyo Co., Ltd.).

[0109] 2. Preparation of fluorescently labelled BSA solution

[0110] Fluorescently (Alexa Fluor(R) 555) labelled BSA was prepared by using commercially available BSA (bovine serum albumin, A7638 manufactured by Sigma-Aldrich) and a fluorescent labeling kit (Alexa Fluor(R) 555 NHS Ester (Succinimidyl Ester) A20009) manufactured by Thermo Fisher Scientific Inc., according to the protocol attached to the kit, and the fluorescently labelled BSA was diluted with PBS and adjusted so as to nave a concentration of 10 g/mL, and the resulting fluorescently labelled BSA solution was used in the following experiment.

[0111] 3. Adsorption of fluorescently labelled BSA

[0112] To each of containers A and B was dispensed 1 mL of the fluorescently labelled BSA solution (10 g/mL) by a micropipette, and left to stand at 37 C. for 1 hour. The liquid contact area to the bag was about 600 mm.sup.2.

[0113] With respect to container H, the fluorescently labelled BSA solution was dropped by a micropipette into the frame border prepared by PAP Pen Super-Liquid Blocker so as to have a concentration of 167 L/cm.sup.2, and placed in a petri dish and thereafter left to stand at 37 C. for 1 hour. Each reaction was performed at N=3.

[0114] 4. Washing

[0115] After 1 hour, the fluorescently labelled BSA solution was removed from each of containers A, B and H, and thereafter each of the containers was washed with 2 mL of a PBS solution four times.

[0116] 5. Measurement of fluorescence intensity

[0117] With respect to containers A and B, a part (square of about 1010 mm) in contact with the fluorescently labelled protein solution was cut out by scissors, ProLong(R) Diamond antifade mountant (manufactured by Thermo Fisher Scientific Inc.) was dropped thereon, and thereafter cover glass was then mounted thereon, and the resultant was imaged by a fluorescence microscope (LSM700 manufactured by Zeiss, 20).

[0118] Also with respect to container H, similarly, ProLong(R) Diamond antifade mountant (manufactured by Thermo Fisher Scientific Inc.) was dropped thereon after washing, new cover glass was mounted thereon, and the resultant was imaged by a fluorescence microscope (LSM700 manufactured by Zeiss, 20).

[0119] Main imaging conditions are as follows; [0120] Objective lens: Plan-Apochromat 20X/0.8 M27 [0121] Pinhole: 147 m [0122] Number of pixels: 10241024 [0123] Laser power: 0.5%

[0124] After imaging, analysis was made by Fiji software, thereby calculating the average fluorescence intensity derived from the fluorescently labelled BSA adsorbed, with respect to each sample, (analyzed at 5 fields of view with respect to each sample)

[0125] The proportion of the average fluorescence intensity (relative adsorption rate (%) of BSA) of each of containers A and B under the assumption that the average fluorescence intensity of container H is 100 is shown in Table 4.

TABLE-US-00004 TABLE 4 Container Relative Adsorption Name Rate of BSA (%) Example 4 B 1.45 Comparative A 54.03 Example 5 Comparative H 100 Example 6

[0126] As shown in Table 4, it was revealed that BSA remarkably hardly adsorbed to the surface of container B using a perfluoropolymer having a total number of non-fluorinated group terminals and CF2H group terminals of 70 or less per 110.sup.6 carbon atoms as compared with not only the surface of glass container H, but also the surface of container A using a perfluoropolymer having a total number of non-fluorinated group terminals and CF.sub.2H group terminals of more than 70 per 110.sup.6 carbon atoms.

INDUSTRIAL APPLICABILITY

[0127] The fluororesin in the present invention exhibits extremely excellent low-protein adsorption properties, and therefore can be used in any equipment where protein or a composition including protein is used. Particularly, the fluororesin in the present invention can be utilized in various equipments associated with a protein formulation such as an antibody pharmaceutical product, for example, a culturing container (bag and the like), a pipe of production facility, etc., a purification equipment (filter, column and the like), a container for storing and delivering, a container for administering (syringe, administering bag and the like), and various equipments for producing associated with culturing of cells including a protein ingredient in a regenerative medicine application and the like, for example a culturing container (bag and the like) (particularly, for culturing iPS cells in large amounts and for differentiation induction) and a culture medium container (also including a container for a protein ingredient such as a growth factor).