JP6685644B2 - Infusion container and manufacturing method thereof - Google Patents

Description

  The present invention relates to an infusion container and a method for manufacturing the same.

  An infusion container including an infusion bag obtained by filling a drug solution in a bag-shaped body made of a plastic film and sealing it, and a port member which is a plastic molded product fixed to the outer peripheral portion of the infusion bag is known. is there. The infusion solution container is passed through a sterilization process under moist heat and then housed in an outer bag to be a product. As a method for filling a vertically elongated bag-shaped body made of a plastic film with a chemical solution, the bag-shaped body may be placed horizontally and upright (Patent Document 1). In this case, prior to the filling of the liquid medicine, the bag-shaped body is leaned against the tray somewhat obliquely, and the upper sides of both sides are held upright by the chucks so that the bag-shaped body is erected upright, and the liquid medicine is filled through the openings left in the upper portion of the bag-shaped body. Done. In the case of this filling method, it is important that the bag-shaped body is leaned against the tray without bending so as to ensure a gripping operation by the chuck.

  Further, as a related art of the present invention, there is known a plastic film having a multi-layer structure, and one of the layers is made of an ethylene-vinyl alcohol copolymer resin to give the plastic film a gas barrier property.

International publication WO2014 / 104281 Japanese Patent No. 5100308

  When a bag-shaped body made of a plastic film is filled with a chemical solution by placing the bag-shaped body horizontally and standing upright, the bag-shaped body leans against the tray without bending because of the reliable gripping operation by the chuck. However, it is important to maintain that posture, but polyethylene and polypropylene, which have been conventionally used as the material for bag-shaped bodies for filling chemicals, do not become too hard after being made into products, so they are easy to handle after being made into products. It has excellent safety in that it will not be injured even if sharp parts remain on the product or the product, but since it has a flexible property, it is recommended to use a film thickness of about 300 μm that is commonly used for infusion containers. In particular, when the bag-shaped body is leaned against the tray in the process of filling the chemical liquid, the bag is easily bent, and the chuck cannot perform a reliable gripping operation, which lowers the work efficiency. It had become a cause of increase in product cost.

  As a result of investigations, the present inventors have found that the film loop strength by the stiffene tester method is strongly related to the bending resistance when the vertically elongated bag-shaped body made of a plastic film is placed horizontally and stood up. The invention was reached. That is, according to the present invention, it is provided with an infusion bag obtained by filling a bag-shaped body made of a plastic film with a liquid medicine and sealing it, and a port member which is a plastic molded product fixed to an outer peripheral portion of the infusion bag. An infusion container is provided in which the plastic film has a film loop strength of 500 mN or more before the moist heat sterilization treatment by the stiffene tester method and the elastic modulus of the plastic film is 400 MPa or less after the moist heat sterilization treatment.

  In the infusion container of the present invention, the film loop strength before the wet heat sterilization treatment by the stiffene tester method is more preferably 570 mN or more for realizing the desired gripping action by the chuck. The elastic modulus of the plastic film before the heat and moisture sterilization is preferably 700 MPa or less from the viewpoints of the sealing property of the port member and the necessary filling amount of the chemical liquid, and also the handleability after being made into a product. .

  In the present invention, the plastic film may have a multi-layer structure, and the base material layer may be composed of a polyolefin resin such as polyethylene or polypropylene which has been often used conventionally. Then, in order to increase the strength of the film loop before the wet heat sterilization treatment of the multilayer film, a layer made of a polyamide resin such as an ethylene-vinyl alcohol copolymer resin (EVOH resin) or nylon can be added. The EVOH resin layer, etc., enhances the film loop strength before the wet heat sterilization process to improve the bending resistance when the bag is laid horizontally and is upright, and the workability when filling the bag with the chemical solution is improved. The value of the film loop strength is not proportional to the value of the elastic modulus of the film, but there is some relationship, but after the wet heat treatment of the infusion bag, the elastic modulus of the EVOH resin layer is before the wet heat treatment. Since it becomes smaller and 400 MPa or less, there is an effect that the handleability as a product does not deteriorate.

The use of one layer in the multilayer film as the EVOH resin layer makes the infusion container non-air-permeable (gas barrier property) as described in Patent Document 2 and easily oxidizes amino acid preparations and some vitamin preparations. This is advantageous in that stable storage stability of the infusion preparation can be secured. Then, the infusion solution bag which has been subjected to the sterilization by heat and humidity as described in this patent can be accommodated in an outer bag made of a gas barrier film together with an oxygen scavenger. That is, the infusion bag is heated by steam or the like (wet heat treatment) for sterilization, and the EVOH resin loses air permeability once by heating, but slowly returns to non-air permeability when returned to room temperature. Immediately after the moist heat treatment, the infusion bag is stored in the outer bag together with the oxygen scavenger, and while the resin layer has air permeability, the oxygen remaining in the infusion bag is adsorbed by the oxygen scavenger in the outer bag, and ethylene-vinyl In the state where the alcohol copolymer resin layer is completely air-impermeable, the oxygen remaining in the infusion bag is suppressed to the original low level. In the present invention, since the EVOH resin layer has a large thickness value of 20 to 60 μm in order to enhance the bending resistance of the bag-like body at the time of filling with the chemical solution, even if the oxygen permeability of the plastic film within 12 hours after the wet heat sterilization treatment is maximum. Although it is only about 300cc / m ² · day · atm, after the chemical barrier is filled with inert gas such as nitrogen gas, the residual oxygen amount at the time of filling is kept to 3cc or less, so that the gas barrier property of the EVOH resin layer is completely restored. Can exert an effect of suppressing the amount of residual gas in the infusion bag to a level at which stable storage stability of infusible infusion preparations such as amino acid preparations and some vitamin preparations can be secured.

FIG. 1 is a plan view of an infusion container embodying the present invention. FIG. 2 is a sectional view taken along the line II-II of FIG. FIG. 3 is a sectional view taken along the line III-III of FIG. FIG. 4 is a schematic cross-sectional view of a multi-layer film that constitutes the infusion bag in the infusion container of FIG. FIG. 5: is a figure explaining shaping | molding of the bag-shaped body from a tubular film sheet. FIG. 6 is a diagram schematically showing steps (a)-(c) in the process of manufacturing an infusion solution container from the bag-shaped body of FIG. FIG. 7 is a view schematically showing this step (d)-(e) following FIG. FIG. 8 is a diagram schematically illustrating a step of leaning the bag-shaped body on a tray for filling the bag-shaped body with the liquid medicine. FIG. 9 is a diagram schematically illustrating a film loop strength measuring method by the stiffener tester method. FIG. 10 is a graph showing the relationship between the oxygen permeability and the elapsed time after sterilization (days) for each value of the thickness X of the EVOH resin layer in the plastic film constituting the infusion container of the present invention.

