JP2014054373A - Propylene-based composition for kit preparation for medical use, and kit preparation for medical use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a propylene-based resin composition for kit preparations for medical use, which satisfies test items of aqueous injection containers made from polyethylene or polypropylene in Japanese Pharmacopoeia and is excellent in processing stability and long-term stability and to provide the kit preparation for medical use.SOLUTION: The propylene-based resin composition for kit preparations for medical use contains: 100 parts weight of a propylene-based polymer (A) containing 0.0001-0.1 wt.% aluminum metal to be detected by X-ray fluorescence analysis; and 0.001-1.0 part weight of a hindered phenol compound (B).

Description

  The present invention relates to a propylene-based resin composition for a medical kit preparation and a medical kit preparation. More specifically, the 16th revision Japanese Pharmacopoeia plastic drug container test method, polyethylene or polypropylene aqueous injection container test The present invention relates to a propylene-based resin composition for a medical kit preparation and a medical kit preparation which satisfy all the items and have excellent processing stability and long-term stability.

Propylene-based polymers are used in various medical devices, taking advantage of their excellent safety and hygiene, molding processability, mechanical properties, and gas barrier properties. In particular, in recent years, the use of metal and glass as an alternative container for foods, drugs, and chemical solutions that require a high level of safety and hygiene has become increasingly common, and materials for such applications have been developed. (For example, refer to Patent Document 1).
These resins for storage containers are required to have long-term stability as storage containers, and the product performance as a container does not deteriorate due to deterioration within the period of use, and the gas barrier properties of water vapor and oxygen are maintained. It is necessary that the additive does not interact with the contents and the contents liquid. Specifically, as a medical drug or a chemical solution storage container, specifically, “16th revision Japanese Pharmacopoeia General Test 7.02 Plastics” Pharmaceutical container test method 2 Standard of water-soluble plastic injection container 2.1 It is an essential requirement to satisfy all the test items of “Polyethylene or polypropylene aqueous injection container”.

  Propylene-based polymers themselves are vulnerable to heat and light, and easily cause open polymerization and oxidative degradation. For this reason, the propylene-based polymer itself alone causes significant thermal deterioration during the molding of the storage container, resulting in poor processing stability, and also deteriorates due to the influence of heat, light, etc. even after being distributed to the market as a storage container. Can not have long-term stability as a container. Therefore, it is necessary to add an antioxidant in order to maintain processing stability and long-term stability.

  A hindered phenolic antioxidant is generally mentioned as an antioxidant having excellent processing stability and long-term stability. Hindered phenolic antioxidants have been widely used in medical propylene resin compositions (see, for example, Patent Documents 2 and 3).

  Examples of medical applications that need to pass the Japanese Pharmacopoeia test include medicinal solutions, prefilled syringes that are kit preparations pre-filled with drugs, infusion bags, infusion bottles, infusion port members, and the like. In addition, materials for these applications have also been developed (see, for example, Patent Documents 2 and 3).

  On the other hand, in recent years, propylene polymer catalysts and resin powders after polymerization of propylene polymers have been converted into n-butane, isobutane, n-pentane, isopentane, hexane, heptane, and octane by improving the efficiency and simplifying the production process. The number of steps for washing with an inert hydrocarbon solvent such as cyclohexane, benzene, toluene, xylene, water, or a liquid monomer is decreasing. The step of washing the resin powder after polymerization is mainly intended to remove volatile components such as oligomers, catalyst residues, promoter residues, scavenger residues, and metal residues. Volatile components lead to increased fogging and outgassing, and metal residues lead to the generation of chlorine compounds, such as titanium tetrachloride. However, in recent years, more and more products are produced without a washing step because of higher performance such as polymerization activity of a catalyst of a propylene polymer and reduction of manufacturing cost.

  Conventionally, there has been one designed by blending a phenolic antioxidant for a kit preparation. However, when a conventional phenolic antioxidant is blended with a propylene polymer containing a specific amount or more of an aluminum metal compound without obtaining a washing step, “16th revision Japanese Pharmacopoeia General Test 7.02 made of plastic” This is the first time that the possibility of non-compliance with the UV absorption spectrum standard in the test method “2.1 Water-soluble injection container standards made of plastics 2.1 Water-based injection containers made of polyethylene or polypropylene” It was issued.

