JP6898478B2 - Infusion container and its manufacturing method - Google Patents

Description

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

An infusion container including an infusion bag in which a bag-shaped body made of a plastic film is filled with a chemical solution and sealed, and a port member which is a plastic molded product fixed to the outer periphery of the infusion bag is known. is there. The infusion container is put into an outer bag after undergoing a sterilization process under moist heat to be a product. As a method of filling a vertically long 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 filling the bag-like body, the bag-shaped body is leaned against the tray at a slight angle, and the upper parts of both sides are gripped with chucks to make it stand upright, and the chemical solution is filled through the opening left in the upper part of the bag-shaped body. Will be done. In the case of this filling method, it is important that the bag-shaped body is leaned against the tray without bending for a reliable gripping operation by the chuck.

Further, as a related technique of the present invention, there is known a technique in which a plastic film has a multilayer structure and one layer thereof is composed of an ethylene-vinyl alcohol copolymer resin to give the plastic film gas barrier property.

International Publication WO2014 / 104281 Japanese Patent No. 5100308

When the bag-shaped body is placed horizontally and upright as a method of filling a vertically long bag-shaped body made of a plastic film with a chemical solution, the bag-shaped body leans against a tray without bending for a reliable gripping operation by the chuck. However, it is important to maintain that posture, but polyethylene and polypropylene, which have been used as materials for bag-shaped bodies for filling chemicals, do not become too hard after being made into a product, so they are easy to handle after being made into a product. It has excellent safety, such as not being injured even if sharp parts remain on the product, but since it is inherently flexible, the film thickness is about 300 μm, which is commonly used for infusion containers. In the process of filling the chemical solution, when the bag-shaped body is leaned against the tray, it is easily bent, and it is not possible to perform a reliable gripping operation by the chuck, which causes a decrease in work efficiency and an increase in product cost.

As a result of studies, the present inventors have found that the film loop strength by the stiffness tester method is strongly related to the bending resistance when a vertically long bag-shaped body made of a plastic film is placed horizontally and stands upright. The invention has been reached. That is, according to the present invention, the bag-shaped body made of a plastic film is filled with a chemical solution and sealed, and the port member which is a plastic molded product fixed to the outer peripheral portion of the infusion bag is provided. The plastic film is provided with an infusion container having a film loop strength of 500 mN or more before the moist heat sterilization treatment by the Stiff Nestester method and an elastic coefficient of 400 Mpa or less after the moist heat sterilization treatment.

In the infusion container of the present invention, the film loop strength before the moist heat sterilization treatment by the stiffness tester method is more preferably 570 mN or more in order to realize the desired gripping operation by the chuck. Further, it is preferable that the elastic modulus of the plastic film before the moist heat sterilization treatment is 700 Mpa or less from the viewpoint of the sealing property of the port member and the securing of the required filling amount of the chemical solution, and also from the viewpoint of the handleability after the product is made. ..

In the present invention, the plastic film has a multi-layer structure, and the base material layer can be composed of a polyolefin resin such as polyethylene, which has been often used in the past, such as polyethylene and polypropylene. Then, in order to increase the film loop strength of the multilayer film before the moist heat sterilization treatment, a layer made of a polyamide resin such as an ethylene-vinyl alcohol copolymer resin (EVOH resin) or nylon can be added. By increasing the film loop strength before the moist heat sterilization treatment, the EVOH resin layer, etc. has good bending resistance when the bag-shaped body is placed horizontally and stands up, and the workability when filling the bag-shaped body 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 a tentative 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 becomes 400 Mpa or less, there is an effect that the handleability as a product does not deteriorate.

As described in Patent Document 2, making one layer in the multilayer film an EVOH resin layer makes the infusion container non-breathable (gas barrier property) and easily oxidizes amino acid preparations and some vitamin preparations. It is advantageous in that the stable storage stability of the infusion preparation can be ensured. Then, as described in this patent, the infusion bag treated with moist heat sterilization can be housed 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 for sterilization (wet heat treatment), and the EVOH resin loses its air permeability by heating, but when it is returned to room temperature, it slowly recovers its non-air permeability. The infusion bag immediately after the moist heat treatment is housed in the outer bag together with the oxygen scavenger, and while the resin layer is breathable, the oxygen remaining in the infusion bag is adsorbed by the oxygen scavenger in the outer bag, and ethylene-vinyl is used. When the alcohol copolymer resin layer is completely non-breathable, 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 improve the bending resistance of the bag-shaped body when filled with the chemical solution, the oxygen permeability of the plastic film within 12 hours after the moist heat sterilization treatment is maximum. Although it is only about 300 cc / m ² , day, atm, after the gas barrier property of the EVOH resin layer is completely restored by suppressing the residual oxygen amount at the time of filling to 3 cc or less by substituting an inert gas such as nitrogen gas at the time of filling the chemical solution. Can exert the effect of suppressing the amount of residual gas in the infusion bag to a level at which stable storage stability of easily oxidizable infusion preparations such as amino acid preparations and some vitamin preparations can be ensured.