[Infusion bag and its multi-layer plastic film]
The infusion bag in the infusion container of the present invention is composed of a multi-layered plastic film, and is provided with an infusion bag for filling a drug solution, and a plastic port member such as a discharge port and a mixed injection port fixed to the outer periphery of the infusion bag. are doing.

  Since the multilayer plastic film that constitutes the infusion bag is used as an infusion bag by suspending it on a stand, it is not suitable if it is too thin, and if it is too thick it will not be easy to handle, so its thickness (total thickness of the multilayer film) Is 200 μm to 300 μm. A polyolefin resin can be used for the base layer of the plastic film from the viewpoints of transparency and cost, and the polyolefin resin includes polyethylene resin, polypropylene resin and the like, and polyethylene is most preferable from the viewpoint of infusion use. As will be described later, the multilayer film that constitutes the infusion bag has at least one layer that increases the loop strength when the drug solution is filled, and softens after moist heat sterilization of the infusion bag filled with the drug solution to reduce the elastic modulus to an appropriate value. For this purpose, a non-polyethylene layer such as an ethylene-vinyl alcohol copolymer resin or a polyamide resin is provided, and the above thickness range includes the non-polyethylene layer.

  The infusion bag in the infusion container of the present invention has a vertically long substantially rectangular flat shape. Such an infusion bag has a tubular plastic film as a sheet, and the sheet is welded along the contour line of the infusion bag (non-peelable welding) and cut along the welded portion to obtain the upper and lower parts. A vertically long bag-like body is obtained in which the outer periphery of the plastic multilayer film section is welded up and down according to the outline of the infusion bag. The bag has a state in which a port member (a discharge port in the case of only one side, a discharge port in the case of both sides, a discharge port in one side, a mixed injection port in the opposite side) is attached by welding to the welded part on one side or both sides in the vertical direction. Has become. In the practice of the present invention, as will be described later in detail, when the bag-shaped body is filled with the liquid medicine, the vertically long bag-shaped body is leaned against a tray having a key-shaped cross section. Since the port member is already attached to the end, the bag is placed horizontally so as not to interfere with the port member. The free part of the bag-like body that protrudes from the part higher than the side wall of the tray is held upright by gripping it on both sides with chucks, and the upper part of the bag-like body in the horizontal state is cut off to open it, and the chemical solution is filled. Do. Since the tray is leaned against the tray and the tray is erected upright for filling, the multilayer plastic film forming the bag-shaped body needs to be difficult to bend. If it is chucked while it is bent, it is not possible to ideally discharge air by nitrogen replacement when filling the chemical liquid, and it becomes impossible to suppress the residual air amount to the desired value (3 cc as described above), eventually filling the chemical liquid. Will result in defective products and increase costs. Regarding the bending resistance when the chemical solution bag is leaned against the tray, the bending becomes difficult even by increasing the thickness of the film. Regarding the film thickness, it cannot be made too thick due to the handling property of the finished product as described above. As a result of earnest studies on the difficulty of bending when leaning, the present inventors have found that there is a strong correlation between the loop strength of the film by the stiffness tester method, and the loop strength by the stiffness tester method is 500 mN or more, preferably 570 mN. In view of the above, it has been found that no bending occurs when it is leaned against, an incorrect chuck does not occur, and good workability of filling the chemical liquid can be obtained. The loop strength has a certain degree of correlation with the elastic modulus of the film, although it does not have a one-to-one relationship. When the loop strength is 600 mN or more, the elastic modulus is 500 Mpa or more, but after the heat-and-moisture sterilization treatment, the normal elasticity is obtained. It was found that the film did not become too hard even when it was made into a product by setting the pressure to 400 Mpa, which is about the same as an infusion bag made of a polyethylene multilayer film, and a tear did not occur even if the product was dropped.

Further, as to the elastic modulus of the film, as described above, it is 500 MPa or more in relation to the film loop strength before sterilization, and the fact that the elastic modulus is high means that it is a port member to the bag-like body for filling the chemical liquid. Adhesion over the entire circumference (sealability) and ease of swelling when the bag-shaped body is filled with the drug solution (drug solution filling property) can be deteriorated. It was found that by setting the elastic modulus of the film to 700 MPa or less, it is possible to secure necessary performances in terms of sealing property and chemical liquid filling property.
As the multilayer film exhibiting such characteristics, in addition to the base material layer such as polyethylene described above, polyethylene as a base material is used in order to reliably perform the chemical solution filling with the bag body leaning before the chemical solution filling. The film is made flexible (reinforcement of the film) by strengthening layers etc. to make it difficult to bend (enhancing the loop strength) and filling it with a chemical liquid to prevent it from dropping after tearing after moist heat sterilization. It has a special layer for lowering). Examples of plastics for forming such a special layer in the multi-layer film of the present invention when filled with a chemical solution include ethylene-vinyl alcohol copolymers and polyamide resins. Since these resins have oxygen impermeability, they are suitable for accommodating infusible infusion preparations such as amino acids. Among these resins, ethylene-vinyl alcohol copolymer resin (hereinafter referred to as EVOH resin) is preferable from the viewpoint of infusion use. The ethylene content in the EVOH resin is 19 to 38 mol from the viewpoint of heat resistance in the sterilization step at 110 ° C. or higher required for infusion products.

  The infusion solution container of the present invention is subjected to heat sterilization treatment after the drug solution is filled and sealed. The heat sterilization treatment is performed with steam under moist heat, and the conditions thereof are a temperature of 105 ° C. to 115 ° C. and a heating time of 20 minutes to 40 minutes.

  The EVOH resin layer has a thickness of 20 μm to 60 μm, preferably 30 μm to 50 μm in the above-mentioned total thickness range of 200 μm to 300 μm in the multilayer film. As is well known, EVOH resin has oxygen impermeability, and can be used as a so-called oxygen barrier layer for infusion preparations such as amino acid preparations and vitamin preparations that are susceptible to oxidative deterioration.