  As a result of intensive studies, the conventional phenolic antioxidants are hydrolyzed and reduced in molecular weight by the aluminum metal compound contained in the propylene polymer, especially in the elution stage of the eluate test of the pharmacopoeia test. It has been found that phenolic antioxidants having a low molecular weight are extracted, and in particular, there is a possibility that they may not meet the specifications of the ultraviolet absorption spectrum. In this case, when a chemical solution or a drug is stored as a kit preparation, a phenolic antioxidant having a low molecular weight may be extracted in the chemical solution or the drug, which may affect the drug efficacy.

JP-A-1-178541 JP-A-3-28246 JP-A-5-222078

  In view of the above problems, the object of the present invention is to eliminate the propylene polymer washing step. Specifically, the propylene polymer contains propylene polymer containing a specific amount or more of a catalyst, a promoter, and a scavenger-derived aluminum metal compound. Even if a polymer is used, it has low elution of necessary additives as a storage container, and more specifically, “Sixteenth revision Japanese Pharmacopoeia General Test 7.02 Test Method for Plastic Drug Containers 2” Standards for water-soluble injection containers made of 2.1 Propylene for medical kit preparations that meet the test item standards of "Polyethylene or polypropylene water-based injection containers" and have excellent processing stability and long-term stability It is providing a resin composition and a medical kit formulation using the same.

The inventor suppresses decomposition of the additive even when the propylene-based resin composition contains a specific amount or more of an aluminum metal compound when a specific amount of a phenol-based antioxidant having a specific chemical structure is used. It has been found that it can be a resin composition that is excellent in low elution and that satisfies all the test items of the Japanese Pharmacopoeia, which have strict acceptance criteria, and that has excellent processing stability and long-term stability. The invention has been completed.
The present invention provides the following propylene-based resin composition for medical kit preparation and medical kit preparation.

[1] From the group consisting of the following (B1) to (B6) with respect to 100 parts by weight of the propylene polymer (A) containing 0.0001 to 0.1% by weight of aluminum metal detected by fluorescent X-ray analysis A propylene-based resin composition for medical kit preparations, comprising 0.001 to 1.0 part by weight of one or more selected hindered phenol compounds (B).
(B1): 1,3,5-tris (3,5-di-tert-butyl-4-hydroxybenzyl) -s-triazine-2,4,6 (1H, 3H, 5H) -trione (B2): Octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid ester (B3): ethylenebis [3,3-bis [3- (1,1-dimethylethyl) -4-hydroxyphenyl ] Butyric acid ester]
(B4): 2,2 ′, 2 ″, 6,6 ′, 6 ″ -hexa-tert-butyl-4,4 ′, 4 ″-[(2,4,6-trimethyl-1,3,5- Benzenetolyl) trismethylene] triphenol (B5): 2- [1- (2-hydroxy-3,5-di-tert-pentylphenyl) ethyl] -4,6-di-tert-pentylphenyl acrylate (B6) : 1,3,5-tris (4-t-butyl-3-hydroxy-2,6-dimethylbenzyl) -isocyanuric acid

[2] Aluminum-containing compound in which aluminum metal is any of trialkylaluminum, dialkylaluminum halide, alkylaluminum sesquihalide, alkylaluminum dihalide, alkylaluminum hydride, organoaluminum alkoxide, aluminum hydroxide, or aluminum oxide The propylene-based resin composition for medical kit preparation according to the above [1], which is derived from
[3] A medical kit preparation using the propylene-based resin composition according to [1] or [2].
[4] The medical kit preparation according to [3], wherein the kit preparation is a prefilled syringe, an infusion bag, an infusion bottle, or an infusion port member.
[5] The medical kit preparation according to the above [3] or [4], which has been subjected to radiation sterilization, ethylene oxide gas sterilization, or high-pressure steam sterilization.

The propylene-based resin composition of the present invention is excellent in low elution property by containing a hindered phenol-based antioxidant having a specific chemical structure in a propylene-based polymer containing a specific amount of aluminum metal, and has extremely strict acceptance criteria. , "16th revision Japanese Pharmacopoeia General Examination 7.02
Test method for plastic drug containers 2 Plastic water-soluble injection container standards 2.1 While satisfying the test item standard of “Polyethylene or polypropylene water-based injection container”, it has excellent processing stability and long-term stability. It can be used very suitably for medical kit formulations.
And a medical kit preparation using a molded product obtained by molding this, for example, a syringe barrel and a container filled with a drug solution, specifically, a prefilled syringe, an infusion bag, an infusion bottle, an infusion port material, a kit formulation It can be used particularly preferably.

