JP2009219792A - Multi-chamber container for medical treatment - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a multi-chamber container for medical treatment having a liquid formulation compartment and a pharmacological agent compartment being liquid-tightly combined to the medicine formulation compartment wherein deformation, transparency deterioration such as whitening, and blocking between internal layers do not occur even after sterilization at 121°C or higher, weak welding property is good, and communication is easy, and which is excellent in water-vapor barrier property and impact resistance as well. <P>SOLUTION: For this multi-chamber container for medical treatment, the liquid formulation compartment is formed of a multi-layer film having at least three layers of an external layer which is formed of an ethylene-based polymer, an internal layer which is formed of a propylene-based copolymer, and an intermediate layer which is located between those layers. The propylene-based copolymer is a polymer composition which is prepared with propylene and ethylene as the major components. In this case, (1) the ethylene content of the propylene-based copolymer is from 7 wt.% to 8 wt.%, (2) the fusion peak temperature is 150°C or higher and lower than 160°C, (3) the heat of crystallization is from 55 J/g to 65 J/g. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  TECHNICAL FIELD The present invention relates to a medical multi-chamber container having a liquid medicine compartment formed by using a multilayer film and a medicine compartment connected to the liquid medicine compartment in a fluid-tight manner, in particular liquid tight.

  Conventionally, vials, bags, syringes, and the like have been used as containers for storing medicinal solutions such as nutrient infusions, and most of these containers are made of plastic. Among such plastic containers, a multi-chamber container that separately accommodates at least two components is well known. In such a multi-chamber container, since flexibility and transparency are required, a plastic film is used to form a sheet-like plastic film into a bag shape, and two bags are joined together to form at least two chambers. Alternatively, the tubular film is partitioned to form at least two chambers. Between such a plurality of compartments, a weakly welded part called a weakly bonded part is formed, and one of the compartments is pressed from the outside, and the adhered film in the weakly welded part is Separating each other and communicating the compartments on both sides of the welded portion, mixing components contained in the respective chambers to prepare a chemical solution.

  For example, in JP-A-8-280775, a liquid agent compartment comprising an inner layer made of polyethylene or a blend of polyethylene and polypropylene, a sheet obtained by laminating a polyethylene film with a silica-coated polyethylene terephthalate film, an aluminum foil, and a water absorbing layer. A multi-compartment container is disclosed in which a drug compartment (typically, a compartment for solid medicine) consisting of

  However, particularly in a liquid agent compartment, the heat resistance of a sheet formed from polyethylene or a blend of polyethylene and polypropylene constituting the inner layer is not sufficient, and a high pressure of 121 ° C. or higher set as standard in various countries such as Europe and America The container cannot withstand steam sterilization treatment (hereinafter also simply referred to as “sterilization”), and the container is deformed and the transparency is lowered such as whitening, so that a container that can withstand practical use has not been obtained.

  Japanese Patent Application Laid-Open No. 2001-172441 discloses a heat-resistant sheet made of an ethylene polymer composition containing a metallocene catalyst-based linear polyethylene (hereinafter referred to as M-LLDPE) and an infusion bag using the same. However, such a container can withstand sterilization at 115 ° C., but cannot withstand sterilization at 121 ° C. or higher.

  On the other hand, a multi-chamber container that can withstand sterilization at 121 ° C. with a propylene copolymer composition having a specific composition as an inner layer is disclosed in, for example, Japanese Patent Application Laid-Open Nos. 2001-226499 and 2003-52791. Has been. However, according to the study by the present inventors, when a sheet made of the composition of these propylene copolymers is used for the inner layer of the container, the inner layer of the container is blocked so that it is difficult to peel off after sterilization, while the weakly welded portion When it is used for a multi-chamber container consisting of a liquid agent compartment and a medicine compartment having a relatively small capacity of about 200 ml at maximum, the communication is difficult and the practicality is poor. I understood that. Moreover, the sheet | seat which consists of these compositions has comparatively high water vapor permeability | transmittance, the amount of liquid agents falls after sterilization and a preservation | save, and the problem that the appropriate liquid agent amount set at the time of filling cannot be mixed with a chemical | medical agent inherently exists.

  The object of the present invention is at least one of the problems related to water vapor barrier properties, such as deterioration of transparency such as deformation and whitening, blocking of inner layers, easier communication of good weak welding characteristics, and sterilization at 121 ° C. or higher. Preferably at least one liquid agent compartment and at least one fluid-tightly connected to the compartment, in particular liquid-tight, preferably further improved with respect to a plurality, more preferably all, desirably also having better impact resistance. It is to provide a medical multi-chamber container having one medicine compartment.

  The present invention for solving the above-mentioned problems is a medical multi-chamber container comprising a liquid medicine compartment containing a liquid medicine and a medicine compartment containing a medicine, usually a solid medicine, preferably a powder medicine. The liquid agent compartment has an outer layer formed from an ethylene-based polymer, an inner layer formed from the following specific propylene-based copolymer, and an intermediate layer located between these layers, It is a medical multi-chamber container formed from a multilayer film composed of three layers.

The propylene-based copolymer is a polymer composition obtained by polymerizing a monomer mixture containing propylene and ethylene as main monomer components,
1) The ethylene content is 7% by weight or more and 8% by weight or less 2) The melting peak temperature is 150 ° C. or more and less than 160 ° C. 3) The heat of crystallization is 55 J / g or more and 65 J / g or less.

  The present invention comprises at least three layers in which a film formed from an ethylene-based polymer is used as an outer layer, a film formed from the above-mentioned specific propylene-based copolymer is used as an inner layer, and an intermediate layer is further provided therebetween. By constructing the liquid agent compartment using a multilayer film, the above problems have been solved. The intermediate layer may be formed of one layer or a film composed of two or more layers. For example, the intermediate layer may be a film in which two layers or three layers are laminated. If necessary, another layer may be present between the outer layer and the inner layer in addition to the intermediate layer. Further, if necessary, an additional layer may exist outside the outer layer, and an additional layer may exist inside the inner layer.

