JP4119920B2 - Medical multi-chamber container - Google Patents

Description

  The present invention relates to a medical multi-chamber suitable for storing two or more kinds of chemical solutions in separate storage chambers separated from each other and mixing the plurality of chemical solutions in a closed state by breaking the isolation portion during use. Concerning the container.

In the medical field, it is very common to administer a plurality of drug components in a living body in a mixed state. However, the following methods are explored depending on the combination of drug components to be mixed. For example, in the case of infusion, a solution containing amino acids and glucose is likely to be altered by the Maillard reaction, so each component is often stored in a separate closed system and mixed immediately before administration to the patient. In order to perform the mixing operation aseptically (in a closed system) and easily, a container partitioned into a plurality of storage chambers is used, and different infusion components are stored in each of the storage chambers. Therefore, a method has been put to practical use in which the storage chamber partitioned immediately before use is communicated and mixed in the closed system by some means.
As a compartment means, it is important that each infusion component can be stably isolated until just before use and can be easily communicated during use (during mixing). Various forms have been devised and proposed for this purpose. Has been. Typical ones are: (1) the space between the storage chambers is clamped from the outside (Japanese Patent Laid-Open Nos. 53-38189, 61-103823, 1-160558, etc.); The chambers are connected by a tube exposed outside the container, and the tube is narrowed with a clamp (Japanese Utility Model Publication No. 57-76636, etc.), (4) Japanese Patent Application Laid-Open No. Sho 63-19149 (Japanese Patent Application Laid-Open No. 63-19149 (patent document)). JP-B-6-265563), JP-A-63-309263, JP-A-1-240469, JP-A-2-4671, JP-A-2-57584, JP-A-2-241457, JP-A-2-255418, JP 4-24 647 No., JP-A-5-31153, JP-A-5-68702, etc.), a.
Among them, the so-called easy-to-wear type multi-chamber container (4) that is practical and practical is the most noticeable. The technical point of this type is that the bulkhead seal between the storage chambers is relatively stable and difficult to break during manufacture or transportation, and can be easily broken by hand or jig when used (mixed). The fracture seal strength at the boundary portion having the seal strength and connected to the outside world (atmosphere) is sufficient. Therefore, the selection of the material that forms the inner wall of the container (that is, the molding of the seal portion) is the most important. A mixture with polyethylene or the like (which is a type that causes so-called cohesive peeling when the seal portion is broken) is used.
However, the problem is whether these materials satisfy the requirements of the material for the infusion container, that is, safety, flexibility, transparency, heat resistance (high-pressure steam sterilization resistance), etc. The application of a mixture of polyethylene has difficulty in transparency and flexibility. The sheet obtained by mixing polypropylene and polyethylene loses transparency. In addition, polypropylene has high rigidity (inferior in flexibility), and even if a relatively flexible polyethylene is mixed, it is difficult to reach a flexible region that is satisfactory as an infusion container. Copolymerization of other monomers (for example, ethylene and butene-1) is known as an effective means for softening polypropylene. If the amount of comonomer is increased in order to increase flexibility, the container (sheet) obtained from the copolymer can be obtained. There is a problem of stickiness on the surface (due to low molecular weight components and amorphous components).
The “polypropylene” mentioned here is a normal crystalline polypropylene produced with a heterogeneous titanium catalyst.

JP 53-38189 JP 61-103823 JP-A-1-160558 Shokai 57-76636 JP-A-57-52455 JP 63-19149 (Japanese Patent Publication No. 6-26563) JP-A 63-309263 JP-A-1-240469 JP-A-2-4671, JP-A-2-57584, JP-A-2-241457 JP-A-2-255418 JP-A-4-242647 JP-A-5-31153 Japanese Patent Laid-Open No. 5-68702

  An object of the present invention is to solve the problem of selecting the material of the easy-to-use and easy-to-use medical multi-chamber container.

What achieves the above object is as follows.
(1) A medical multi-chamber container in which a part of opposing inner wall surfaces is partitioned into a plurality of storage chambers by a peelable heat seal, wherein the medical multi-chamber container is manufactured with a metallocene catalyst, And a polypropylene having a melting point of 128 to 134 ° C. and a melt flow rate of 2.6 to 3.0 , an ethylene-propylene copolymer, a block (polystyrene-ethylenebutylene copolymer-polystyrene) copolymer, a block (polystyrene-ethylenepropylene copolymer) Polystyrene) copolymer or block (polystyrene-ethylenebutylene copolymer-polyethylene) copolymer with a thermoplastic elastomer, and the weight ratio of the polypropylene to the thermoplastic elastomer is 85:15 to 15:15. A polymer that is 65:35 Multi-chamber medical container made of sheet alone of Narubutsu.
(2) Before Kinetsu thermoplastic elastomer is an ethylene - propylene copolymer or ethylene - multi-chamber medical container according to butene -1 copolymer (1).
(3) The medical use according to (1), wherein the thermoplastic elastomer is a block (polystyrene-ethylenebutylene copolymer-polystyrene), a block (polystyrene-ethylenepropylene copolymer-polystyrene) or a block (polystyrene-ethylenebutylene copolymer-polyethylene). Multi-chamber container.