FIG. 1 is a plan view of an infusion container according to the embodiment of the present invention. FIG. 2 is a cross-sectional view taken along the line II-II of FIG. FIG. 3 is a cross-sectional view taken along the line III-III of FIG. FIG. 4 is a schematic cross-sectional view of the multilayer film constituting the infusion bag in the infusion container of FIG. FIG. 5 is a diagram illustrating molding of a bag-shaped body from a tubular film sheet. FIG. 6 is a diagram schematically showing steps (a)-(c) in the process of manufacturing the infusion container from the bag-shaped body of FIG. FIG. 7 is a diagram schematically showing the steps (d)-(e) following FIG. FIG. 8 is a diagram schematically illustrating a step of leaning the bag-shaped body against a tray for filling the bag-shaped body with a chemical solution. FIG. 9 is a diagram schematically illustrating a method for measuring the film loop strength by the stiffness tester method. FIG. 10 is a graph showing the relationship between the oxygen permeability and the elapsed time (days) after sterilization for each value of the thickness X of the EVOH resin layer with respect to 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 multilayer plastic film, and includes an infusion bag for filling a chemical 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. doing.

The multi-layer plastic film that makes up the infusion bag is not suitable if it is too thin because it is used as an infusion bag by hanging it on a stand, and if it is too thick, it will not be easy to handle. Is 200 μm to 300 μm. A polyolefin resin can be used for the base layer of the plastic film from the viewpoint 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. As will be described later, at least one of the multilayer films constituting the infusion bag increases the loop strength when the infusion bag is filled with the chemical solution, and softens after moist heat sterilization of the infusion bag filled with the chemical solution to reduce the elasticity to an appropriate value. It is provided with a non-polyethylene layer such as an ethylene-vinyl alcohol copolymer resin or a polyamide resin, and the above thickness range is the thickness including the non-polyethylene layer.

The infusion bag in the infusion container of the present invention has a vertically long, substantially rectangular flat shape. In such an infusion bag, a tubular plastic film is formed into a sheet, and this sheet is welded (non-peelable welding) along the contour line of the infusion bag and cut along the welded portion to form upper and lower parts. A vertically long bag-like body is obtained in which the outer periphery of the plastic multilayer film section is vertically welded according to the substantially contour line of the infusion bag. The bag is in a state where a port member (excretion port if only one side, discharge port on one side, mixed injection port on the other side), which is a plastic molded product, is attached to the welded part on one side or both sides in the vertical direction by welding. It has become. In carrying out the present invention, as will be described in detail later, when the bag-shaped body is filled with the chemical solution, 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 back is placed horizontally so as not to interfere with the port member. The free part of the bag-shaped body protruding from the part higher than the side wall of the tray is held upright by grasping it with chucks on both sides, and the upper part of the bag-shaped body in the horizontal state is cut off to open it and fill with the chemical solution. To do. Since the tray is leaned against the tray and filled upright, the multilayer plastic film constituting the bag-like body needs to be hard to bend. If the chuck is chucked while being bent, air cannot be ideally discharged due to nitrogen replacement during filling of the chemical solution, and the residual air amount cannot be suppressed to the desired value (3 cc as described above), and eventually the chemical solution is filled. Will fail, causing an increase in cost due to the occurrence of defective products. Regarding the bending resistance when the chemical solution bag is leaned against the tray, it becomes difficult to bend by increasing the wall thickness of the film. As mentioned above, the film wall thickness cannot be made very thick in relation to the handleability of the finished product. As a result of diligent studies on the difficulty of bending when leaning against the film, 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. Based on the above, it was found that no bending occurs when leaning against the surface, no illegal chuck is generated, and good chemical filling workability can be obtained. The loop strength has a certain degree of correlation with the elastic modulus of the film, although it is not one-to-one. When the loop strength is 600 mN or more, the elastic modulus is 500 Mpa or more, but after the moist heat sterilization treatment, it is normal. It was found that the film does not become too hard even in the state of being a product and no crevices occur even if the product is dropped by setting 400 MPa, which is about the same as that of an infusion bag made of a polyethylene multilayer film, and the present invention has been reached.

Regarding the elastic modulus of the film, as described above, before sterilization, it is 500 MPa or more in relation to the film loop strength, and the high elastic modulus is that of the port member to the bag-shaped body for filling the chemical solution. It may worsen the all-around adhesion (sealing property) and the ease of swelling (chemical solution filling property) when filling the bag-shaped body with the chemical solution, but according to the study, the plastic at the time of chemical solution filling, that is, before the moist heat sterilization treatment It was found that by setting the elastic modulus of the film to 700 Mpa or less, the required performance can be ensured for the sealing property and the chemical filling property.
As a multilayer film exhibiting such characteristics, in addition to the above-mentioned base material layer such as polyethylene, polyethylene as a base material is used to ensure that the chemical solution is filled with the bag body leaning against the chemical solution before filling. The film is made flexible (elastic modulus) to reinforce the layers, etc. to prevent the film from bending (increasing the loop strength), and to improve the handleability as a product such as not falling and tearing after moist heat sterilization by filling with a chemical solution. Has a special layer for lowering). Examples of the plastic for forming such a special layer in the multilayer film of the present invention when filled with a chemical solution include an ethylene-vinyl alcohol copolymer and a polyamide resin. Since these resins have oxygen impermeable properties, they are suitable for accommodating infusion preparations that are easily oxidized such as amino acids. Among these resins, an 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 process at 110 ° C. or higher required for infusion products.