Embodiments of the Invention

  In the medical multi-chamber container according to the present invention, the compartment is bonded by forming a flat plastic sheet-like film into a bag-like material by, for example, bending or overlapping, or cutting a tubular film. Can be formed. The medical multi-chamber container of the present invention can be formed by connecting a plurality of compartments thus formed (that is, two or more) to each other in series. A weakly peeled portion called a weak welded portion is formed between adjacent compartments, one compartment is pressed from the outside, the weak welded portion is peeled off, and two adjacent compartments are communicated with each other. In addition, a chemical solution can be prepared by mixing components contained in each chamber, specifically, a drug and a liquid (or a liquid and another liquid). The structure itself of such a medical multi-chamber container itself is known, and such a structure can also be adopted in the present invention.

  In the present invention, the liquid agent is a substance in a liquid state to be mixed with the drug contained in the drug compartment in order to prepare the drug solution, for example, water for injection, physiological saline, dialysate, replacement liquid for medical treatment, Examples include amino acid preparations, trace element preparations, fat-containing preparations, vitamin preparations, blood preparations, and the like. In addition, a drug is a substance that is usually in a solid state mixed with a liquid agent contained in a liquid agent compartment to prepare a drug solution, for example, an antibiotic, an antibacterial agent, an anticancer agent, a hormone agent, a Chinese medicine, Examples include solid preparations such as concentrates in powder form. The solid preparation is not particularly limited as long as it is in a solid state, but is preferably in a powder form, but in another aspect, it may be in a granular form or a tablet form. It is known to use such solutions and medicines in a medical multi-chamber container, and the same can be used in the medical multi-chamber container of the present invention.

  In the present invention, the medical multi-chamber container is a multi-chamber container composed of at least two compartments each having at least one of the liquid medicine compartment and the medicine compartment, and at least one compartment, particularly at the end. The compartments that are positioned preferably have ports that allow the interior and exterior to communicate. This port can be used for supplying a medicine or a liquid into the compartment, or for taking out a chemical prepared from the medicine and the liquid from the inside of the multi-chamber container. Such a port is generally a plastic tube port. Such a multi-chamber container itself is known, and the medical multi-chamber container of the present invention may be the same as such a known one.

The outer layer of the liquid compartment of the present invention In the medical multi-chamber container of the present invention, the ethylene polymer constituting the outer layer of the liquid compartment is obtained by polymerizing only ethylene or a monomer mainly composed of ethylene. The polymer is not particularly limited as long as the polymer is obtained. Specifically, a polymer formed from a monomer containing 50 mol% or more of ethylene is preferable. As the ethylene polymer, for example, the following can be used:
Density 0.91~0.94g / cm ³ of a high-pressure low-density polyethylene density 0.94~0.97g / cm ³ of high density polyethylene density 0.91~0.95g / cm ³ linear low-density polyethylene of ethylene and 1-butene density 0.88~0.91g / cm metallocene ethylene -α- olefin copolymer of ³ density 0.85~0.88g / cm ^3, 1- hexene, and 1-octene α -Copolymer with olefin Ethylene-α-olefin copolymer rubber having a density of 0.85-0.88 g / cm ³

Among them, a density 0.93 g / cm ³ or more blend heat resistance and flexibility of the linear low density polyethylene and high-pressure low density polyethylene having a density of 0.91~0.95g / cm ^3, in terms of moldability preferable. When the density of the linear low-density polyethylene is less than 0.93 g / cm ³ , the heat resistance tends to decrease and deformation may occur after sterilization, and when the density is 0.95 g / cm ³ or more, transparency and flexibility Tends to be insufficient.

  High-pressure low-density polyethylene is superior in that it can improve the moldability as a multilayer film. If it is not blended, molding as a multilayer film may be difficult, and a good appearance cannot be obtained. There is. When blending high-pressure low-density polyethylene, the amount is preferably 5% by weight or more and 15% by weight or less, and if it is less than 5% by weight, the effect of improving the moldability is poor. May be worsened.

Inner layer of liquid agent compartment of the present invention In the medical multi-chamber container of the present invention, the propylene polymer composition constituting the inner layer of the liquid agent compartment is a monomer mixture mainly composed of propylene and ethylene. Is a composition obtained by polymerizing and satisfies the following items as described above:
1) The ethylene content is 7% by weight or more and 8% by weight or less 2) The melting peak temperature is 150 ° C. or more and less than 160 ° C. 3) The heat of crystallization is 55 J / g or more and 65 J / g or less.

The "ethylene content", infrared spectroscopy or ^{13 C-NMR Kang-Bong Lee} et spectrally. al, Polymer J. et al. 28, pages 696-702 (1996). “Melting peak temperature” and “heat of crystallization” can be determined by the methods described in JIS K7121 and JIS K7122, respectively, by differential scanning calorimetry (DSC).

  When the ethylene content is less than 7% by weight, the welding strength tends to increase rapidly at a specific temperature, and a stable weak welding strength cannot be obtained. On the other hand, if the ethylene content exceeds 8% by weight, the weak welding strength tends to be too strong, and the blocking of the inner layer of the container after sterilization tends to become strong.

  When the melting peak temperature is less than 150 ° C., the welding strength tends to increase rapidly at a specific temperature, a stable weak welding strength cannot be obtained, and further, the blocking of the container inner layer after sterilization tends to become stronger. On the other hand, when the melting peak temperature is 160 ° C. or higher, the weak welding strength tends to be too strong.

  If the heat of crystallization is less than 55 J / g, the weak welding strength tends to be too strong, and further, the blocking of the inner layer of the container after sterilization tends to become strong. On the other hand, if it exceeds 65 J / g, the weak welding strength itself is difficult to obtain, The welding strength tends to increase rapidly at a specific temperature, and a stable weak welding strength cannot be obtained.

  The propylene-based polymer composition of the present invention comprises propylene and ethylene as essential components, and is copolymerized with other α-olefins having 4 to 8 carbon atoms as long as the above items 1) to 3) are satisfied. May be obtained. Here, examples of the α-olefin include 1-butene, 3-methyl-1-butene, 1-pentene, 4-methyl-1-pentene, 1-hexene, 1-octene and the like.

  In the present invention, the propylene copolymer composition has the above items 1) to 3), that is, the ethylene content is 7% by weight or more and 8% by weight or less, and the melting peak temperature is 150 ° C. or more and less than 160 ° C. And what is necessary is just to be obtained with what kind of manufacturing method, as long as it satisfy | fills that the heat of crystallization is 55 J / g or more and 65 J / g or less. For example, after producing a propylene-ethylene copolymer of propylene and a small amount of ethylene of about 1.0 wt% or more and less than 1.5 wt% by continuous polymerization, propylene and about 10 to 20 wt% of ethylene A method for producing a copolymer, or a propylene-ethylene copolymer of propylene and a small amount of ethylene of about 1.0% by weight or more and less than 1.5% by weight of propylene and about 10 to 20% by weight of ethylene By blending separately polymerized copolymers, the total ethylene content is 7 wt% or more and 8 wt% or less, the melting peak temperature is 150 ° C. or more and less than 160 ° C., The method of manufacturing the copolymer composition whose conversion heat is 55 J / g or more and 65 J / g or less is mentioned.