  In the present invention, the infusion container is stored in the outer bag together with the oxygen scavenger immediately after the sterilization process, and the outer bag is sealed by welding to form a final product. The exterior bag can be formed of a gas barrier aluminum vapor deposition film or aluminum foil.

It is known that the EVOH resin loses its oxygen impermeability temporarily when the vinyl alcohol bond reacts with water when heated in the presence of water. It is essential for the infusion bag to be subjected to the moist heat sterilization process after filling and sealing the drug solution, and even when at least one of the multilayer films constituting the infusion bag is made of EVOH resin, it is temporarily oxygen permeable after the moist heat sterilization. Is gradually decreased with time (oxygen permeability), and finally returns to the original state of functioning as an oxygen barrier before the wet heat sterilization process. The oxygen permeability after sterilization by moist heat is represented by the amount of oxygen per unit area of film per day at 1 atm (cc / m ² · day · atm). In the technique of Patent Document 2, the oxygen permeability after sterilization by moist heat is set to 200 cc / m ² · day · atm or more within 12 hours after the sterilization treatment. In the technique of Patent Document 2, the amount of residual air in the infusion bag after filling the chemical solution is large because oxygen substitution is not performed during filling the chemical solution, but the oxygen permeability is 200 cc / m ² within 12 hours after sterilization treatment. By setting it to more than day · atm, a large amount of oxygen remaining in the infusion bag is absorbed by the oxygen scavenger contained in the outer bag through the film forming the infusion bag, and finally the oxygen in the infusion bag is It is said that the dissolved oxygen concentration can be reduced to a level at which stable storage stability of infusible infusion preparations such as amino acid preparations and vitamin preparations can be secured. In the present invention, the oxygen permeability after moist heat sterilization is at most 300 cc / m ² · day · atm within 12 hours after the sterilization treatment. This is because the EVOH resin layer is thickened to increase the loop strength of the multilayer film constituting the infusion bag in order to obtain posture stability when the infusion bag is leaned against the infusion bag. That is, also in the present invention, the infusion bag after the heat and moisture treatment is housed together with the oxygen scavenger in an outer bag having a gas barrier property, so that oxygen remaining in the infusion bag can be adsorbed through the film constituting the infusion bag. However, the permeability of residual oxygen is not good as compared with the technique of the cited document 2. However, according to the study by the present inventors, by setting the residual oxygen amount in the infusion bag head space to 3 cc or less as the value immediately before sterilization after filling the chemical liquid, the oxygen permeability after sterilization by moist heat is 12 hours after the sterilization treatment. Even when the maximum is about 300 cc / m ² · day · atm, it is possible to make the amount of oxygen remaining in the infusion bag equal to that in Patent Document 1 at the time of equilibrium when the oxygen permeability is restored. When filling an infusion bag with a drug solution, a step of replacing the infusion solution injection site of the infusion bag with an inert gas such as nitrogen is additionally required, but with respect to the amount of 250 cc to 500 cc of the drug solution contained in the infusion bag, It is sufficient to set the head space of the infusion bag to 20 cc to 60 cc and the residual oxygen amount to 3 cc if the nitrogen substitution rate of the space above the liquid surface of the infusion bag is 5% to 15%, and the inert gas substitution is performed. It is not necessary to be technically special, and it can be said that it is a factor of cost increase, but it is not so much, and workability (prevention of unauthorized chucking) in the case of horizontally placing the chemical liquid as in the present invention is prevented. It does not outweigh the benefits of improvement.

According to the present invention, the oxygen permeability after moist heat sterilization is up to 300 cc / m ² · day · atm within 12 hours after the sterilization treatment. Therefore, in a formulation that releases carbon dioxide gas such as a baking soda formulation used for dialysis, sterilization is performed. Since the release of carbon dioxide gas is sometimes suppressed, there is an advantage that the increase in pH can be suppressed.

  The infusion container of the present invention may be one in which the drug solution is stored in the infusion bag or two or more spaces. When there is only one space for accommodating the drug solution, it is suitable for an amino acid preparation such as isoleucine or leucine or a specific vitamin preparation (such as ascorbine) which is susceptible to oxidation. In addition, the present invention can be applied to the case where there are two or more spaces for containing the drug solution, and these spaces are formed by peelably welding the upper and lower opposing surfaces of the infusion bag, and the drug solution is placed in each space. Fill. By pressing the infusion solution containing portion of the infusion solution bag at the time of infusion, the welded portion is peeled off, and the drug solutions contained in the respective spaces are mixed. In such a two-liquid mixed type, the drug solution contained in one space is an amino acid preparation or a specific vitamin preparation (such as ascorbine), and the drug solution contained in the other space is glucose or electrolyte. Etc.

  As the infusion solution container of the present invention, there is also an infusion solution bag of the above-mentioned two-chamber (or multiple-chamber) type in which a small bag is installed. The small bag is for accommodating trace elements such as iron and magnesium, and is designed to open in tandem with the opening of the peeling seal for mixing chemicals between the two chambers. A small amount of drug from a small bag is mixed with the mixed drug solution.

  In a preferred embodiment of the present invention, the multi-layer film has a base layer of polyethylene, which has a single-layer or multi-layer structure having an appropriate density on each of the outer layer side and the inner layer side, and between the polyethylene layers of the inner layer and the outer layer. It has a total of 5 to 6 layers in which an EVOH resin layer is arranged via an adhesive layer made of polyethylene. Such a multilayer structure film is formed into a cylindrical shape by blow molding using annular nozzles arranged in concentric circles for the total number of films. Each annular nozzle is connected via a respective passage to a pelletized resin hopper for the respective material to be extruded therefrom. As for polyethylene, pellets having various densities are provided, and a desired density can be obtained by mixing the pellets at an appropriate ratio. The pellets from the hoppers are extruded by the screw extruders toward the annular nozzles, melted in the meantime, and blow-molded by blow air from the center of the nozzles to form a multilayer film.

[Specific structural example of infusion container according to the present invention]
1 to 3 show a multi-chamber container embodying the present invention. The structure of this multi-chamber container is the same as that of Patent Document 1 by the present inventors, and is formed of a multilayer plastic film. A sealed outer bag 10 (which is the infusion bag of the present invention in a state where a liquid medicine is housed in an inner compartment and sealed with a port member), an inner bag 12 also formed of a multilayer plastic film, and a plastic molded product. And a mixed injection port 16 which is a plastic molded product.