  The medical multi-chamber container of the present invention utilizes that the characteristics of polypropylene produced by a metallocene catalyst having a relatively low melting point of 140 ° C. or less are well exhibited in combination with an olefin-based or styrene-based thermoplastic elastomer. As well as the performance as a multi-chamber container (easy-to-wear property), it has excellent balance of transparency, flexibility and appearance. In addition, because it is rich in productivity, it is expected to contribute greatly to the medical field.

The present invention relates to a thermoplastic elastomer (hereinafter referred to as “M-PP”) made of a metallocene catalyst and having a melting point of 140 ° C. or lower and an olefin thermoplastic elastomer or styrene thermoplastic elastomer. It is a medical multi-chamber container that has a polymer composition with an inner wall surface and is partly separated into a plurality of storage chambers by heat seals that can be peeled off. This is a multi-chamber container for medical use that is superior in terms of balance among properties, flexibility, heat resistance and appearance.
Polypropylene produced with a metallocene catalyst exhibits a homogeneous catalyst effect, has a very narrow molecular weight distribution, and is random compared to “normal” polypropylene (hereinafter referred to as PP) produced with a heterogeneous titanium catalyst. It is well known that it has a high molecular weight and a homogeneous molecular structure, so it has excellent transparency, and even when it has a low melting point, there are very few low molecular weight and amorphous materials (atactic polymer), so there is no stickiness and the amount of eluted components is very small. Although it is obvious that a material having a relatively low melting point is necessarily flexible, the present invention has been found to satisfy the requirements for a multi-chamber container in combination with a specific thermoplastic elastomer. It was issued. There is room for elucidation as to whether the polymer composition with the M-PP thermoplastic elastomer in the present invention forms a micro-layer separation structure or a compatible system, but the molecule of M-PP and the thermoplastic elastomer It is considered that the interaction between them is intimately linked with appropriate seal strength, transparency, flexibility and the like.

  In the present invention, M-PP is a metallocene catalyst (generally called Zr, Hf, Ti, etc.) called Kaminsky-Sinn catalyst (also called single site catalyst or homogeneous catalyst focusing on the fact that the properties of active sites are the same). Of polypropylene produced using a metal cyclopentadienyl, indenyl or fluorenyl compound) having a melting point of 140 ° C. or less, the degree of isotactic or syndiotactic stereoregularity, It is produced by adjusting the content of 1-bond (head-head bond or tail-tail bond) or 1,3-bond (trimethylene bond). Further, it may be a copolymer obtained by copolymerizing a small amount (2 to 20 mol%) of an α-olefin such as ethylene, butene-1, hexene-1 or octene-1. The production of M-PP is described in, for example, Kazuo Soga et al., “The Chemical Society of Japan, New Industrial Chemistry Series, Polymerization Process Technology—Polyolefin” (issued in 1994 by Dai Nippon Book Co., Ltd.).

M-PP in the present invention is required to have a melting point of 140 ° C. or lower.
This is because when the melting point exceeds 140 ° C., the rigidity becomes high, the flexibility becomes poor, and the characteristics of M-PP do not survive. The thermoplastic elastomer acts as a softening agent for M-PP, but it needs to be added in a large amount in a region where the rigidity of M-PP is high, leading to a decrease in moldability. Considering the temperature during autoclaving (usually performed at 100 to 121 ° C), the preferable melting point is 120 to 135 ° C. In this region, the flexural modulus of M-PP is about 4,000 kg / cm ² or less, it becomes flexible with the addition of a relatively small amount of thermoplastic elastomer, and exhibits good sealing behavior that is a requirement as a multi-chamber container. . In consideration of moldability and mechanical properties of the molded product (container sheet), the MFR (melt flow rate) at a temperature of 230 ° C. and a load of 2,160 g is preferably 0.3 to 15, more preferably 0.5 to 15. It is good.