Hereinafter, the manufacturing method by continuous polymerization is explained in full detail.
The catalyst used for this polymerization is not particularly limited, but a catalyst comprising an organoaluminum compound and a solid component essentially comprising a titanium atom, a magnesium atom, a halogen atom and an electron donating compound is preferable.

Here, as the organoaluminum compound, a known general formula in this type of polymerization: R ¹ _m AlX _(3-m) (wherein R ¹ is a hydrocarbon residue having 1 to 12 carbon atoms, and X is a halogen atom) M is a number of 1 to 3.), for example, trialkylaluminum such as trimethylaluminum and triethylaluminum, dialkylaluminum halide such as dimethylaluminum chloride and diethylaluminum chloride, methylaluminum sesquichloride Alkyl aluminum sesquihalides such as ethylaluminum sesquichloride, alkylaluminum dihalides such as methylaluminum dichloride and ethylaluminum dichloride, and alkylaluminum hydrides such as diethylaluminum hydride. That.

A solid component essentially comprising a titanium atom, a magnesium atom, a halogen atom, and an electron donating compound is also known in this type of polymerization, and a titanium compound serving as a supply source of the titanium atom includes a general formula Ti ( OR ² ) _(4-n) X _n (wherein R ² represents a hydrocarbon residue having 1 to 10 carbon atoms, X represents a halogen atom, and n is a number from 0 to 4). Among them, titanium tetrachloride, tetraethoxytitanium, tetrabutoxytitanium, etc. are preferable. Examples of magnesium compounds that can supply magnesium atoms include dialkylmagnesium, magnesium dihalide, dialkoxymagnesium, and alkoxymagnesium. Halide etc. are mentioned, Magnesium dihalide etc. are preferable in it. Examples of the halogen atom include fluorine, chlorine, bromine, iodine, etc. Among them, chlorine is preferable, and these are usually supplied from the titanium compound or the magnesium compound. Or other halogen sources such as tungsten halides.

Electron-donating compounds include alcohols, phenols, ketones, aldehydes, carboxylic acids, oxygen-containing compounds such as organic or inorganic acids and their derivatives, nitrogen-containing compounds such as ammonia, amines, nitriles, and isocyanates. Among them, inorganic acid esters, organic acid esters, organic acid halides and the like are preferable, silicic acid esters, phthalic acid esters, acetic acid cellosolve esters, phthalic acid halides, and the like are more preferable, and the general formula R ³ R ⁴ _{(3 ^{-p) Si (oR 5) p}} ( wherein, ^{R 3} is 3 to 20 carbon atoms, preferably a branched aliphatic hydrocarbon residue having 4 to 10, or 5 to 20 carbon atoms, preferably 6 to 10 shows a cyclic aliphatic hydrocarbon residue, R ⁴ is from 1 to 20 carbon atoms, preferably represents a branched or linear aliphatic hydrocarbon residue 1 to 10, R ⁵ is a carbon 1 to 10, preferably 1 to 4 aliphatic hydrocarbon residues, and p is a number of 1 to 3.), for example, t-butyl-methyl-dimethoxysilane, t Particularly preferred are -butyl-methyl-diethoxysilane, cyclohexyl-methyl-dimethoxysilane, cyclohexyl-methyl-diethoxysilane and the like.

  In the production of the propylene copolymer composition of the present invention, first, propylene and ethylene are supplied, and further, if necessary, propylene and another α-olefin having 2 to 8 carbon atoms are supplied. Propylene copolymer or propylene under the conditions of a temperature of 50 to 150 ° C., preferably 50 to 100 ° C. and a partial pressure of propylene of 0.5 to 4.5 MPa, preferably 1.0 to 3.5 MPa in the presence of the catalyst. Polymerization to obtain an ethylene-α-olefin copolymer is carried out, and subsequently, propylene and ethylene and / or α-olefin having 4 to 8 carbon atoms are fed, and the temperature is 50 to 150 in the presence of the catalyst. C., preferably 50 to 100.degree. C., propylene and ethylene under partial pressure conditions of 0.3 to 4.5 MPa, preferably 0.5 to 3.5 MPa. Propylene - is done by carrying out the polymerization to obtain ethylene -α- olefin copolymer.

  The polymerization at that time may be carried out by any of batch, continuous and semi-batch methods. The first polymerization is in the gas phase or liquid phase, and the subsequent polymerization is also in the gas phase or liquid phase. The residence time in each stage is, for example, 0.5 to 10 hours, preferably 1 to 5 hours.

  Further, when problems such as stickiness occur in the powder particles of the composition produced by the above method, the active hydrogen-containing compound is added before or during the polymerization for the purpose of imparting fluidity of the powder particles. It is preferable to add in the range of 100 to 1000 times mol of titanium atoms in the solid component of the catalyst and 2 to 5 times mol of the organoaluminum compound of the catalyst.

  Here, examples of the active hydrogen-containing compound include water, alcohols, phenols, aldehydes, carboxylic acids, acid amides, ammonia, amines, and the like.

  The propylene copolymer of the present invention may be blended with various additives such as an antioxidant, a light stabilizer, a lubricant and a neutralizing agent as necessary.

Intermediate layer of the liquid agent compartment of the present invention The multilayer film forming the liquid agent compartment of the present invention is preferably adjacent to the inner layer and more preferably adjacent to the inner layer and the outer layer between the outer layer and the inner layer. As a layer, it has an intermediate layer. This intermediate layer is a layer that supplements the performance of the multilayer film in the presence of the outer layer and the inner layer, and is preferably excellent in strength, heat resistance, transparency, barrier properties, and the like. In a particularly preferred embodiment, the multilayer film forming the liquid compartment of the present invention has an intermediate layer formed from a propylene-based polymer composition containing a propylene-based polymer or a styrene-based elastomer, and thus the multilayer film is A multilayer film composed of at least three layers. This intermediate layer contributes to the impact resistance of the container to be formed, and may be formed of only one layer or may be formed of two or more layers.