The infusion container of the present invention undergoes heat sterilization after being filled with a chemical solution and sealed. The heat sterilization treatment is carried out under moist heat with steam, 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 wall thickness of 20 μm to 60 μm, preferably 30 μm to 50 μm in the above-mentioned total wall thickness range of 200 μm to 300 μm in the multilayer film. As is well known, EVOH resin has oxygen impermeable property and can be used as a so-called oxygen barrier layer for infusion preparations which are easily oxidatively deteriorated such as amino acid preparations and vitamin preparations.

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

It is known that the EVOH resin temporarily loses oxygen permeability by reacting the vinyl alcohol bond with water when heated in the presence of water. It is essential for the infusion bag to be subjected to a moist heat sterilization process after filling and sealing the chemical solution, and even when at least one layer of the multilayer film constituting the infusion bag is made of EVOH resin, it is temporarily oxygen permeable after moist heat sterilization. It gradually decreases with time (oxygen permeability), and finally returns to the original state that functions as an oxygen barrier before the moist heat sterilization process. The oxygen permeability after moist heat sterilization is expressed by the amount of oxygen permeated per day per unit area of the film at 1 atm (unit: cc / m ² , day, atm). In the technique of Patent Document 2, the oxygen permeability after moist heat sterilization 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, since oxygen replacement is not performed at the time of filling the chemical solution, the amount of residual air in the infusion bag after filling the chemical solution increases, but the oxygen permeability is 200 cc / m ^{2 within 12 hours after the sterilization treatment.} By setting the day / atm or more, a large amount of oxygen remaining in the infusion bag is absorbed by the oxygen scavenger contained in the outer bag via the film constituting the infusion bag, and finally in the infusion bag. It is said that the dissolved oxygen concentration can be lowered to a level at which stable storage stability of easily oxidizable infusion preparations such as amino acid preparations and vitamin preparations can be ensured. In the present invention, the oxygen permeability after moist heat sterilization is 300 cc / m ² · day · atm at the maximum within 12 hours after the sterilization treatment. This is due to the fact that the EVOH resin layer is thickened in order 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 chemical solution. That is, also in the present invention, the infusion bag after the moist heat treatment is stored in the gas barrier outer bag together with the oxygen scavenger, so that the oxygen remaining in the infusion bag is adsorbed through the film constituting the infusion bag. However, the permeability of residual oxygen is not good as compared with the technique of Cited Document 2. However, according to the study by the present inventors, by setting the oxygen residual amount in the infusion bag headspace to 3 cc or less as the value immediately before sterilization after filling with the chemical solution, the oxygen permeability after moist heat sterilization is 12 hours after the sterilization treatment. Even if the maximum is about 300 cc / m ² , day, atm within the range, it is possible to make the amount of oxygen remaining in the infusion bag equivalent to that of Patent Document 1 at the time of equilibrium in which the oxygen permeability is restored. When filling the infusion bag with the chemical solution, an additional step of replacing the infusion solution injection site of the infusion bag with an inert gas such as nitrogen is required, but the filling amount of the chemical solution contained in the infusion bag is 250 cc to 500 cc. To set the head space of the infusion bag to 20 cc to 60 cc and the residual oxygen amount to 3 cc, it is sufficient to set the nitrogen substitution rate in the space above the liquid level of the infusion bag to 5% to 15%, and to replace the inert gas. It is not necessary to be technically special, and it can be said that it is a factor that increases the cost, but it is not so much, and the workability (prevention of unauthorized chucking) when the chemical solution is filled horizontally as in the present invention. It does not surpass the benefits of improvement.

According to the present invention, the oxygen permeability after moist heat sterilization is a maximum of 300 cc / m ² · day · atm within 12 hours after the sterilization process. Since the release of carbon dioxide gas is sometimes suppressed, there is an advantage that an increase in pH can be suppressed.

The infusion container of the present invention may have one space for accommodating the drug solution in the infusion bag or may have two or more spaces. When there is only one space for accommodating the drug solution, it is suitable for amino acid preparations such as isoleucine and leucine, and specific vitamin preparations (ascorbin, etc.) that are susceptible to oxidation. The present invention can also be applied to cases where there are two or more spaces for accommodating the drug solution, and these spaces are formed by detachably welding the vertically opposed surfaces of the infusion bag, and the drug solution is placed in each space. Fill. When the infusion solution bag is pressed during infusion, the welded portion is peeled off, and the chemical solutions contained in the respective spaces are mixed. In such a two-component mixture type, the drug solution contained in one space is an amino acid preparation, a specific vitamin preparation (ascorbin, etc.), etc., and the drug solution contained in the other space is glucose or an electrolyte. And so on.