  The schematic structure of the multilayer film constituting the outer bag 10 is shown in FIG. 4, and has a six-layer structure, and the first layer which is the outer surface of the outer bag 10 is a surface layer made of polyethylene or the like, a second layer and a fourth layer. Is an adhesive layer made of polyethylene or the like, the third layer is a gas barrier layer made of EVOH resin or the like, the fifth layer is made of polyethylene or the like, and the sixth layer is the innermost layer of the outer bag 10 made of polyethylene or the like.

  In FIG. 1, the outer bag 10 has a substantially flat, vertically long rectangular shape, and as shown in FIGS. 2 and 3, the plastic soft film forming the outer bag 10 is a pair (upper and lower) of film pieces 18 and 20. And is formed into a bag shape by non-peelable welding, that is, strong sealing, on the entire outer edge along the facing surface. This strong seal portion along the outer bag 10 is indicated by reference numeral 22 in FIG. A discharge port 14 is fixed to the strong seal portion 22 at the lower part of the outer bag 10 and a mixed injection port 16 is fixed to the upper part of the outer bag 10 so as to maintain a liquid-tight state. The discharge port 14 and the mixed injection port 16 are integrated with the outer bag 10 at the strong seal portion 22. The discharge port 14 and the mixed injection port 16 are molded products of thick plastic that can maintain their cylindrical shapes, and their structures are basically the same, but the discharge port 14 will be explained. As shown in FIG. 2, a tubular body 23, a cap 24, and a rubber plug 26 are provided. The tubular body 23 has a distal end portion 23-1 integrated with the outer bag 10 by a strong seal portion 22. A cap 24 is fixed (welded) to the end of the cylindrical main body 23 by protruding to the outside of the outer bag 10 via the tapered portion 23-2. A rubber stopper 26 is attached to the end of the cap 24, and the rubber stopper 26 is for puncturing the needle of the infusion set. The mixed injection port 16 (FIG. 1) has a structure similar to that of the discharge port 14, and although not shown, it is provided with a rubber plug similar to the rubber plug 26 of the discharge port 14, so as to puncture a needle for mixed injection. You can do it.

  1 to 3, the strong seal portion (non-peelable weld portion) and the weak seal portion (peelable weld portion) are all formed by welding the film facing surfaces, but the cross section (FIGS. 2 and 3) clearly shows For the sake of improvement, the welded portions in the strong seal portion and the weak seal portion are indicated by thick lines (solid line for strong seal, broken line for weak seal).

  An opening 27 (FIG. 1) for suspending the infusion stand at the time of infusion is formed in the upper portion of the strong seal portion 22 on the outer periphery of the outer bag 10.

  In FIG. 1, reference numeral 28 is a weak seal portion formed by welding upper and lower film pieces 18 and 20 constituting the outer bag 10 so as to be peelable from each other on opposite surfaces (see also FIG. 3). The weak seal portion 28 extends over the entire width of the middle portion of the outer bag 10 in the height direction, that is, to the strong seal portions 22 on both sides of the outer bag 10 so as to be integrally fluid-tightly connected to the strong seal portions 22. Therefore, the inner space of the outer bag 10 is divided into upper and lower first and second compartments 29 and 30. The liquid medicines are individually (separated) contained in the first and second compartments 29 and 30. The weak seal portion 28 can be peeled off when the chemical solution containing portions of the compartments 29 and 30 are externally pressurized.

  The inner bag 12 is for storing trace elements such as iron and magnesium. The inner bag 12 has a flat and elongated rectangular shape and is housed inside the outer bag 10 between the lower compartment 30 and the discharge port 14. The inner bag 12 has a horizontally long rectangular shape, but the upper side portion which is close to the compartment 30 is connected and fixed to the outer bag 10 by the strong seal portion 34, and the inner bag 12 is opened in response to the hydraulic pressure inside the outer bag 10. Done. The inner bag 12 can be formed by forming a cyclic polyolefin resin (COP) surface layer (a layer to be the inner surface of the inner bag 12) on a base material layer made of a multilayer polyethylene film. Due to the strong affinity between the polyethylene layer and the COP resin layer, which form the base material layer, the resin can be molded into a bag shape while being firmly integrated under the heat of inflation molding. As shown in FIG. 2, the inner bag 12 is composed of upper and lower film pieces 36, 37, and the upper and lower film pieces 36, 37 are welded along the entire circumference. This welded portion is configured as a weak seal portion 40. The weak seal 40 internally forms the drug accommodating chambers 42 and 44 in which the trace element-containing liquids are separately accommodated. Since the strong seal portion 34 is strongly welded to the upper side of the weak seal 38 on the outer periphery of the inner bag 12 as shown in FIG. 1, the weak seal portion 28 is urged by an external force to mix the chemical liquid between the compartments 29 and 30. When opened, the weak seal portions 38, 40 of the inner bag 12 are also opened, and the chemicals are mixed. The inner bag 12 may be only one room.

  The discharge control chamber 46 is formed inside the outer bag 10 between the lower compartment 30 and the discharge port 14 and is always open to the discharge port 14. Further, the inner bag 12 is arranged inside the discharge control chamber 46 between the second compartment 30 and the discharge port 14 in a general positional relationship with the inner bag 12.

  The structure for fixing the inner bag 12 to the outer bag 10 will be further described. The upper side portion of the inner bag 12 extends to the strong seal portion 34 and the strong seal portion 22 in the width direction, and together with both side portions of the inner bag 12, the outer bag. A strong seal is made between the upper and lower film pieces 18 and 20 which form the film 10. Therefore, the inner bag 12 is fixed to the outer bag 10 in a state where the lower compartment 30 and the discharge control chamber 46 are separated. The discharge control chamber 46 is filled with a small amount of water, and at the time of sterilizing the infusion container after filling the compartments 29, 30 with the chemical liquid, the small amount of water filled in the discharge control chamber 46 becomes steam, and the outer bag 10 It can be used for efficient sterilization of the outer peripheral portion of the inner bag 12 inside the container. Further, on the side of the discharge port 14 of the inner bag 12, the inner surface of the outer bag 10 is welded to the inner bag 12 at the weak seal portion 38 by the local strong seal 47, and this local strong seal 47 is also described in Patent Document 1. The inner bag 12 is opened smoothly as described above.