  The propylene-based polymer forming the above-mentioned intermediate layer is an ethylene content of 6 wt% or more and 12 wt% or less, a melting peak temperature of 130 ° C. or more and less than 170 ° C., a crystallization heat of 10 J / g or more, 50 J / G or less of propylene and ethylene and / or an α-olefin having 4 to 8 carbon atoms, which is different from the propylene-based copolymer used for the inner layer in terms of heat of crystallization. More specifically, as the propylene polymer, for example, commercially available “Mitsubishi Chemical Zeras 7023” is suitable.

  The above-mentioned styrene elastomer is a hydrogenated derivative of a vinyl aromatic hydrocarbon / conjugated diene block copolymer, and has a general formula: a (ba) n, (ab) n or abc Or a hydrogenated derivative of a block copolymer represented by the formula (wherein (a) is a polymer block of a monovinyl-substituted aromatic hydrocarbon, and (b) is a monovinyl-substituted aromatic) Random copolymer block of hydrocarbon and conjugated diene or elastomeric polymer block of conjugated diene, (c) is a block of monovinyl substituted aromatic hydrocarbon and conjugated diene, and monovinyl substituted aromatic hydrocarbon is gradually increased And n is an integer of 1 to 5).

  Examples of the vinyl aromatic hydrocarbon monomer constituting the polymer block (a), (b) or (c) include styrene, α-methylstyrene, (o-, m-, p-) methylstyrene. 1,3-dimethylstyrene, vinylnaphthalene, vinylanthracene and the like. Among these, styrene or α-methylstyrene is preferable. The conjugated diene monomer in the polymer block (b) or (c) is preferably butadiene and / or isoprene.

  If butadiene is used as the single conjugated diene monomer to form the polymer block (b) or (c), after the block copolymer is hydrogenated to saturate the double bond, For the purpose of increasing the compatibility with the propylene-based polymer, it is preferable to employ polymerization conditions in which the 1,2-microstructure in the microstructure of polybutadiene is 50% by weight or more. A preferred proportion of 1,2-microstructure is 50% to 90% by weight.

  The proportion of the polymer block (a) in the hydrogenated block copolymer or the sum of the content of the vinyl aromatic compound in the polymer block (a) and the polymer block (c) is usually 3 to 30% by weight, preferably Is 5 to 20% by weight. When the ratio of the polymer block (a) or the sum of the content of the vinyl aromatic compound in the polymer block (a) and the polymer block (c) is less than 3% by weight, the mechanical strength of the resulting composition foreign matter is It tends to be inferior. When the ratio of the polymer block (a) or the sum of the vinyl aromatic compound content of the polymer block (a) and the polymer block (c) exceeds 30% by weight, the flexibility and transparency of the composition Tend to be inferior.

  The weight average molecular weight of the styrene-based elastomer (hydrogenated derivative of vinyl aromatic hydrocarbon / conjugated diene block copolymer) is usually 10 to 550,000, preferably 15 as a value in terms of polystyrene measured by gel permeation chromatography. ˜500,000, more preferably 200 to 450,000. When the weight average molecular weight is less than 100,000, rubber elasticity and mechanical strength tend to be inferior, and when it exceeds 550,000, viscosity tends to be high and molding processability tends to be inferior.

  Examples of the styrene elastomers (hydrogenated derivatives of vinyl aromatic hydrocarbon / conjugated diene block copolymer) include “KRATON-G” from Kraton Polymers, “Septon”, “Hibler” from Kuraray, Asahi Kasei. Commercially available products such as “Tuftec” from JSR, “Dynalon” from JSR, and “SIBSTAR”, which is composed of styrene blocks and isobutylene blocks obtained by cationic polymerization from Kaneka, are available.

  As a propylene polymer composition containing a styrene elastomer, “Zeras MC717 made by Mitsubishi Chemical” is suitable. In particular, a propylene-based polymer composition containing a styrene-based elastomer is excellent in flexibility, transparency, and impact resistance, but tends to have a low water vapor barrier property.

  Further, the multilayer film forming the liquid compartment of the present invention of the present invention is composed of at least three or more layers having an intermediate layer preferably formed from a cyclic polyolefin in addition to or instead of the above-mentioned intermediate layer. It may be a multilayer film.

  The cyclic polyolefin has a high water vapor barrier property, and the water vapor barrier property of the multilayer film can be improved by disposing it in the intermediate layer. Cyclic polyolefin refers to a hydrogenated product of a copolymer of ethylene and a cyclic olefin monomer or a ring-opening metathesis polymer of a cyclic olefin monomer. Examples of the cyclic olefin monomer include monocyclic cycloolefins such as cyclobutene, cyclopentene, cyclooctene, and cyclododecene, and derivatives thereof having a substituent, substituted and unsubstituted bicyclic or tricyclic or more polycyclic rings having a norbornene ring. Examples thereof include olefin monomers (hereinafter sometimes referred to as norbornene-based monomers). From the viewpoints of production suitability and content suitability, a norbornene monomer is preferably used.

  More specifically as the norbornene-based monomer, for example, norbornene, norbornadiene, methylnorbornene, dimethylnorbornene, ethylnorbornene, chlorinated norbornene, chloromethylnorbornene, trimethylsilylnorbornene, phenylnorbornene, cyanonorbornene, dicyanonorbornene, methoxycarbonylnorbornene, Bicyclic cycloolefins such as pyridylnorbornene, nadic acid anhydride, nadic imide; tricyclic cycloolefins such as dicyclopentadiene, dihydrodicyclopentadiene and its alkyl, alkenyl, alkylidene and aryl substituents; dimethanohexahydronaphthalene, Dimethanooctahydronaphthalene and its alkyl, alkenyl, alkylidene, and aryl substituents Pentacyclic cycloolefins such as tricyclopentadiene; cycloolefins such hexacyclic cycloolefins such as hexamethylene cycloheptanone decene and the like. It is also possible to use dinorbornene, a compound in which two norbornene rings are bonded by a hydrocarbon chain or an ester group, a compound containing a norbornene ring such as an alkyl or aryl substituent thereof, and the like.