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

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

[Specific Structural Example of Infusion Container in the Present Invention]
FIGS. 1 to 3 show a multi-chamber container in which the present invention is carried out, and the structure of the multi-chamber container has the same structure as that of Patent Document 1 by the present inventors and is formed of a multilayer plastic film. The outer bag 10 (the infusion bag of the present invention is obtained in a state where the chemical solution is stored in the inner compartment and sealed together with the port member), the inner bag 12 also formed of the multilayer plastic film, and the plastic molded product. It is composed of a discharge port 14 which is 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. 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, a third layer is a gas barrier layer made of EVOH resin or the like, a fifth layer is made of polyethylene or the like, and a sixth layer is the innermost layer of the outer bag 10 and is made of polyethylene or the like.

In FIG. 1, the outer bag 10 has a substantially vertically long flat shape, and as shown in FIGS. 2 and 3, the plastic soft films constituting the outer bag 10 are a pair (upper and lower) of film pieces 18 and 20. It is formed in a bag shape by non-peelable welding, that is, strong sealing, along the entire circumference of the outer edge portion on the facing surface. This strong seal portion along the outer bag 10 is represented 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 liquidtight 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 thick plastic mold molded products that can maintain the tubular shape, and their structures are basically the same. However, when the discharge port 14 is described, the discharge port 14 is As shown in FIG. 2, a tubular main body 23, a cap 24, and a rubber stopper 26 are provided, and the tip portion 23-1 of the tubular main body 23 is integrated with the outer bag 10 by a strong seal portion 22, and the tubular main body 23 has a tubular main body 23. The cap 24 is fixed (welded) to the end of the tubular main body 23 so as to project 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 the same configuration as the discharge port 14, and although not shown, the mixed injection port 16 (FIG. 1) is provided with a rubber stopper similar to the rubber stopper 26 of the discharge port 14, and the needle for mixed injection can be punctured. You can do it.

In FIGS. 1 to 3, the strong seal portion (non-peelable welded portion) and the weak seal portion (peelable welded portion) are all formed by welding the film facing surfaces, but are clear in the cross section (FIGS. 2 and 3). The welded parts in the strong seal part and the weak seal part are represented by thick lines (strong seal is a solid line, weak seal is a broken line).

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

In FIG. 1, reference numeral 28 denotes a weakly sealed portion formed by welding the upper and lower film pieces 18 and 20 constituting the outer bag 10 so as to be peelable on the facing surfaces (see also FIG. 3). The weak seal portion 28 extends over the entire width of the intermediate portion in the height direction of the outer bag 10, that is, extends to the strong seal portions 22 on both sides of the outer bag 10 so as to be tightly and integrally connected to the strong seal portion 22. Therefore, the internal space of the outer bag 10 is separated into upper and lower first and second compartments 29 and 30. Liquid agents 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 accommodating sites of the compartments 29 and 30 are pressurized from the outside.

The inner bag 12 is for storing trace elements such as iron and magnesium. The inner bag 12 has a flat and elongated rectangle, and is housed between the lower partition chamber 30 and the discharge port 14 inside the outer bag 10. The inner bag 12 has a horizontally long rectangular shape, but the upper side portion close to the partition chamber 30 is connected and fixed to the outer bag 10 by the strong seal portion 34, and the opening is made in response to the hydraulic pressure inside the outer bag 10. Will be done. The inner bag 12 can form a cyclic polyolefin resin (COP) surface layer (a layer to be the inner surface of the inner bag 12) on a base layer made of a multilayer polyethylene film. The polyethylene layer and the COP resin layer constituting the base material layer can be molded into a bag shape in a state of being firmly integrated under heating by inflation molding due to the strong affinity between the resins. As shown in FIG. 2, the inner bag 12 is composed of upper and lower film pieces 36 and 37, and the upper and lower film pieces 36 and 37 are welded along the entire circumference, and this welded portion is configured as a weak seal portion 40. , The weak seal 40 forms the drug storage chambers 42 and 44 inside, in which the trace element-containing liquid is separately stored. As shown in FIG. 1, the strong seal portion 34 is strongly welded to the upper side of the weak seal 38 on the outer circumference of the inner bag 12, so that the weak seal portion 28 is subjected to an external force due to the mixing of the chemical solution between the compartments 29 and 30. When opened, the weakly sealed portions 38 and 40 of the inner bag 12 are also opened, and the chemicals are mixed. The inner bag 12 may be used for only one room.