[Explanation of manufacturing process of infusion container in the present invention]
Next, the aligning process of the infusion container of FIGS. 1 to 3 will be described. The multilayer film blow-molded as described above is flatly crushed into a sheet, which is once wound up on a roll. In FIG. 5, reference numeral 50 indicates a sheet pulled out from the roll, and the sheet is in a state in which two upper and lower layers are stacked. The seat 50 is shown only on one side of the center line L. The sheet 50 is subjected to strong welding (non-peelable welding) of upper and lower layers in a repeating pattern (one repeat is indicated by a) as shown in FIG. Further, one repeat length a corresponds to one infusion bag. Similar patterns are formed symmetrically on the opposite side of the center line L. That is, it is possible to cut out a bag-shaped body to be two infusion bags from one repeat length a. A strong sealing die is installed at a predetermined position in the sheet feeding direction, and in the same station, non-peelable welding of upper and lower layers (strong sealing) is performed between the sealing dies outside the contour line 52 in one repeat length a, The inside of the contour line 52 is not welded and remains as the cavity of the infusion bag. The weak seal mold is arranged at a processing position on the downstream side of the strong seal mold, and the weak seal mold is peelable welded at the portion 54 crossing the strong weld part, which results in the weak seal part 28 of the product. Becomes Then, in the cutting station from the sheet 50, the bag-shaped body 58 is cut out along the contour line 56.

  6 (a)-(c) and FIG. 7 (d)-(e), the manufacturing process of the infusion bag of FIGS. In a), the parts 58-1, 58-2, 58-3 become the part of the strong seal portion 22 on the outer periphery in the final product (FIG. 1), and the part 54 becomes the weak seal 28 in the final product as described above. It is a part. In the parts indicated by 60 and 62, the upper and lower film sections present cavities that have not been welded, the cavities 60 become the upper compartments 29 of the product, the cavities 62 become the lower compartments 30 of the product, and the inner bag 12 This is the part that serves as the accommodation site. An unwelded portion 64 between the welded portions 58-1 and 56-2 is an opening portion for mounting the mixed injection port 16 in a later step. The unwelded portion 66 between the welded portions 58-2 and 58-3 is an opening for introducing an infusion solution into the cavity 60 which becomes the upper compartment 29 of the product.

  In FIG. 6A, the inner bag 12 is in a completed state. As already described with reference to FIGS. 1 to 3, the inner bag 12 has a weak seal portion 38 on the outer periphery, and a small amount of the medicine is already stored in the medicine storage chambers 42 and 44. Although the bag-shaped body 58 is illustrated as being placed horizontally in FIG. 6A, it is preferable that the inner bag 12 is arranged vertically and the inner bag 12 is inserted from the lower side. That is, the bag-like body 58 is attached to the pair of suction cups (not shown) from both sides in the cavity portion 62, and the film is opened in the cavity portion 62 by moving the pair of suction cups away from each other. In this state, the inner bag 12 is sent out in the direction of the arrow by the robot, and the inner bag 12 is set at the fixed position 14 ′ in the hollow portion 62.

  Step (b) shows a step of fixing (strongly sealing) the bag-shaped body 58 after inserting the inner bag 12 into the bag-shaped body 58. In this case, the bag-like body 58 is sequentially positioned between a series of seal dies (not shown), and the series of seal dies are sequentially combined in the vertical direction, whereby the weak seal portion 38 of the inner bag 12 in the longitudinal direction. The welded portions 58-4 and 58-5 for integrating both side portions with the bag-like body 58 and the side portion on the lower compartment 30 side of the inner bag 12 in the product (FIG. 1) are integrated with the outer bag 10. The strong seal portion 34 is formed, and the cavity portion 62 in FIG. 6A becomes a cavity portion 70 whose lower side is closed in FIG. 6B. The welded portion 58-5 forms an opening 68 together with the welded portion 58-3, and the opening 68 serves as an opening for filling the chemical solution into the cavity 70 that serves as the lower compartment 30 of the product. Further, the welded portion 58-4 forms an opening 72 that serves as a mounting portion for the discharge port.

  Although the seal molds for forming the welded parts 58-4, 58-5, 34 are separately configured, in particular, regarding the operation of the seal molds for forming the strong seal part 34, the strong seal part 34 The sealing mold for forming the sheet has a heating surface having a size corresponding to the size of the sealing portion 34, but the inner surface of the film pieces 18 and 20 forming the outer bag 10 and the inner bag 12 are formed. The outer surfaces of the films 36 and 37 are polyethylene films, and the end portion 36-1 of the inner bag 12 shown in FIGS. , 37-1 (FIG. 2) are strongly sealed to form a strong seal portion 34. The sealing mold naturally pressurizes the inner surfaces of the end portions 36-1, 37-1 of the film pieces 36, 37 forming the inner bag 12 that extend toward the compartment 30 side. Since the cyclic polyolefin resin forming the inner surface has a high melting temperature, the end portions 36 of the film pieces 36, 37 forming the inner bag 12 extending to the compartment 30 side in the sealing die heated to about 150 ° C. The inner surfaces of 1, 37-1 are not welded. Further, the heat of the sealing mold is also applied to the weak seal portion 38 of the inner bag 12, but the weak seal portion 38 remains a weak seal.

  In step (c) of FIG. 6, the mixed injection port 16 is inserted into the opening 64, the upper and lower films forming the opening 64 are welded to the opposing surface of the mixed injection port 16, and the mixed injection port 16 is sealed at the entire circumference. In addition, the discharge port 14 is inserted into the opening 72, the discharge port 14 is attached to the unsealed portion of the bag-shaped body 58 around the periphery and strongly sealed, and the upper and lower films forming the opening 72 are removed. It is welded to the opposite surface of the discharge port 14 so that the discharge port 14 is sealed around the entire circumference. At the time of welding each of the mixed injection port 16 and the discharge port 14, a pair of upper and lower sealing molds having a substantially semi-circular heating surface is used, and the upper and lower films forming the openings 64 and 72 are mixed and mixed. 14 is pressed and sealed. At this time, if the film is too hard, it becomes difficult for the film to follow the mixed injection port 16 and the discharge port 14 along the entire circumference, and seal leakage may occur. Therefore, from the viewpoint of adhesion to the peripheral surfaces of the mixed injection port 16 and the discharge port 14, the hardness (= elastic modulus) of the film has an upper limit, and the upper limit is about 700 MPa as described later.