  As the copolymer of ethylene and a cyclic olefin monomer, for example, commercially available products such as “Appel” manufactured by Mitsui Chemicals, Inc. and “TOPAS” manufactured by TICONA can be suitably used. Further, as the hydrogenated product of the ring-opening metathesis polymer of the norbornene-based monomer, commercially available products such as “ZEONEX”, “ZEONOR” manufactured by Nippon Zeon Co., Ltd., and “ARTON” manufactured by JSR can be suitably used. .

  As the cyclic polyolefin-based resin in the present invention, a cyclic polyolefin-based resin composition using a plurality of types of cyclic polyolefin-based resins can be used as long as the transparency and water vapor barrier properties are not impaired. Mixtures with elastomers can be used.

  As an intermediate | middle layer, the layer formed from the 1 type, or 2 or more types of mixture selected from the group which consists of the propylene-type polymer which may contain the above-mentioned styrene-type elastomer, and cyclic polyolefin may be sufficient. Such an intermediate layer may be formed of one layer or two or more layers, and in particular, may be a three layer composed of a propylene polymer layer containing a styrene elastomer sandwiching a cyclic polyolefin layer. In this embodiment, when the inner layer, the intermediate layer, and the outer layer are extruded together, the propylene polymer layer containing the styrene-based elastomer may function as an adhesive layer that adheres the cyclic polyolefin layer as the intermediate layer to the inner layer and the outer layer. Is possible. The stacking order can be variously selected according to the purpose.

  As described above, the multilayer film of the present invention is a multilayer film having at least three layers having an intermediate layer between the inner layer and the outer layer.

  In this invention, the thickness of the whole multilayer film is 100-500 micrometers normally, Preferably it is 230-290 micrometers, and the thickness of an inner layer is 30-70 micrometers, Preferably it is 40-60 micrometers. The thickness of the outer layer is usually 50 to 90 μm, preferably 60 to 80 μm. Moreover, the thickness of an intermediate | middle layer is 100-180 micrometers normally, Preferably it is 120-160 micrometers.

  In the three-layer film as the multilayer film of the present invention comprising the inner layer, the intermediate layer, and the outer layer, the thickness ratio is preferably inner layer: intermediate layer: outer layer = 15-23: 70-64: 15-24. .

  Any appropriate lamination method may be used as the method for producing the multilayer film of the present invention. For example, dry lamination, extrusion lamination, coextrusion lamination (T-die method, inflation method), heat lamination, etc., or a lamination method combining these methods can be exemplified.

  Note that the inner layer, the intermediate layer, and the outer layer may be in direct contact, or an adhesive layer may exist between the layer and another layer. Any of the above laminating methods is known, and a person skilled in the art can appropriately select an optimum one according to the type of layer to be laminated, the presence or absence of an adhesive layer, and the like.

  The adhesive layer is a layer of an adhesive or an adhesive resin that is located between these layers and bonds them when the layers are laminated as described above. Examples of adhesives include polyurethane adhesives, adhesive resins include polyolefins, acid-modified polyolefins modified with acids such as maleic anhydride, and copolymers of ethylene and a monomer having a carboxyl group. Can be mentioned. The thickness of the adhesive is appropriately selected depending on the type and thickness of the film to be bonded.

  As a method for producing the liquid compartment of the present invention using the multilayer film, a sheet forming method (thermoforming method) such as vacuum forming or pressure forming, a blow forming method such as multilayer coextrusion blow molding, or a predetermined shape Any suitable method may be used, such as a method of producing a bag-like product by bonding the peripheral portions of multi-layer films in a single wafer form to each other by heat fusion (strong welding) or an adhesive. In the present invention, the inner layer of the multilayer film constituting the liquid agent compartment can be a weak weld.

  The medical multi-chamber container of the present invention comprises a liquid medicine compartment for containing a liquid medicine and a medicine compartment for containing a medicine liquid-tightly coupled to the compartment.

  The liquid agent compartment is, for example, a bag in which a peripheral portion is strongly welded by interposing a port portion at one end of the tubular multilayer film with the inner layer on the inside, and a weak weld portion is formed by thermally bonding the other end. A container. The combination of the liquid medicine compartment and the medicine compartment is performed by various methods.

  The medicine compartment has a main body for containing the medicine, and the main body is a bag-like container formed by adhering the periphery of a sheet-like front sheet and a sheet-like rear sheet, for example, The rear sheet is preferably formed from a multilayer film. In another aspect, it may be a bag-like container formed from a tubular film. In order to couple | bond with a chemical | medical agent compartment, the separate member (for example, small piece) which comprises a weak welding part may be joined.

  The material constituting the drug compartment is not particularly limited, but the amount of low molecular weight components and adhesive layer components eluted from the container is small, forming a container that suppresses or eliminates problems such as an increase in insoluble fine particles in the drug. Preferably it can be done.

  In the present invention, the peelable welded portion is a portion having an easy peel function, and is a portion where the innermost layer forming the liquid agent compartment and the drug compartment is welded, or has a welding strength with respect to the innermost layer. It is a portion where a separate member (for example, a sheet-like member, a small piece, etc.) formed from a small resin and the innermost layer are weakly welded. The easy peel function is a force that can be applied by, for example, hands or jigs (specifically, by hand) when preparing a medicine for mixing a medicine and a liquid after the films forming the container are adhered and welded to each other. This means that the welded part can be easily peeled off by pressing the liquid agent compartment with a force.

  Examples of the material constituting the above-described separate member include a blend polymer of polyethylene and polypropylene, an ethylene / propylene copolymer, a propylene / α-olefin copolymer (a), the copolymer (a) and α- And a blend of propylene / α-olefin copolymer (b) and / or propylene homopolymer (c) having different olefin contents (Japanese Patent No. 3573091). In addition, the container which has the above-mentioned peelable weld part is well-known, For example, patent 3016348 gazette, patent 3804504 grade | etc., Can be referred to. In addition, the innermost layer of the multilayer film that constitutes the liquid agent compartment of the present invention can form a weakly welded portion when they are heat-bonded together.

  In one embodiment of the present invention, the peel strength at the strong weld is usually 15 to 30 N, and the peel strength at the weak weld is usually 1.0 to 2.0 N.

  Below, an Example and a comparative example are given and the medical multi-chamber container of this invention is demonstrated in detail. In the examples and comparative examples, each measurement item was measured by the following method.

Heat resistance : T-shaped peel strength (0.49 to 2.94 N / 15 m) before and after high pressure steam sterilization at 121 ° C. for 20 minutes was measured after laminating two tubular multilayer films.