The propylene-based resin composition for a medical kit preparation of the present invention is based on 100 parts by weight of a propylene-based polymer (A) containing 0.0001 to 0.1% by weight of aluminum metal detected by fluorescent X-ray analysis. It contains 0.001 to 1.0 part by weight of one or more hindered phenolic compounds (B) selected from the group consisting of the following (B1) to (B6).
(B1): 1,3,5-tris (3,5-di-tert-butyl-4-hydroxybenzyl) -s-triazine-2,4,6 (1H, 3H, 5H) -trione (B2): Octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid ester (B3): ethylenebis [3,3-bis [3- (1,1-dimethylethyl) -4-hydroxyphenyl ] Butyric acid ester]
(B4): 2,2 ′, 2 ″, 6,6 ′, 6 ″ -hexa-tert-butyl-4,4 ′, 4 ″-[(2,4,6-trimethyl-1,3,5- Benzenetolyl) trismethylene] triphenol (B5): 2- [1- (2-hydroxy-3,5-di-tert-pentylphenyl) ethyl] -4,6-di-tert-pentylphenyl acrylate (B6) : 1,3,5-tris (4-t-butyl-3-hydroxy-2,6-dimethylbenzyl) -isocyanuric acid Hereinafter, components and resins constituting the propylene-based resin composition for medical kit preparation of the present invention The production method of the composition and the medical kit preparation will be described in detail.

[Components constituting propylene-based resin composition]
[Propylene polymer (A)]
The propylene polymer (A) used in the propylene resin composition of the present invention may be a propylene homopolymer, a propylene copolymer, or a mixture thereof.
In the present invention, a propylene polymer (A) containing 0.0001 to 0.1% by weight of aluminum metal detected by fluorescent X-ray analysis is used.

  The aluminum metal may be derived from an aluminum compound used in a polymerization catalyst as described later, or may be derived from an aluminum metal or an aluminum-containing compound blended as an additive, or a propylene polymer as an impurity. It may have been brought to (A). Conventional phenolic antioxidants are hydrolyzed by aluminum or an aluminum metal compound contained in the propylene polymer. In the present invention, even if such an aluminum metal content is present, low molecular weight is suppressed. be able to.

  Examples of the aluminum compound used for the polymerization catalyst include trialkylaluminum such as triethylaluminum, triisopropylaluminum, triisobutylaluminum, dialkylaluminum halide, alkylaluminum sesquihalide, alkylaluminum dihalide, alkylaluminum hydride, organoaluminum alkoxide, An organic aluminum oxy compound etc. are mentioned.

The measurement of the aluminum metal content is performed by fluorescent X-ray analysis, and specific measurement conditions and the like are as described in the examples.
In the present invention, one or more hindered phenol compounds selected from (B1) to (B6) can be applied to a propylene polymer (A) having an aluminum metal content of 0.1% by weight or less. is there. If the propylene polymer (A) contains 0.0001% by weight or more of aluminum metal, it can be applied without any problem. Even if it contains 0.0003% by weight or more of aluminum metal, it can be applied sufficiently. There is no problem even if the amount is 0.0005% by weight or more. As described above, the upper limit of the aluminum metal content of the propylene polymer (A) is 0.1% by weight or less, preferably 0.08% by weight or less, and more preferably 0.06% by weight or less.

The propylene-based copolymer as the propylene-based polymer (A) is a copolymer of propylene and α-olefin, and may be either a random copolymer or a block copolymer, The total light transmittance specified in the Japanese Pharmacopoeia needs to be 55% or more.
Examples of the α-olefin used for copolymerization include α-olefins having 2 to 20 carbon atoms excluding propylene, and examples thereof include ethylene, butene-1, hexene-1, and octene-1. One or more α-olefins copolymerized with propylene may be used. Of these, ethylene and butene-1 are preferable, and ethylene is more preferable.
The α-olefin content is preferably 10.0% by weight or less.

  Specific examples of the copolymer include propylene-ethylene copolymer, propylene-ethylene-diene copolymer, propylene-butene-1 copolymer, propylene-hexene-1 copolymer, propylene-octene- 1 copolymer etc. can be illustrated. Of these, propylene-ethylene copolymer, propylene-butene-1 copolymer, and propylene-ethylene-butene-1 copolymer are particularly preferable. In the polymerization stage, a so-called polypropylene polymer alloy in which a rubber component such as EPR is introduced as a soft segment into a hard segment composed of a crystal phase mainly composed of polypropylene can also be used.

The glass transition temperature of the propylene polymer (A) is preferably -100 to 20 ° C. Moreover, when autoclaving, it is desirable that the melting point exceeds the sterilization temperature from the viewpoint of heat resistance.
Moreover, you may use a propylene polymer (A) in mixture of 2 or more types.