  FIG. 7 (d) shows a step of filling the drug solution into the hollow portions 60, 70 of the bag-like body that will become the first and second compartments 29, 30 in the product (FIG. 1). Since the openings 66, 68 of the bag-like body 58 for filling the drug solution are opened laterally, the drug solution should be filled upright with the vertically elongated bag-like body 58 as shown in FIG. 7D. Is done. FIG. 8 schematically shows an apparatus for standing the bag-shaped body 58 in a horizontal state. As shown in FIG. 8, the bag-shaped body 58 is held by suction at the tip of the robot arm 75 near the center thereof. The cup 76 is suction-held. The robot arm 75 can be moved forward / downward, carried to the tray 78 having a key-shaped cross section as shown in FIG. 8, and the suction of the suction holding cup 76 can be released to lean the bag-like body 58 on the tray 78. The suction holding cup 76 is retracted to the initial position. The holding tray 78 has a sufficient groove width for the robot to attach it to the tray 78, and the bag-shaped body 58 is located on the holding tray 78 in a state where it is higher than the tray 78 in the key shape in cross section. Slightly lean to lean against the wall. A pair of chucks 80 are provided apart from each other in the direction orthogonal to the paper surface of FIG. 8, and each chuck 80 has a pair of gripping portions 80A and 80B. Although the chuck 80 is normally retracted in the direction orthogonal to the paper surface of FIG. 8 and the pair of gripping portions 80A and 80B are open, when the bag-like body 58 is leaned against the tray 78, it is orthogonal to the paper surface of FIG. Direction to a predetermined position. Then, the pair of gripping portions 80A, 80B of each chuck 80 move forward so as to face each other as shown by the arrows, and the pair of gripping portions 80A, 80B are located at both upper end portions of the bag-like body 58 as shown by 80A ', 80B'. And the bag-like body 58 is positioned upright on the tray 78 as indicated by an imaginary line 58 '. FIG. 7D shows the state of gripping the upper and lower sides of the bag-like body 58 by the gripping portions 80A 'and 80B' of the pair of chucks 80. Then, in the upright state of the bag-shaped body 58 on the tray 78, the cavity portions 60, 70 are filled with the chemical liquid. That is, in FIG. 7D, the chemical liquid filling pipes 82 and 84 are positioned so as to face the openings 60 and 70, respectively. Nitrogen gas pipes 86 and 88 for nitrogen substitution are arranged in parallel in the chemical liquid filling pipes 82 and 84, respectively. The film forming the bag-like body 58 is engaged and adsorbed on the suction cups (not shown) from both sides at the portions forming the openings 60 and 70, and the films forming the bag-like body 58 by separating the respective suction cups. Are opened on both sides and the openings 60, 70 are wide open. Then, the chemical liquid filling pipes 82, 84 and the nitrogen gas pipes 86, 88 arranged side by side are introduced into the hollow portions 60, 70 through the openings 60, 70. Then, while injecting nitrogen gas to replace the cavities 60 and 70 with nitrogen, an infusion solution is introduced into the cavities 60 and 70 from the filling pipes 82 and 84.

  The bag-like body 58 leans against the tray 78 slightly obliquely for filling with the chemical liquid, but a portion above the wall surface of the tray 78 may be bent as an imaginary line 58 ″ in FIG. Therefore, the bag-like body 58 chucked by the chuck 80 also remains bent, and the chemical solution is filled as it is, the air is not discharged properly by nitrogen substitution, and the residual oxygen amount can be suppressed to a desired level. According to the study of the present inventors, such bending of the bag-like body 58 has a strong correlation with the film loop strength by the stiffene tester method, and the film loop strength is 500 mN or more, preferably 570 mN or more. As a result, efficient filling of the chemical liquid can be realized without causing a chuck error.

  FIG. 7 (e) is completed as an infusion bag by strongly sealing the upper edge facing surface of the film forming the openings 60, 70 of FIG. 7 (d) after the completion of filling with the chemical solution and forming the local strong seal 47. The state (FIG. 1).

By a well-known blow molding method, a tubular film (film diameter: 440 mm) having a six-layer structure shown in FIG. 4 was obtained. The first layer was a polyethylene layer serving as the outer layer of the infusion bag (polyethylene density = 0.93, and the thickness was 50 μm).

  The second layer and the fourth layer were adhesive layers made of polyethylene (polyethylene density = 0.89) and had a thickness of 20 μm.

  The third layer was a gas barrier layer made of EVOH resin, which was obtained from pellets of EVAL under the trade name of Kuraray Co., Ltd., and the ethylene content in the EVOH resin constituting this layer was 27 mol.

  The fifth layer is a layer of an infusion bag made of polyethylene (polyethylene density = 0.9).

  The sixth layer is the innermost layer of the polyethylene infusion bag (polyethylene density = 0.95).

  Regarding the thickness (X) of the gas gas barrier layer of the third layer and the thickness (Y) of the polyethylene layer of the fifth layer, the thickness X of the gas gas barrier layer of the third layer is 10μ, 20μ, 30μ, 40μ, 50μ, 60μ. And the thickness (Y) of the fifth layer (polyethylene layer) is 145μ, 135μ, 125μ, 115μ, 105μ, 95μ, that is, X + Y = 155μ, and 6 layers The total thickness was fixed at 50 + 20 × 2 + 155 + 25 = 270 μm. In this way, a blow-molded tubular film composed of six types of multilayer films having an EVOH resin layer was obtained. With respect to each of the tubular films having the respective thicknesses X of the six types of gas gas barrier layers, the bag-shaped body was formed, the chemical solution was filled, the infusion container was formed by sealing the opening, and the wet heat treatment was performed in the following procedure. From the test results shown in the table, the third layer is the first, second, third and fourth examples of the present invention for the thickness X = 20μ, 30μ, 40μ, 50μ in the gas barrier layer made of EVOH resin, The thicknesses X = 10 μ and 60 μ are the first and second comparative examples, respectively.

  The blow-molded multilayer film is crushed into a sheet shape (sheet width is 440 mm) and wound into a roll to form a roll. For the sheet pulled out from the roll, for each sheet section a in the longitudinal direction shown in FIG. A strong seal having a pattern shown (sealing temperature: 150 ° C.) was performed, and a bag 58 having a length of 380 mm and a width of 280 mm was obtained by cutting along a cutting line 56.