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

To further explain the structure of fixing the inner bag 12 to the outer bag 10, 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 the outer bag is extended together with both side portions of the inner bag 12. A strong seal is formed between the upper and lower film pieces 18 and 20 constituting the 10. Therefore, the inner bag 12 is fixed to the outer bag 10 in a state where the lower partition chamber 30 and the discharge control chamber 46 are separated from each other. The discharge control chamber 46 is filled with a small amount of water, and when the infusion container is sterilized after the compartments 29 and 30 are filled with the chemical solution, the small amount of water filled in the discharge control chamber 46 becomes vapor and the outer bag 10 is used. It can be used for efficient sterilization of the outer peripheral portion of the inner bag 12 inside the inner bag 12. Further, on the discharge port 14 side 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 if it were.

[Explanation of Manufacturing Process of Infusion Container in the Present Invention]
Next, the matching step of the infusion container of FIGS. 1 to 3 will be described. The multilayer film blow-molded as described above is formed into a flatly crushed sheet, and is once wound up on a roll. In FIG. 5, 50 indicates a sheet pulled out from the roll, and the sheet is in a state where two upper and lower layers are stacked. The sheet 50 shows only one side of the center line L. The sheet 50 is subjected to strong welding (non-peelable welding) of the 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. A similar pattern is symmetrically formed on the opposite side of the center line L. That is, it is possible to cut out two bag-shaped bodies to be infusion bags from one repeat length a. A strong sealing die is installed at a predetermined position in the sheet feeding direction, and at the same station, non-peelable welding (strong sealing) of upper and lower layers is performed between the sealing dies outside the contour line 52 at one repeat length a. The inside of the contour line 52 is not welded, and this remains as a cavity of the infusion bag. A weak seal mold is placed at a processing position on the downstream side of the strong seal mold, and the weak seal mold is peelable welded at a portion 54 crossing the strong weld portion, and this is the weak seal portion 28 of the product. It becomes. Then, at the cutting station from the sheet 50, the bag-shaped body 58 is cut out along the contour line 56.

According to FIGS. 6 (a)-(c) and 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 outer peripheral strong seal portion 22 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 show unwelded cavities, the cavities 60 are the upper compartments 29 of the product, the cavities 62 are the lower compartments 30 of the product, and the inner bag 12 This is the part that will be the containment site. The 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 process. The unwelded portion 66 between the welded portions 58-2 and 58-3 is an opening for introducing the infusion solution into the cavity 60 which is the upper compartment 29 of the product.

In FIG. 6A, the inner bag 12 is already in a completed state. As already described with reference to FIGS. 1 to 3, the inner bag 12 has a weakly sealed portion 38 on the outer circumference, and trace amounts of the drug are stored in the drug storage chambers 42 and 44. Although the bag-shaped body 58 is shown 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, in the hollow portion 62, the bag-shaped body 58 is attached to a pair of suction cups (not shown) from both sides, and the film is opened in the hollow portion 62 by moving the pair of suction cups apart. 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 a fixed position 14'in the cavity 62.

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

The seal molds for forming the welded portions 58-4, 58-5, 34 are separately configured, but in particular, the operation of the seal mold for forming the strong seal portion 34 is added to the strong seal portion 34. The seal mold for forming the seal has a heating surface having a size corresponding to the size of the seal portion 34, but constitutes the inner surface of the film pieces 18 and 20 constituting the outer bag 10 and the inner bag 12. The outer surfaces of the films 36 and 37 are polyethylene films, and at a temperature of about 150 ° C., the extending end portion 36-1 of the inner bag 12 shown in FIGS. , 37-1 (Fig. 2) is strongly sealed, and the strong seal portion 34 is formed. Naturally, the seal mold also pressurizes the inner surfaces of the extending ends 36-1, 37-1 of the film pieces 36, 37 constituting the inner bag 12 toward the partition chamber 30, but the inner bag 12 Since the cyclic polyolefin resin constituting the inner surface has a high melting temperature, in the seal mold heated to about 150 ° C., the extending end portion 36- of the film pieces 36 and 37 constituting the inner bag 12 toward the partition chamber 30 side. 1, 37-1 are not welded to each other on the inner surface. Further, although the heat of the seal mold is applied to the weak seal portion 38 of the inner bag 12, the weak seal portion 38 remains a weak seal.

In the 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 opposite surfaces of the mixed injection port 16, and the mixed injection port 16 is sealed all around. In addition, the discharge port 14 is inserted into the opening 72, and the discharge port 14 is attached to the unsealed portion of the surrounding bag-shaped body 58 and strongly sealed, so that the upper and lower films forming the opening 72 are formed. It is welded to the opposite surface of the discharge port 14 so that the discharge port 14 is sealed all around. When welding the mixed injection port 16 and the discharge port 14, a pair of upper and lower seal molds having a substantially semicircular heating surface are used, and the upper and lower films forming the openings 64 and 72 are formed into the mixed injection port 16 and the discharge port. A pressing seal is performed on 14. At this time, if the film is too hard, it becomes difficult for the film to adhere to the mixed injection port 16 and the discharge port 14 all around, and seal leakage may occur. Therefore, there is an upper limit to the hardness (= elastic modulus) of the film from the viewpoint of adhesion to the peripheral surfaces of the mixed injection port 16 and the discharge port 14, and the upper limit is about 700 Mpa as described later.