The propylene polymer (A) used in the present invention preferably has a melt flow rate (MFR) at 230 ° C. and a load of 2.16 kg of 0.3 to 100 g / 10 min. When the MFR is within this range, a resin composition suitable for the high production rate derived from the rigidity and impact resistance of the resin composition and the molding temperature is provided. If the MFR is less than 0.3 g / 10 minutes, molding becomes difficult. On the other hand, if it exceeds 100 g / 10 minutes, good impact resistance may not be obtained for a medical kit preparation.
Here, MFR at 230 ° C. is a value measured under a load of 230 ° C. and 2.16 kg in accordance with JIS K7210.

When the propylene homopolymer is used as the propylene polymer (A), the isotactic pentad fraction (mmmm) is preferably 90% or more, more preferably 94% or more, and still more preferably 97% or more. . If the isotactic pentad fraction (mmmm) is less than 90%, the molded product may be easily deformed at the time of molding due to a decrease in rigidity and heat distortion temperature. Conversely, as the stereoregularity is improved, Rigidity and heat resistance are also improved, and deformation of the molded product can be prevented.
Here, the isotactic pentad fraction (mmmm) is a value measured by ¹³ C-NMR method.

In the case of using a propylene random copolymer (hereinafter sometimes referred to as “random copolymer”) as the propylene polymer (A), the amount of α-olefin in the random copolymer is 10.0. % By weight or less is preferred. If it exceeds 10.0% by weight, the crystallinity will not be exhibited, and the heat resistance will be significantly reduced, making it unsuitable as a medical kit preparation.
Here, the α-olefin content is a value measured by the IR method using a propylene copolymer whose composition is tested by ¹³ C-NMR as a reference substance.

The random copolymer preferably has a melting temperature (peak value) obtained by a differential scanning calorimeter of 121 ° C. or higher. If the melting temperature (peak value) is less than 121 ° C., there is a possibility of deformation during high-pressure steam sterilization.
Here, the melting temperature (peak value) obtained from the differential scanning calorimeter is a value to be measured in accordance with “Method for measuring plastic transition temperature” of JIS K7121.

  When the propylene-based block copolymer (hereinafter sometimes referred to as a block copolymer) comprising a polypropylene segment and a propylene copolymer segment is used as the propylene-based polymer (A), it occupies the block copolymer. The polypropylene segment is 70 to 99% by weight, the propylene copolymer segment is preferably 1 to 30% by weight, the polypropylene segment is 86 to 98% by weight, and the propylene copolymer segment is more preferably 2 to 14% by weight. Within this range, it is suitable as a medical kit preparation from the viewpoint of mechanical properties and heat resistance.

At this time, the isotactic pentad fraction (mmmm) of the polypropylene segment is 90% or more, preferably 94% or more, more preferably 97% or more. If the isotactic pentad fraction (mmmm) is less than 90%, the molded product is easily deformed during molding.
Here, the isotactic pentad fraction (mmmm) is a value measured by ¹³ C-NMR method.

Further, as the propylene polymer (A), after propylene homopolymer or α-olefin-propylene copolymer is polymerized in the first stage, α-olefin-propylene copolymers having different α-olefin contents are obtained. It may be a propylene-based block copolymer polymerized in the second stage (hereinafter also referred to as “block copolymer”). Also, the second stage α-olefin species may be different from the first stage.
The total α-olefin content contained in the block copolymer is preferably 0.5 to 15% by weight, and more preferably 2 to 9% by weight. Moreover, as an alpha olefin, ethylene is preferable. When the α-olefin content is within this range, the resulting resin composition is suitable for impact resistance. When the total α-olefin content is less than 0.5% by weight, the block copolymer has insufficient impact resistance, and when it exceeds 15% by weight, the heat resistance becomes insufficient.
Here, the α-olefin content is a value measured by the IR method using a propylene copolymer whose composition is tested by ¹³ C-NMR as a reference substance.

  Although it does not specifically limit as a manufacturing method of a propylene polymer (A), The polymerization method using a stereoregular catalyst is preferable. Examples of stereoregular catalysts include Ziegler catalysts and metallocene catalysts.

  As Ziegler catalysts, transition metal components such as titanium trichloride, titanium tetrachloride, trichloroethoxytitanium, etc., contact materials of the above-mentioned titanium halide compounds and magnesium compounds represented by magnesium halide, and alkylaluminum Compounds or their two-component catalysts with organic metal components such as halides, hydrides, alkoxides, and further, electron-donating compounds containing nitrogen, carbon, phosphorus, sulfur, oxygen, silicon, etc. are added to these components 3 Component-based catalysts can be mentioned.