Next, among the thermoplastic elastomers used in the present invention, olefinic thermoplastic elastomers (hereinafter referred to as TPO) are amorphous or copolymers of ethylene and α-olefins such as propylene, butene-1 and hexene-1. low crystalline soft polymer (elastomer) is a typical example, in particular a density 0.90 g / cm ³ or less Vicat softening point of 50-70 ° C. in those ethylene content of 25 to 80 wt% is preferably chosen . In consideration of moldability and mechanical properties of the molded product, the TPO has an MFR at a temperature of 230 ° C. and a load of 2,160 g of 0.5 to 15, more preferably about 1 to 10.

In addition, representative examples of styrenic thermoplastic elastomers (hereinafter referred to as SBC) among the thermoplastic elastomers in the present invention are listed below. These are usually produced by known methods.
(1) Block (polystyrene-ethylenebutylene copolymer-polystyrene) (hereinafter referred to as SEBS): Polystyrene-polybutadiene (copolymer of 1,2-conjugate and 1,4-conjugate) -polystyrene type triblock copolymer (SBS) ) Is a block copolymer obtained by hydrogenation. Considering the affinity with M-PP and the easy-to-wear properties of the resulting sheet, the total of polystyrene parts (S part) at both ends is 10 to 40% by weight in SEBS, more preferably 12 to 30% by weight. Occupy better. In the ethylene butylene copolymer part (EB part), the proportion of the butylene part in the EB part is preferably 20 to 90% by weight, more preferably 30 to 80% by weight. From the viewpoint of moldability and mechanical properties of the molded product, SEBS having a MFR of 0.5 to 20 and more preferably 1 to 15 at a temperature of 230 ° C. and a load of 2,160 g is recommended.
(2) Block (polystyrene-ethylenepropylene copolymer-polystyrene) (hereinafter referred to as SEPS): It is obtained by hydrogenation of a polystyrene-polyisoprene-polystyrene type triblock copolymer (SIS) in the same manner as in SEBS. In consideration of the same matter as SEBS, the total of polystyrene parts (S part) at both ends should be 8 to 40% by weight in SEPS, more preferably 10 to 35% by weight, and MFR should be 0.5 to 20 Preferably the thing of 1-15 is good.

(3) Block (polystyrene-ethylenebutylene copolymer-polyethylene) (hereinafter referred to as SEBE): polystyrene-polybutadiene (copolymer of 1,2-bond and 1,4-bond) -poly-1,4-butadiene type Obtained by hydrogenation of a triblock copolymer. Considering the same matter as SEBS, the weight ratio of polystyrene part (S part), ethylene butylene copolymer part (EB part) and polyethylene part (E part) is preferably 5-30: 40-80: 10-40, more preferably. Is 8-25: 45-75: 12-35, and the amount of butylene in EB is 25-90 wt%, more preferably 30-80 wt%. Further, the MFR is preferably the same as that of SEBS.
(4) Block (polystyrene-ethylenepropylene copolymer-polyethylene) (hereinafter referred to as SEPE): It can be produced by hydrogenation of a triblock copolymer having a polystyrene-poly-1,4-isoprene-poly-1,4-butadiene structure. Considering the same matter as SEBS, the weight ratio of polystyrene part (S part), ethylene propylene copolymer part (EP part) and polyethylene part (E part) is preferably 5-30: 40-80: 10-40, more preferably. Is 8 to 25:45 to 75:12 to 35, and the MFR is preferably about the same as SEBS.
(5) Block (polystyrene-poly-1,2-polyisoprene-polystyrene) comb is a hydrogenated product: polystyrene content is 10 to 50% by weight, more preferably 15 to 40% by weight, and MFR is SEBS. The same level is good.
Of the styrenic thermoplastic elastomers (1) to (5), SEBS (1) and SEPS (2) are the most versatile.

As described above, the inner wall surface of the medical multi-chamber container of the present invention is a polymer composition of M-PP and a thermoplastic elastomer. Generally, the composition has a heat sealing property. In view of sealing strength, flexibility, transparency, heat resistance, etc., the weight ratio of M-PP to thermoplastic elastomer is 90:10 to 60:40, more preferably 85:15 to 65:35. Good. In this range, it is easy to obtain a good performance balance.
The medical multi-chamber container of the present invention has a case where the inner wall surface is a polymer composition of M-PP and a thermoplastic elastomer, and is made of a single sheet of a polymer composition of M-PP and a thermoplastic elastomer. In some cases, a multilayer sheet having a polymer composition of M-PP and a thermoplastic elastomer as an inner layer (inner wall surface of a container) and another polymer (or polymer composition) as an outer layer or an intermediate layer. The latter is combined with other polymers (or other polymer compositions) depending on the required performance such as barrier properties, transparency, flexibility, heat resistance, strength, etc. of the container gas (water vapor, oxygen, etc.). Typical examples of other polymers (or other polymer compositions) preferable for the following are shown below.