Communication strength : As an evaluation standard, a disk having a diameter of 80 mm was pressed into the liquid agent compartment, and the strength when communicating was measured. In medical use, it is usually required to be 49 to 245N.

Insoluble fine particles in liquid : A test method according to the Japanese Pharmacopoeia liquid insoluble fine particle test using a light-shielding automatic fine particle analyzer (Lion, KL-04) or liquid insoluble fine particle analyzer (Hiac / Royco80000A) Measure the number of insoluble fine particles. The principle of light-blocking fine particle measurement is that insoluble fine particles present in a solution sucked at a constant flow rate by a projected laser beam are scattered by a sensor unit. The measured value is counted by converting the frequency of the scattered light into a numerical value and converting the intensity of the scattered light into a particle diameter.

  As an evaluation criterion, if the number of particles having a particle size of 2 to 5 μm is <30, or the number of particles having a particle size of 5 μm or more is <10, it is judged as good.

  The method for measuring insoluble fine particles in injections is described in the section of injections in the Japanese Pharmacopoeia General Rules for Preparations. In principle, the first method “method using a light shielding type automatic fine particle measuring apparatus” is used, and when measurement cannot be performed using the first method, measurement can be performed using the second method “method using a microscope”. . As a standard for injection, when measured by the first method, 25 particles or less having a particle size of 10 μm or more per mL and 3 or less particles having a particle size of 25 μm or more per mL must be used. Further, when measured by the second method, it is necessary that 12 particles or less having a particle diameter of 10 μm or more per mL and 2 or less particles having a particle diameter of 25 μm or more per mL.

Transparency : Underwater light transmittance at a wavelength of 450 nm is measured with a spectrophotometer.

Impact strength : It was performed according to JISK7160 using a pendulum impact test (DG-TB) of Toyo Seiki Co., Ltd.

Low temperature drop strength : Drop from a height of 150 cm at 4 ° C., and check if there is a broken bag when dropped.

Example 1
Production of tubular film Inner layer formed from propylene polymer composition (Mitsubishi Chemical Zelas MC611) having an ethylene content of 7.5% by weight, a melting peak temperature of 157 ° C., and a crystallization heat of 60 J / g, propylene containing a styrene elastomer An intermediate layer formed from a polymer (MC717 manufactured by Mitsubishi Chemical), an ethylene polymer (LLDPE (MFR 3.5 g / 10 min, density 0.94 g / cm ³ )) and LD (MFR 0.9 g / 10 min, density 0. 93 g / cm ³ ) and a three-layer tubular film (total thickness 230 μm, thickness ratio, inner layer: intermediate layer: outer layer = 1: 3: 1) formed from a mixture (LD is 10% with respect to LLDPE) , Diameter 100 mm) was produced by coextrusion (see Table 1).

Manufacture of liquid compartment A tubular product (folded diameter: 100 μm × length: 150 mm) is produced from the tubular multilayer film, a port is sandwiched at one end, and the edge of the one end is strongly welded at 145 ° C. for 3.0 seconds. The central edge of the other end was weakly welded at a pressure of 0.3 MPa, a welding temperature of 150 ° C. for 3.5 seconds, and the remaining edge was strongly welded at 145 ° C. for 3.0 seconds. The obtained container is a liquid agent compartment having a port attached at one end and a weak weld at the other end. The liquid compartment was filled with 105 ml of powder drug dissolving liquid (specifically, physiological saline) as a liquid from the port, the end of the port was closed with a cap, and steam sterilization was performed at 121 ° C. for 20 minutes. The insoluble fine particles in the liquid before and after the sterilization were measured using a fine particle insoluble fine particle meter (Lion, KL-04). Further, the communication strength, transparency, impact strength, and low temperature drop strength of the liquid agent compartment were measured. The results are shown in Table 2. FIG. 1 schematically shows a liquid agent compartment.

Manufacture of drug compartment: Cyclic polyolefin (product name: ZEONOR manufactured by Nippon Zeon Co., Ltd.) is extruded together with medium density polyethylene (density 0.938) using a co-extruder at 250 ° C. to form a two-layer film (former 30 μm, latter 20 μm) ) Was formed. A polyethylene terephthalate film (Mitsubishi Chemical, thickness 12 μm) and a medium density polyethylene film (density 0.938, through a polyolefin-based adhesive resin (LLDPE) on the medium density polyethylene layer of this two-layer film.
A multilayer film (front sheet A) was formed by sequentially laminating 40 μm thickness). The thickness of the adhesive layer was 20 μm.

  Next, a cyclic polyolefin (manufactured by ZEON, trade name ZEONOR) was extruded at 250 ° C. together with a medium density polyethylene (density 0.938) using a co-extruder to produce a two-layer film (the former 30 μm, the latter 20 μm). Filmed. Separately, an aluminum foil (manufactured by Sun Aluminum, thickness 20 μm) and a polyethylene terephthalate film (manufactured by Toyobo, thickness 16 μm) are laminated using a polyurethane adhesive (manufactured by Takeda Pharmaceutical) to form a two-layer laminate. Obtained. A multilayer film (rear sheet B) was manufactured by laminating an aluminum foil of a two-layer laminate on a medium-density polyethylene layer of the two-layer film via a polyolefin-based adhesive resin (LLDPE). The thickness of the adhesive layer was 20 μm.

  The front sheet A (length 300 mm × width 150 mm) and the rear sheet B (length 300 mm × width 150 mm) are overlapped, and a small piece (length) made of a blend polymer containing polyethylene and polypropylene at a position 25 mm above the lower ends of both films. 20 mm × 75 mm in width), and the peripheral portion excluding the lower ends of the front seat and the rear seat was strongly welded at 170 ° C. and a pressure of 0.3 MPa. A portion of the front sheet and the rear sheet sandwiching the small pieces was weakly welded at a welding temperature of 160 ° C. for 1 second to create a bag-like container (140 mm × 115 mm) in which a weakly welded portion was formed. From the weakly welded portion to the lowermost end portion, there exists an open state where the two films are not bonded.