  An outer layer (thickness 20 μm) made of polyethylene resin (density = 0.93), an adhesive layer (thickness 90 μm) made of polyethylene resin (density = 0.94), and a cyclic polyolefin resin (trade name of Nippon Zeon Co., Ltd.). A multi-layer film consisting of three inner layers (20 μm thick) made of Zeonex pellets) was welded to the outer peripheries of the inner layers in a peelable manner (welding temperature = 170 ° C.) and separated into compartments 42, 44 defined by a peelable seal 40. An inner bag 12 having a length of 170 mm and a width of 50 mm, each containing a trace element-containing liquid, was obtained.

  As shown in FIG. 6 (a), the inner bag 12 is introduced into the bag-shaped body 58 and sealed with a series of seal dies (seal temperature is 150 ° C.), and the non-peelable welded portion 34 shown in FIG. 6 (b). , 58-3, 58-4, 58-5, 58-6 and openings 64 and 72 were obtained. Next, as shown in FIG. 6 (c), the mixed injection port 16 and the discharge port 14 are inserted into the openings 64 and 72 of the bag-like body 58, respectively, and the openings are formed by a seal mold having a semicircular cross section (the sealing temperature is 150 ° C.). By pressing the film parts forming 64 and 72 against the mixed injection port 16 and the discharge port 14 and welding them, the mixed injection port 16 and the discharge port 14 are integrated with the bag-like body 58, respectively, and the infusion bag in which the drug solution filling is completed. Got At this time, the adhesion of the film parts forming the openings 64 and 72 to the mixed injection port 16 and the discharge port 14 in the entire circumference is evaluated by the seal strength, the visual judgment of leakage or not, and the microscopic observation. The results are shown as sealability.

  Further, a film loop strength test was performed on the multilayer film constituting the bag-shaped body 58 by the stiffness tester method. This film loop strength test was performed using a stiffene tester (manufactured by Toyo Seiki Seisakusho). That is, the plastic film forming the bag-shaped body 58, that is, the infusion bag before sterilization is cut into a test piece S having a width of 15 mm and a length of 150 mm, and this test piece is chucked with a stiffener tester 90 as shown in FIG. , 92 to make a loop with a length of 100 mm between them, and the repulsive force (unit: mN) when crushing the loop at a crushing distance of 15 mm and a crushing speed of 3.3 mm / sec by the pressurizing portion 94 of the stiffener tester. ) Was measured. The results are shown in the table.

  Similarly, the plastic film forming the bag-like body 58 was cut into a test piece having a width of 15 mm and a length of 150 mm, and the elastic modulus of the test piece was measured by a tensile tester (manufactured by A & D Co., Ltd.). . The tensile test condition was that the chuck was mounted at a distance of 100 mm, and the pulling speed was 50 mm / min. The results are shown in the table.

  The bag-like body 58 obtained as shown in FIG. 6D was held by the robot arm by adsorbing the central portion thereof with a suction cup as shown in FIG. 8, and leaned against the tray 78. A sensory evaluation was performed on each sample as to whether or not the infusion bag at this time was kept in a standing state without being bent, and the results are shown in Table 1 as bending resistance.

  The bag-like body 58 leaning against the tray 78 is chucked by the chucks 80 on both upper sides of the tray 78, and is erected upright as shown by an imaginary line 58 'in FIG. 8, and then the openings 66, 68 of the bag-like body 58 are suction cups. 7 (d), the filling pipes 82 and 84 and the nitrogen gas pipes 86 and 88 are inserted through the openings 66 and 68 so as to face the cavities 60 and 70 of the bag-like body 58, and the chemical solution is opened. Was filled. The cavity 60 was filled with 300 cc of the amino acid- and vitamin-containing liquid, and the cavity 70 was introduced with 500 cc of the glucose- and electrolyte-containing liquid from the nozzle, and the amount of nitrogen gas ejected at that time was 10 to 16 L / min. . The film parts forming the openings 66, 68 are sandwiched by a seal mold (seal temperature 150 ° C.) immediately after filling the cavity parts 60, 70 with the drug solution, and the infusion container shown in FIG. Obtained. The bag-shaped body 58 needs to swell in response to an increase in the filling amount when the hollow portions 60 and 68 are filled with the chemical liquid, and the filling amount depends on whether or not a smooth bulge is obtained. Evaluation was performed.

  The infusion container obtained as shown in FIG. 6 (e) was immediately subjected to sterilization under moist heat. The sterilization conditions were a steam temperature of 110 ° C., a pressure of 0.2 atm, and a sterilization time of 25 minutes.

  The infusion bag after sterilization was sealed together with an oxygen scavenger (trade name “Ageless” manufactured by Mitsubishi Gas Chemical Co., Inc.) in an outer bag made of an aluminum vapor deposition film having a size of 330 mm × 330 mm without a gap.

In addition, regarding the infusion bags after sterilization of Examples 1 to 4 and Comparative Examples 1 and 2 provided with the EVOH resin layer, the oxygen permeability of the multilayer film constituting them was measured using OX-TRAN2 / 20 manufactured by MOCON. , JIS K 7126 B method (isobaric method). The results are shown in the figure. In the figure, the horizontal axis represents the elapsed time (days) after sterilization, and the vertical axis represents the oxygen permeability (cc / m ² · day · atm). The values of oxygen permeability after 12 hours (half a day) after the sterilization treatment are shown in the table.

Comparative example

  For a polyethylene single-layer film (polyethylene resin density was 0.93) and a thickness of 250 μm, an infusion container was manufactured by the same procedure as described in the above examples. This is Comparative Example 3.

  For a three-layer polyethylene film (resin composition is density 0.95 / 0.92 / 0.95) and a thickness of 300 μm, an infusion container was manufactured by the same procedure as described in the above examples. This is Comparative Example 4.

  A polypropylene multi-layer film (trade name "Cryovac" manufactured by Shield Air Japan G.K.) having a thickness of 190 .mu. Was manufactured by the same procedure as described in the above examples. This is Comparative Example 5.

  The values of elastic modulus and loop strength before and after sterilization in Table 1 are average values of three data for each Example and Comparative Example.