(A) A line having a density of 0.910 to 0.930 g / cm ³ using α-olefins such as butene-1, pentene-1, hexene-1, octene-1, and 4-methylpentene-1 as a copolymerization component. Low density polyethylene. The catalyst is produced with a Ziegler-Natta catalyst or a metallocene catalyst, and the latter is particularly preferable in terms of transparency.
(B) a crystalline polypropylene or crystalline polypropylene-based copoly mer composed mainly of it. As in the case of (a), it is produced with a Ziegler-Natta catalyst (heterogeneous titanium catalyst) or a metallocene catalyst. In particular, the latter case is excellent in that it is easy to obtain a polymer having good flexibility and transparency.

(C) (b) and amorphous polypropylene (atactic polypropylene)
And a polymer composition.
(D) Ethylene vinyl alcohol copolymer, which can be used for the purpose of imparting oxygen gas barrier properties to containers.
Further, the thickness of the sheet forming the medical multi-chamber container of the present invention is suitably 0.2 to 0.6 mm as a whole, more preferably 0.25 to 0.45 mm. The polymer composition layer of M-PP and thermoplastic elastomer has a thickness of 0.01 mm or more, preferably 0.02 mm or more.

The multi-chamber container of the present invention can be usually produced by a known method. That is, extraction is performed through a T die or a circular die for single layer or outer layer (melting temperature is 170 to 250 ° C., more preferably 180 to 230 ° C.), and the obtained flat sheet, tubular sheet, parison For example, thermoforming, blowing, stretching (non-stretching is better in consideration of heat sealability), cutting, fusing, and the like may be used as appropriate to be processed into a predetermined shape and form. The most important point in the production of the multi-chamber container is the heat sealing process. The seal at the partition (melting wall) between multiple storage chambers is less likely to break during manufacturing or transportation, and has a sealing strength that can be easily broken by hand or jig when used (mixed) (generally The seal strength (180 ° C peel strength is more than 1.5kg / 15mm). Therefore, it is required to control the conditions of the partition seal and the peripheral seal. In the case of the container of the present invention, the partition seal has a temperature of 110 to 150 ° C., a pressure of 1 to 4 kg / cm ² , a time of 0.2 to 5 seconds, a seal width of 2 to 10 mm, and the peripheral seal has a temperature of 130 to 200 ° C. and a pressure Usually, it is carried out in the range of ^{2 to} 5 kg / cm ² , time of 0.2 to 10 seconds, and seal width of 5 mm or more. The number of storage chambers is generally 2-4.

The polymer composition of M-PP and a thermoplastic elastomer can be prepared by using a known single or biaxial melt mixing extruder or static melt mixer. The melting temperature during mixing is preferably 160 to 220 ° C.
The multi-chamber container of the present invention is altered when present in the same solution, such as a combination of an amino acid solution and a glucose solution in an infusion solution, or a combination of a sodium bicarbonate solution and a glucose-containing electrolyte solution in a peritoneal dialysis solution used for CAPD. It is effective for combinations of chemicals that are likely to occur, and can be applied not only to infusions but also to the blood field.

Hereinafter, the present invention will be described more specifically with reference to examples.
1) Experimental method (1) Preparation of raw material polymer: The raw material polymer (pellet shape) used is shown in Table 1. The melting point was measured using a differential scanning calorimeter at a heating rate of 10 ° C./min.

  (2) Preparation of polymer composition: The polymer shown in Table 1 was appropriately selected, and kneaded at a predetermined ratio in a temperature range of 180 to 200 ° C. and extruded using a biaxial melt kneading extruder of 45 mm. The strand was cooled with water and cut to obtain pellet-shaped polymer compositions shown in Table 2.