Integration of liquid compartment and medicine compartment The above medicine compartment is sterilized with gamma rays in the form of a bag (140 mm x 115 mm), and 1.5 mg of solid preparation (specifically, antibiotics) is aseptically obtained. Accommodated. Next, the tubular film end portion (including the weakly welded portion) of the liquid agent compartment is inserted between the two films at the lowermost end of the medicine compartment, and the temperature is set to 150 ° C. and 4.0 seconds from the outside of the medicine compartment. Thus, a multi-chamber container in which the drug compartment and the liquid agent compartment were combined was manufactured.

Sample preparation and measurement A multi-chamber container containing a solid preparation (specifically, antibiotics) in a drug compartment and a solution for injection (specifically, physiological saline) in a liquid compartment at room temperature After storing for 24 hours, the weakly welded portion was peeled off, and the solid preparation and the injection solution were mixed to prepare an injection solution.

Example 2
A tubular film was produced in the same manner as in Example 1, except that the total thickness of the tubular film was 260 μm (inner layer: 70 μm, intermediate layer: 140 μm, inner layer: 50 μm). Using this tubular film, a liquid agent compartment was produced in the same manner as in Example 1. Table 2 shows the physical properties of the liquid agent compartment.

Example 3
An inner layer (50 μm) formed from a propylene polymer composition (Mitsubishi Chemical Zelas MC611) having an ethylene content of 7.5% by weight, a melting peak temperature of 157 ° C., and a crystallization heat of 60 J / g, and a propylene-based polymer containing a styrene-based elastomer Three layers (130 μm, layer ratio, 30:70:30) formed from a polymer composition (MC717 made by Mitsubishi Chemical) / propylene polymer composition (MC717 made by Mitsubishi Chemical) containing cyclic polyolefin / styrene elastomer. A tubular 5-layer film (50 μm) composed of an outer layer formed from an intermediate layer composed of an ethylene polymer (LLDPE / LD (10%)) was produced by a coextrusion method (total thickness 230 μm).

  A tubular product (diameter: 110 μm × length: 155 mm) is prepared from the tubular multilayer film, and a port is attached to one end thereof, and the edge surrounding the port is strongly welded at 145 ° C. for 3.0 seconds, and the center edge of the other end The part was weakly welded from the outside at a pressure of 0.3 MPa, a welding temperature of 150 ° C. and a time of 3.5 seconds, and the remaining edge was strongly welded at 145 ° C. and 3.0 seconds. The obtained container is a liquid agent compartment having a port attached at one end and a weak weld at the other end. The liquid compartment was filled with 105 ml of powder drug dissolving liquid (specifically, physiological saline) as a liquid from the port, the end of the port was closed with a cap, and steam sterilization was performed at 121 ° C. for 20 minutes. The insoluble fine particles in the liquid before and after the sterilization were measured using a fine particle insoluble fine particle meter (Lion, KL-04). Table 2 shows the communication strength, transparency, impact strength, and low temperature drop strength of the liquid compartment.

Comparative Example 1
A two-layer film without an intermediate layer in Example 1 was produced, and a liquid agent compartment was produced in the same manner as in Example 1. Table 2 shows the physical properties of the liquid agent compartment. The obtained liquid agent compartment was inferior in impact resistance.

Comparative Example 2
A single-layer tubular film consisting only of a layer formed from LLDPE / LD (10%) in Example 1 was produced, and a liquid agent compartment was produced in the same manner as in Example 1. When the obtained liquid agent compartment was filled with water and then autoclaved, whitening and deformation were severe, making it difficult to measure each physical property.

Comparative Example 3
Metallocene catalyst-based linear polyethylene (M-PE-1) having a production density of 0.928 g / cm ³ or higher, high-pressure low-density polyethylene (LDPE), metallocene catalyst system having a density of 0.91 g / cm ³ or less Chain polyethylene (M-PE-2) is mixed at a weight ratio of 7: 1: 2 using a blender, and using an inflation machine, a lip clearance of 2.5 mm, a drawing speed of 8 m / min, and a die temperature of 190 ° C. A tubular film having a folded shape of 100 mm and a wall thickness of 250 μm was prepared under the molding conditions described above.

  Next, the tubular film is cut to a length of 150 mm, one end is strongly welded to create a container as a liquid agent compartment, and physiological saline is injected into the container. Property, transparency, presence / absence of fine particles, and flexibility (impact resistance, drop strength) were evaluated. The results are shown in Table 2. The obtained liquid compartment was inferior in impact resistance and weak weldability.

  As is clear from Table 2, the liquid compartment (Examples 1, 2 and 3) of the present invention withstood high-pressure steam sterilization at a temperature of 121 ° C. and improved impact strength. Further, after storage for 24 hours, the number of fine particles was 5 to 18 for 2 to 5 μm, and 1 to 2 for 5 μm or more.

Comparative Examples 5-8
Instead of the propylene polymer composition (Mitsubishi Chemical's Zelas MC611) (Sample A) used for the inner layer of the liquid compartment of the present invention, propylene having different ethylene content and melting peak temperature as shown in Table 3 below Although the multi-chamber container was manufactured similarly to Example 1 using the system polymer (samples B to E), as shown in Table 3 below, a satisfactory weakly welded portion was not obtained. Moreover, when the mouth of the liquid agent compartment was opened, the drug compartment was inserted, and the liquid agent compartment and the drug compartment were joined, in Comparative Examples 5 to 8, blocking of the inner layers occurred.

「弱溶着性」の「強すぎる」とは強溶着の状態を意味し、「出ないとは」弱溶着より弱い状態を意味する。
「製袋性」とは、シートを製袋機にかけた場合、スムーズに流動する状態であって、「口開き」とは、シートの両面がポート装入して溶着される際に容易に開くことを意味する。

“Too strong” in “weak weldability” means a state of strong welding, and “not coming out” means a state weaker than weak welding.
“Bag-making” means a state in which a sheet flows smoothly when it is put on a bag-making machine, and “open mouth” is easily opened when both sides of a sheet are inserted into a port and welded. Means that.

Example 4
Inner layer (30 μm) formed from a propylene copolymer (Mitsubishi Chemical Zelas MC611) having an ethylene content of 7.5 wt%, a melting peak temperature of 157 ° C., and a crystallization heat of 60 J / g, each containing a styrene elastomer An intermediate layer (meaning a layer located between the inner layer and the outer layer, 170 μm) composed of three layers (thickness ratio of these layers: 50:70:50) formed of a propylene polymer (MC717 manufactured by Mitsubishi Chemical) , A mixture of an ethylene-based polymer (LLDPE (MFR 3.5 g / 10 min, density 0.94 g / cm ³ )) and LD (MFR 0.9 g / 10 min, density 0.93 g / cm ³ ). 10%) was used to produce a tubular film (total thickness 230 μm) using a five-layer coextrusion machine (see Table 4).