FIG. 7D shows a step of filling the cavities 60 and 70 of the bag-shaped body having the first and second compartments 29 and 30 in the product (FIG. 1) with the chemical solution. Since the openings 66 and 68 of the bag-shaped body 58 for filling the chemical solution are open sideways, the filling of the chemical solution is performed in a state where the vertically long bag-shaped body 58 is laid on its side as shown in FIG. 7 (d). Is done. FIG. 8 schematically shows a device for making the bag-shaped body 58 stand upright, and as shown in FIG. 8, the bag-shaped body 58 sucks and holds the tip of the robot arm 75 near the center thereof. It is sucked and held in the cup 76. The robot arm 75 is advanced and lowered, carried to the tray 78 having a key-shaped cross section as shown in FIG. 8, and the bag-shaped body 58 can be leaned against the tray 78 by releasing the suction of the suction holding cup 76. The suction holding cup 76 is retracted to the initial position. The holding tray 78 has a groove width with a margin for mounting on the tray 78 by a robot, and the bag-shaped body 58 is on the higher side in the cross-sectional key shape of the tray 78 when leaning against the holding tray 78. Slightly tilt to lean against the wall. A pair of chucks 80 are provided so as to be separated from each other in the direction orthogonal to the paper surface of FIG. 8, and each chuck 80 has a pair of grip portions 80A and 80B. The chuck 80 is normally retracted in the direction orthogonal to the paper surface of FIG. 8, and the pair of grip portions 80A and 80B are open, but when the bag-shaped body 58 is leaned against the tray 78, it is orthogonal to the paper surface of FIG. Advance to a predetermined position in the direction. Then, the pair of grips 80A and 80B of each chuck 80 advance so as to face each other as shown by arrows, and the pair of grips 80A and 80B are both side portions at the upper end of the bag-shaped body 58 as shown in 80A'and 80B'. The bag-shaped body 58 is positioned upright on the tray 78 as shown by the imaginary line 58'. The gripping states of the pair of chucks 80 at the upper ends of the bag-shaped body 58 by the gripping portions 80A'and 80B' are shown in FIG. 7 (d). Then, the cavities 60 and 70 are filled with the chemical solution in the upright state of the bag-shaped body 58 on the tray 78. That is, in FIG. 7D, the chemical 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 replacement are arranged side by side in the chemical filling pipes 82 and 84, respectively. The film forming the bag-shaped body 58 is engaged and attracted to suction cups (not shown) from both sides at the portions constituting the openings 60 and 70, and the film forming the bag-shaped body 58 is formed by pulling each suction cup apart. Is open on both sides, and openings 60 and 70 are wide open. Then, the chemical filling pipes 82 and 84 and the parallel nitrogen gas pipes 86 and 88 are introduced downward into the cavities 60 and 70 through the openings 60 and 70. Then, the infusion solution is introduced from the filling pipes 82 and 84 into the cavities 60 and 70 while replacing the cavities 60 and 70 with nitrogen by ejecting nitrogen gas.

The bag-shaped body 58 leans against the tray 78 at a slight angle for filling with the chemical solution, but the portion above the wall surface of the tray 78 may be bent as shown by the imaginary line 58 "in FIG. 8 (it becomes an illegal chuck). Therefore, the bag-shaped body 58 chucked by the chuck 80 also remains bent, and the chemical solution is filled as it is, the air is not discharged well by nitrogen substitution, and the residual oxygen amount can be suppressed to the desired level. According to the study by the present inventors, such bending of the bag-shaped body 58 has a strong correlation with the film loop strength by the stiff nestester method, and the film loop strength is 500 mN or more, preferably 570 mN or more. As a result, chuck mistakes do not occur and efficient chemical filling can be realized.

FIG. 7 (e) is completed as an infusion bag by strongly sealing the upper edge facing surfaces of the films constituting the openings 60 and 70 of FIG. 7 (d) and forming a locally strong seal 47 after the completion of the chemical solution filling. The state (Fig. 1).

A 6-layer tubular film (film diameter: 440 mm) shown in FIG. 4 was obtained by a well-known blow molding method. The first layer was a polyethylene layer (polyethylene density = 0.93, and a thickness of 50 μm), which was an outer layer of the infusion bag.

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

The third layer was a gas barrier layer made of EVOH resin, which was obtained from pellets of the trade name EVAL manufactured by 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 infusion bag made of polyethylene (polyethylene density = 0.95).

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. The thickness (Y) of the fifth layer (polyethylene layer) is 145 μ, 135 μ, 125 μ, 115 μ, 105 μ, 95 μ, that is, X + Y = 155 μ, and the six layers are set according to the thickness X of the gas gas barrier layer. The overall thickness was constant at 50 + 20 × 2 + 155 + 25 = 270 μm. In this way, a blow-molded tubular film composed of six types of multilayer films provided with an EVOH resin layer was obtained. For each tubular film of each thickness X of these six types of gas gas barrier layers, a bag-like body was formed, a chemical solution was filled, an infusion container was formed by sealing an opening, and a moist heat treatment was performed. From the test results shown in the table, the thickness X = 20μ, 30μ, 40μ, 50μ of the gas barrier layer made of EVOH resin was set as the first, second, third and fourth examples of the present invention, respectively. The thicknesses X = 10μ and 60μ are referred to as 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, and the sheet drawn out from the roll is shown in the same figure for each sheet division a in the longitudinal direction shown in FIG. A strong seal of the pattern shown (seal temperature is 150 ° C.) was performed, and the film was cut along the cut line 56 to obtain a bag-shaped body 58 having a length of 380 mm and a width of 280 mm.