[Examination of test results]
Even if the gas barrier layer made of EVOH resin is provided as shown in Table 1, when the thickness X = 10 μ as shown in Comparative Example 1, since the loop strength is small, the bag-shaped body is laterally filled for infusion filling. When it was leaned against the tray, it was easy to bend, and there was a great deal of false chuck mistakes. In the case of X = 20 μ, good bending resistance was generally obtained, but there were cases in which bending did not occur frequently but there were cases where it was bent, so it was marked with Δ. Further, when the thickness X of Comparative Example 2 was 60 μm, the loop strength was large, and thus the filling property was naturally good, but the elastic modulus of the film was too large (the film was too hard). The bulge was not obtained sufficiently, which hindered the filling of the desired amount of chemical liquid, and it was difficult to stick the chemical liquid port member along its entire circumference when sealing the port member, and the sealing property was likely to be poor (indicated by x). . Since the EVOH resin is more expensive than the polyethylene resin or the like, it is advantageous to set the upper limit of the thickness of the EVOH resin layer from the viewpoint of cost. On the other hand, in the case of the gas gas barrier layer thickness X = 20 μm, 30 μm, and 40 μm (Examples 1 to 4), the loop strength before sterilization is appropriate, so that the filling property is good and the elasticity is high. The rate was not too high, and the port sealing property and filling property were good. When X = 50 μ, it is generally good, but since the elastic modulus is high, the filling property and the port sealing property are slightly inferior, and therefore the judgment is Δ. In addition, even if the elastic modulus before sterilization is high, the elastic modulus after sterilization falls to an appropriate value that is almost the same as that of conventional infusion bags made of polyethylene or the like (elastic modulus is 400 mN or less), so the handling of the product is not impaired. Turned out not. In particular, the cases where the thickness X of the gas / gas barrier layer of Examples 2 and 3 was 30 μ and 40 μ were the best modes from the viewpoint of harmonization of the filling property and the port sealing property. From Table 1, whether the filling property and the port sealing property are good or bad depends on the elastic modulus at the time of filling the chemical solution, in other words, before sterilization, and the elastic modulus is preferably 700 mN or less.

  In the case of Comparative Examples 3 to 5 not including EVOH resin, since the elastic modulus was small, there was naturally no problem of port sealing property and filling property, but the loop strength was not sufficiently high, and therefore the present invention was concerned with bending resistance. It can be seen that it is clearly inferior to the example.

FIG. 10 shows changes in oxygen permeability with respect to elapsed time after sterilization (days) in Comparative Examples 1 and 2 and Examples 1 to 4 provided with a gas barrier layer made of EVOH resin. The values of oxygen permeability after 12 hours are shown in Table 1. Oxygen permeability after a lapse of 12 hours in the present invention is a 300cc ^/ m 2 · day · atm at most, be reduced if the number of days has passed almost same value of about 1.5cc ^/ m 2 · day · atm I understand.

In addition, Table 2 shows that a bag-shaped body having an inner size of 110 mm × 235 mm was prepared for the film of Example 2, filled with ascorbic acid (115% liquid) and sealed, and the residual oxygen amount was 0 cc, 1 cc, 2 cc, 3 cc, 5 cc, The actual filling amount value expressed as a% value with respect to the specified filling amount value of 300 cc when changed to 10 cc was measured at the initial stage, 25 ° C. for one month, and 40 ° C. for one month. Show. It can be seen that by suppressing the residual oxygen amount to 3 cc or less, an actual filling amount of 100% or more can be obtained at the end of January regardless of the quality deterioration with time.

DESCRIPTION OF SYMBOLS 10 ... Outer bag 12 ... Inner bag 14 ... Discharge port 16 ... Mixed injection port 22 ... Strong seal part 26 ... Rubber plug 28 ... Weak seal part 29 ... First compartment 30 ... Second compartment 34 ... Strong seal part 38 ... Weak seal part 40 on the outer periphery of the inner bag ... Weak seal part 46 that divides the inside of the inner bag ... Ejection control chamber 50 ... Multi-layer tubular film sheet 58 ... Bag-shaped body 76 ... Suction of a robot for holding the bag-shaped body Cup 78 ... tray 80 for leaning the bag-like body ... chuck
80A, 80B ... Chuck grip
82, 84 ... Chemical filling pipe
86, 88 ... Nitrogen gas pipe

Claims (5)

An infusion bag having a compartment in which a cavity of a bag-shaped body made of a plastic film is filled with a liquid medicine and sealed, and a port member which is a plastic molded product fixed to an outer peripheral portion of the infusion bag. The bag-shaped body has a flat bag-shaped shape having no gusset directly bonded to the entire upper and lower surfaces of the film forming the bag-shaped body except for the welded portion to the port member, and is sterilized by moist heat. Before, the plastic film had an elastic modulus of 449 to 693 Mpa, and the film loop strength by the stiffene tester method was 550 to 635 mN when the test piece was 15 mm wide and 270 μm thick, and the elastic modulus of the plastic film was After the wet heat sterilization treatment, it was 342 to 359 MPa, and the amount of the liquid medicine filled in the compartment was 250 cc to 500 cc. Horizontal infusion filling properties during leaning good infusion container.   In the invention according to claim 1, the plastic film forming the bag-like body has a multilayer structure having a total thickness of 200 μm to 300 μm, and one of the layers is an ethylene-vinyl alcohol copolymer having a thickness of 20 to 60 μm which functions as a gas barrier layer. An outer bag, which is made of a polymerized resin and has a residual oxygen content of 3 cc or less with respect to the liquid filling amount of 250 cc to 500 cc in the infusion bag, accommodates the infusion bag sterilized by moist heat, and further contains an oxygen scavenger. Infusion container.   The invention according to claim 1 or 2, wherein the infusion bag comprises a plurality of compartments partitioned by a peelable seal, and each compartment contains a drug solution.   4. The infusion container according to claim 3, wherein the infusion bag includes an outer bag having the compartment and an inner bag containing a drug solution, and the inner bag is opened when the peelable seal is opened. 2. The method for producing an infusion container according to claim 1, wherein a bag-shaped body is formed by vertically stacking two vertically-long rectangular plastic film pieces for forming an infusion bag, and the outer periphery is a chemical solution between the plastic film pieces. It is formed by welding, leaving an opening communicating with the filling cavity, and the bag-like body is placed horizontally so that the opening is located above and is leaned against a tray for filling with the chemical liquid, and after the chuck so that it stands upright. infusion is filled into the cavity from the opening, then Ri by to welding site two sections of the plastic film forming the opening, the manufacture of medical solution container forming a compartment sealing the drug solution Method.

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