(3) Production of sheet: The polymer or polymer composition of Table 1 and / or Table 2 is supplied to a single-layer or multi-layer circular die (inflation die), and a tubular sheet at 180 to 200 ° C. After cooling with a water cooling ring, a sheet having a thickness of 0.3 mm and a folding diameter of 200 mm was wound up at a speed of 5 m / min. Table 3 shows the configuration of the sheet.
(4) Production of multi-chamber container: The sheet obtained in (3) is cut into a length of 300 mm, and the center width of 7 mm is heat sealed under the conditions of a temperature of 120 ° C., a pressure of 2 kg / cm ² and a time of 5 seconds Put a 3 wt / v% amino acid aqueous solution in one chamber and 400 ml each of a 15 wt / v% glucose aqueous solution in the other chamber, heat seal under the conditions of 10 mm width, 160 ° C, pressure 4 kg / cm ² , time 5 seconds. Then, a multi-chamber container containing two chemical solutions was prepared.
(5) High-pressure steam sterilization: Place the container of (4) in a high-pressure steam sterilizer, sterilize in a nitrogen atmosphere at a temperature of 110 ° C., a gauge pressure of 1.8 kg / cm ² and a time of 30 minutes, and cool to room temperature. did.

(6) Evaluation of transparency of the container: After leaving the container of (5) in a nitrogen atmosphere for 48 hours or more, a part of the container sheet is cut off, and the water transmittance at a wavelength of 450 nm is measured by the Shimadzu double beam self-recording spectrophotometer. It was measured with a total of UV-300 and used as a measure of transparency.
(7) Evaluation of the flexibility of the container: The sheet of the container of (5) after standing for 48 hours or more was cut into a dumbbell shape, and the tensile elastic modulus was measured according to JISK7113 to obtain a measure of flexibility.
(8) Measurement of seal strength: After leaving the container of (5) for 48 hours or more, the center part (partition part) and the end part (peripheral part) of the sheet are cut off and peeled 180 ° at a speed of 300 mm / min. The strength was measured (the peel strength in Table 3 is a value converted to a width of 15 mm).
(9) Investigation of the surface of the container (sheet): The sticky state of the container surface after leaving the container of (5) for 48 hours or more was observed with the naked eye and touched by hand.
(10) Evaluation of breakability (communication) of partition part of container: The sheet of (5) is laid on a desk and the partition part seal is broken to the extent that one compartment is pressed by hand. (5 tests for each case).
(11) Elution test: The sheet obtained in (3) was tested in accordance with the Japanese Pharmacopoeia general test method “Plastic test method for infusion”.

2) Experimental results (see Table 3):
(1) Preparation of the polymer composition and extrusion molding of the sheet were smooth, and no foreign matter, foaming, blocking or the like was observed, and polymer composition pellets and sheets with high uniformity were obtained in any case.
(2) In any composition of Examples 1 to 8, it was confirmed that the eluate was compatible with the Japanese Pharmacopoeia.
(3) Table 3 shows the structure of the sheet and the transparency (water permeability), flexibility (tensile modulus) and seal strength after high-pressure steam sterilization.
It can be seen that the container (sheet) containing the polymer composition of M-PP and thermoplastic elastomer in the present invention as a layer component is excellent in transparency and flexibility. On the other hand, when polypropylene produced with a metallocene catalyst having a relatively high melting point is used, the flexibility is poor (Comparative Example 1).
(4) The stickiness phenomenon does not occur on the surface of the container (sheet), reflecting the narrow molecular weight distribution of M-PP, and the drawbacks of PP (Comparative Example 2) are usually eliminated. That is, in the case of Comparative Example 2, the surface was sticky enough to feel wet.
(5) The breakability (communication) of the partition part of the container was good, including the comparative example, and could be easily communicated. The data on seal strength in Table 3 confirm this.

Claims (3)

A medical multi-chamber container in which a part of opposing inner wall surfaces is partitioned into a plurality of storage chambers by a peelable heat seal, the medical multi-chamber container being manufactured with a metallocene catalyst and having a melting point Polypropylene having a melt flow rate of 2.6 to 3.0 , ethylene-propylene copolymer, block (polystyrene-ethylenebutylene copolymer-polystyrene) copolymer, block (polystyrene-ethylenepropylene copolymer-polystyrene) copolymer at 128 to 134 ° C , Block (polystyrene-ethylenebutylene copolymer-polyethylene) copolymer with any thermoplastic elastomer, and the weight ratio of the polypropylene to the thermoplastic elastomer is from 85:15 to 65:35. Polymer composition which is A multi-chamber medical container, characterized in that it consists of a sheet alone. Before Kinetsu thermoplastic elastomer is an ethylene - multi-chamber medical container according to claim 1 is a propylene copolymer. The medical multi-chamber container according to claim 1, wherein the thermoplastic elastomer is a block (polystyrene-ethylene butylene copolymer-polystyrene), a block (polystyrene-ethylene propylene copolymer-polystyrene) or a block (polystyrene-ethylene butylene copolymer-polyethylene). .