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 manufactured by Nippon Zeon Co., Ltd.). A multilayer film consisting of three layers of inner layers (thickness 20 μm) made of Zeonex pellets) was welded to the outer periphery of the inner layers so that they could be peeled off (welding temperature = 170 ° C.), and into the compartments 42 and 44 partitioned by the peelable seal 40. An inner bag 12 having a vertically long length of 170 mm and a horizontally long length 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, sealed with a series of seal molds (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. Then, as shown in FIG. 6C, the mixed injection port 16 and the discharge port 14 are inserted into the openings 64 and 72 of the bag-shaped body 58, respectively, and the openings are formed by a seal type having a semicircular cross section (seal temperature is 150 ° C.). By pressing the film portions 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 into the bag-shaped body 58, respectively, and the chemical solution filling is completed. Got At this time, the adhesion of the film portion forming the openings 64 and 72 to the mixed injection port 16 and the discharge port 14 on the entire circumference was evaluated by visual judgment of the seal strength and the presence or absence of leakage, and further evaluated by microscopic observation, and Table 1 shows. The result is shown as a sealing property.

In addition, 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 by Stiff Nestester (manufactured by Toyo Seiki Seisakusho). That is, the plastic film constituting 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 cut into a stiffness tester chuck 90 as shown in FIG. The repulsive force (unit: mN) when the loop is crushed with a crushing distance of 15 mm and a crushing speed of 3.3 mm / sec by the pressurizing part 94 of the stiffness tester. ). The results are shown in the table.

Further, the plastic film constituting the bag-shaped body 58 was similarly cut into a test piece having a width of 15 mm and a length of 150 mm, and the elastic modulus of this test piece was measured by a tensile tester (manufactured by A & D Co., Ltd.). .. The tensile test conditions were that the chucks were mounted at a distance of 100 mm and the tensile speed was 50 mm / min. The results are shown in the table.

The bag-shaped body 58 obtained as shown in FIG. 6D was held by the robot arm by sucking the central portion thereof with a suction cup as shown in FIG. 8, and was leaned against the tray 78. Whether or not the infusion bag at this time is maintained in a standing state without bending is sensory evaluated for each sample, and the results are shown in Table 1 as bending resistance.

The bag-shaped body 58 leaning against the tray 78 is chucked by chucks 80 at the upper portions on both sides thereof, is upright as shown by the imaginary line 58'in FIG. The filling pipes 82, 84 and the nitrogen gas pipes 86, 88 shown in FIG. 7 (d) are inserted through the openings 66, 68 so as to face the cavities 60, 70 of the bag-shaped body 58, and the chemical solution is inserted. Was filled. The cavity 60 was filled with 300 cc of amino acid and vitamin-containing liquid, and the cavity 70 was introduced with 500 cc of glucose and electrolyte-containing liquid from a nozzle, and the amount of nitrogen gas ejected at that time was 10 to 16 L / min. .. The film portions constituting the openings 66 and 68 were sandwiched by a seal mold (seal temperature 150 ° C.) shortly after the cavities 60 and 70 were filled with the chemical solution, and the infusion container shown in FIG. 6 (e) was inserted. Obtained. When filling the cavities 60 and 68 with the chemical solution, the bag-shaped body 58 needs to swell in accordance with the increase in the filling amount in order to fill the required amount. Evaluation was performed.

The infusion container obtained as shown in FIG. 6 (e) was immediately sterilized 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 sterilized infusion bag was immediately enclosed in an outer bag made of an aluminum vapor-deposited film having a size of 330 mm × 330 mm together with an oxygen scavenger (trade name “Ageless” manufactured by Mitsubishi Gas Chemical Company, Inc.).

Further, for the sterilized infusion bags 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 the infusion bag was adjusted to OX-TRAN2 / 20 manufactured by MOCON. , JIS K 7126 B method (isobaric method) was followed. The results are shown in the figure. Elapsed time after sterilization horizontal axis shows (day) and the vertical axis represents the oxygen permeability ^{(cc / m 2 · day ·} atm). The values of oxygen permeability 12 hours (half a day) after the sterilization treatment are shown in the table.

Comparative example

An infusion container was produced for a polyethylene single-layer film (polyethylene resin density of 0.93) and a thickness of 250 μm in the same procedure as described for the above-mentioned Examples. This is referred to as Comparative Example 3.