  In addition, as described above, in the intermediate layer, a layer made of a propylene-based polymer containing a styrene-based elastomer (a layer having a thickness of 50 μm) is located on the outer side of the intermediate layer. It functions as an adhesive layer that adheres to the central layer (corresponding to the intermediate layer of the present invention, a layer having a thickness of 70 μm).

  A tubular product (folded diameter: 300 mm × length: 155 mm) is produced from the tubular multilayer film, and a port is attached to one end thereof, and a peripheral portion surrounding the port is strongly welded at 145 ° C. for 3.0 seconds, and the center at the other end The peripheral edge was weakly welded from the outside at a pressure of 0.3 MPa, a welding temperature of 150 ° C. for 3.5 seconds, and the remaining peripheral edge was strongly welded at 145 ° C. for 3.0 seconds. The obtained container was a liquid agent compartment having a port attached to one end and a weak weld on the other end. Table 5 shows the weak sealing performance, transparency, water vapor transmission rate, delamination and film formation / molding state of the liquid compartment.

Example 5
In Example 4 above, except that the ratio of the intermediate layer of propylene-based polymer (MC717 manufactured by Mitsubishi Chemical) containing styrene-based elastomer is 40:60:40, and the total thickness is 200 μm, and Example 4 A liquid compartment was created in the same manner. See Table 4. Table 5 shows the weak sealing performance, transparency, water vapor transmission rate, delamination, and film forming / molding state of the liquid agent compartment as in Example 4.

Example 6
Propylene containing an inner layer (30 μm) composed of a propylene-based copolymer (Mitsubishi Chemical Zelas MC611) having an ethylene content of 7.5% by weight, a melting peak temperature of 157 ° C., and a crystallization heat of 60 J / g, and propylene containing two types of styrene-based elastomers Mixture of polymer polymer composition (MC717 and MC719 manufactured by Mitsubishi Chemical Co., Ltd., mixing ratio (weight basis) 1: 9) / cyclic polyolefin / mixture of propylene polymer containing the two styrene elastomers (MC717 manufactured by Mitsubishi Chemical Corporation) And MC719, mixing ratio 1: 9) intermediate layer consisting of 3 layers (layer ratio, 60:50:60) (meaning a layer located between the inner layer and the outer layer, 170 μm), an ethylene polymer (LLDPE ( MFR3.5g / 10 min, a mixture of a density 0.94 g / cm ³⁾ and LD (MFR0.9g / 10 min, density 0.93g / cm ³⁾ (L . See Table 4 were prepared using the co-extruder outer layer (5 layer tubular film made of 30 [mu] m) (total thickness 230 .mu.m) of 10%) relative to the LLDPE.

  As described above, the layers (layers each having a thickness of 60 μm) made of a mixture of propylene-based polymer compositions containing two kinds of styrene-based elastomers located outside in the intermediate layer are the inner layer and the outer layer. It functions as an adhesive layer that adheres to the middle layer of the intermediate layer (corresponding to the intermediate layer of the present invention, a layer having a thickness of 50 μm made of cyclic polyolefin).

  A tubular product (folded diameter: 300 mm × length: 155 mm) is produced from the tubular multilayer film, and a port is attached to one end thereof, and a peripheral portion surrounding the port is strongly welded at 145 ° C. for 3.0 seconds, and the center at the other end The peripheral edge was weakly welded from the outside at a pressure of 0.3 MPa, a welding temperature of 150 ° C. for 3.5 seconds, and the remaining peripheral edge was strongly welded at 145 ° C. for 3.0 seconds. The obtained container was a liquid agent compartment having a port attached at one end and a weak weld at the other end. Table 5 shows the weak sealing performance, transparency, water vapor transmission rate, delamination and film formation / molding state of the liquid compartment.

Example 7
In Example 6 above, a liquid agent compartment was prepared in the same manner as in Example 4 except that the ratio of the intermediate layer was 45:50:45 and the total thickness was 200 μm. Table 4 and Table 5 show the weak sealing performance, transparency, water vapor transmission rate, delamination, and film formation / molding state of the liquid compartment as in Example 4.

水蒸気透過率とは、ＪＩＳ Ｋ７１２９Ｂ法（赤外センサー法）によって測定する（単位：ｇ／ｍ^２・２４時間）。

The water vapor transmission rate is measured by JIS K7129B method (infrared sensor method) (unit: g / m ² · 24 hours).

  As is apparent from Tables 4 and 5, it can be seen that the presence of the cyclic olefin layer as the intermediate layer further reduces the water vapor transmission rate and provides excellent barrier properties.

Claims (5)

A medical multi-chamber container having a liquid medicine compartment containing a liquid medicine and a medicine compartment containing a medicine;
The liquid agent compartment is formed from a multilayer film having at least three layers of an outer layer formed of an ethylene-based polymer, an inner layer formed of a propylene-based copolymer, and an intermediate layer positioned between these layers. And
The propylene-based copolymer is a polymer composition prepared with propylene and ethylene as main components,
1) Ethylene content is 7 wt% or more and 8 wt% or less 2) Melting peak temperature is 150 ° C or more and less than 160 ° C 3) Crystallization heat is 55 J / g or more and 65 J / g or less Medical multi-chamber container. 2. The medical multi-chamber according to claim 1, wherein the ethylene-based polymer forming the outer layer is a mixture of a linear low density polyethylene having a density of 0.93 g / cm ³ or more and a high pressure method low density polyethylene. container.   The medical multi-chamber container according to claim 1 or 2, wherein the intermediate layer is formed of at least one selected from the group consisting of a propylene-based polymer that may contain a styrene-based elastomer and a cyclic polyolefin. .   The liquid medicine compartment and the medicine compartment are fluid-tightly connected by a peelable seal portion, the medicine compartment is a bag-like material composed of a front sheet and a rear sheet, and the liquid medicine compartment is a multilayer film tubular product The medical multi-chamber container according to any one of claims 1 to 3, wherein the medical multi-chamber container is molded from the above.   5. The medical multi-chamber container according to claim 4, wherein the peelable seal portion is a portion where the inner layers of the multilayer film forming the liquid agent compartment are welded to each other.