An infusion container was produced for a polyethylene three-layer film (resin composition: density 0.95 / 0.92 / 0.95) and thickness 300μ by the same procedure as described for the above-mentioned Examples. This is referred to as Comparative Example 4.

An infusion container was manufactured for a polypropylene multilayer film (trade name “Cryobac” manufactured by Shield Air Japan GK) and a thickness of 190 μ in the same procedure as described in the above-described embodiment. This is referred to as 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]
As shown in Table 1, even if the gas barrier layer made of EVOH resin is provided, when the thickness X = 10μ as shown in Comparative Example 1, the loop strength is small, so that the bag-shaped body is laterally filled with the infusion solution. When leaning against the tray, it was easy to bend, and an illegal chuck mistake occurred greatly. When X = 20μ, generally good bending resistance was obtained, but it did not occur frequently, but it sometimes bent, so it was indicated by Δ. Further, when the thickness X = 60μ of Comparative Example 2, the filling property was naturally good because the loop strength was large, but the elastic modulus of the film was too large (because the film was too hard), so that the bag-like body Sufficient swelling was not obtained, which hindered the filling of the desired amount of chemical solution, and when sealing the chemical solution port member, it was difficult to attach it along the entire circumference, and the sealing property was likely to be poor (x mark). .. Since the EVOH resin is more expensive than the polyethylene resin or the like, it is advantageous to set an upper limit on the thickness of the EVOH resin layer from the viewpoint of cost. On the other hand, when the thicknesses of the gas gas barrier layer X = 20μ, 30μ, 40μ (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 sealability and fillability were good. X = 50μ is generally good, but it is judged as Δ because it has a high elastic modulus and is slightly inferior in filling property and port sealing property. In addition, even if the elastic modulus before sterilization is high, the elastic modulus after sterilization drops to an appropriate value equivalent to that of a conventional infusion bag made of polyethylene or the like (elastic modulus is 400 mN or less), so that the handleability of the product may be impaired. It turned out not. In particular, when the thicknesses of the gas gas barrier layers of Examples 2 and 3 were X = 30μ and 40μ, the filling property and the port sealing property were considered to be the best mode from the viewpoint of harmony. From Table 1, the quality of the filling property and the port sealing property depends on the elastic modulus at the time of filling with the chemical solution, in other words, before sterilization, and the elastic modulus is preferably 700 mN or less.

In the cases of Comparative Examples 3 to 5 not provided with the EVOH resin, since the elastic modulus was small, there were naturally no problems of port sealability and fillability, but since the loop strength was not sufficiently high, the present invention relates to bending resistance. It can be seen that it is clearly inferior to the examples.

FIG. 10 shows changes in oxygen permeability in Comparative Examples 1 and 2 provided with a gas barrier layer made of EVOH resin and Examples 1 to 4 with respect to the elapsed time (days) after sterilization. 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.

Further, Table 2 prepares a bag-like body having an inner size of 110 mm × 235 mm for the film of Example 2, fills and seals with ascorbic acid (115% liquid), and sets the oxygen residual amount to 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, at 25 ° C. after one month, and at 40 ° C. after one month. Shown. 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 after one month regardless of the deterioration of quality over time.

10 ... Outer bag 12 ... Inner bag 14 ... Discharge port 16 ... Mixed injection port 22 ... Strong seal part 26 ... Rubber stopper 28 ... Weak seal part 29 ... First compartment 30 ... Second compartment 34 ... Strong seal part 38 ... Weak seal portion 40 on the outer circumference of the inner bag ... Weak seal portion 46 that partitions the inside of the inner bag ... Discharge control chamber 50 ... Multilayer tubular film sheet 58 ... Bag-like body 76 ... Suction of the robot to hold the bag-like body Cup 78 ... Tray 80 for leaning the bag-shaped body ... Chuck
80A, 80B ... Chuck grip
82, 84… Chemical filling pipe
86, 88… Nitrogen gas pipe

Claims (1)

The gas barrier film layer, which is at least one layer of a plastic film having a multilayer structure with a polyethylene layer as a base material and having a high elastic coefficient value of 449 MPa to 693 MPa, is an ethylene-vinyl alcohol copolymer resin (EVOH resin) layer. A bag-shaped body composed of the above is prepared, and an amino acid preparation or a vitamin preparation as a chemical solution that is easily oxidized while leaning horizontally from an opening provided at the outer edge of the bag-shaped body is filled with an inert gas. The chemical solution bag is formed by sealing, the chemical solution bag is subjected to moist heat sterilization at a temperature of 105 ° C. to 115 ° C., and the plastic film is subjected to moist heat sterilization to form a chemical solution bag before moist heat sterilization. The bag-like body is reduced (softened) to a low elastic coefficient value of 359 MPa or less, which is lower than the high elastic coefficient value, and then the chemical solution bag is housed in a gas barrier outer bag together with a deoxidizer, and the bag having the high elastic coefficient value is used. A method for manufacturing an infusion container, which comprises ensuring the filling property of a chemical solution into a body and obtaining good product handling due to the low elastic coefficient value.

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