  The metallocene catalyst includes (i) a transition metal compound belonging to Group 4 of the periodic table (so-called metallocene compound) containing a ligand having a cyclopentadienyl skeleton, and (ii) a stable ionic state by reacting with the metallocene compound. A catalyst comprising an activatable cocatalyst and, if necessary, (iii) an organoaluminum compound, any known catalyst can be used. The metallocene compound is preferably a bridged metallocene compound capable of stereoregular polymerization of propylene, and more preferably a bridged metallocene compound capable of isoregular polymerization of propylene.

  Examples of (i) metallocene compounds include JP-A-60-35007, JP-A-63-130314, JP-A-63-295607, JP-A-1-275609, JP-A-2-41303, and JP-A-2-41303. JP-A-2-131488, JP-A-2-76887, JP-A-3-163888, JP-A-4-30087, JP-A-4-21694, JP-A-5-43616, JP-A-5-209913, JP-A-6 No. 239914, JP-A-7-504934, and JP-A-8-85708.

  More specifically, methylene bis (2-methylindenyl) zirconium dichloride, ethylenebis (2-methylindenyl) zirconium dichloride, ethylene 1,2- (4-phenylindenyl) (2-methyl-4-phenyl) -4H-azulenyl) zirconium dichloride, isopropylidene (cyclopentadienyl) (fluorenyl) zirconium dichloride, isopropylidene (4-methylcyclopentadienyl) (3-t-butylindenyl) zirconium dichloride, dimethylsilylene (2- Methyl-4-t-butyl-cyclopentadienyl) (3′-t-butyl-5′-methyl-cyclopentadienyl) zirconium dichloride, dimethylsilylenebis (indenyl) zirconium dichloride, dimethylsilylenebis (4,5 6,7-tetrahydroindenyl) zirconium dichloride, dimethylsilylene bis [1- (2-methyl-4-phenylindenyl)] zirconium dichloride, dimethylsilylene bis [1- (2-ethyl-4-phenylindenyl)] Zirconium dichloride, dimethylsilylenebis [4- (1-phenyl-3-methylindenyl)] zirconium dichloride, dimethylsilylene (fluorenyl) t-butylamidozirconium dichloride, methylphenylsilylenebis [1- (2-methyl-4, (1-naphthyl) -indenyl)] zirconium dichloride, dimethylsilylenebis [1- (2-methyl-4,5-benzoindenyl)] zirconium dichloride, dimethylsilylenebis [1- (2-methyl-4-phenyl-) 4H-azuleni ] Zirconium dichloride, dimethylsilylenebis [1- (2-ethyl-4- (4-chlorophenyl) -4H-azulenyl)] zirconium dichloride, dimethylsilylenebis [1- (2-ethyl-4-naphthyl-4H-azurenyl) ] Zirconium dichloride, diphenylsilylene bis [1- (2-methyl-4- (4-chlorophenyl) -4H-azulenyl)] zirconium dichloride, dimethylsilylene bis [1- (2-ethyl-4- (3-fluorobiphenyl) Ryl) -4H-azurenyl)] zirconium dichloride, dimethylgermylenebis [1- (2-ethyl-4- (4-chlorophenyl) -4H-azurenyl)] zirconium dichloride, dimethylgermylenebis [1- (2-ethyl) -4-phenylindenyl)] zirconium di Zirconium compounds such as chloride can be exemplified.

In the above, compounds in which zirconium is replaced with titanium or hafnium can be used in the same manner. In some cases, a mixture of a zirconium compound and a hafnium compound can be used. Further, the chloride can be replaced with other halogen compounds, hydrocarbon groups such as methyl, isobutyl and benzyl, amide groups such as dimethylamide and diethylamide, alkoxide groups such as methoxy group and phenoxy group, hydride groups and the like.
Among these, a metallocene compound in which an indenyl group or an azulenyl group is crosslinked with silicon or a germyl group is preferable.

The metallocene compound may be used by being supported on an inorganic or organic compound carrier. The carrier is preferably an inorganic or organic porous compound. Specifically, ion-exchange layered silicate, zeolite, SiO ₂ , Al ₂ O ₃ , silica alumina, MgO, ZrO ₂ , TiO ₂ , B Organic compounds composed of inorganic compounds such as ₂ O ₃ , CaO, ZnO, BaO, ThO ₂ , porous polyolefins, styrene-divinylbenzene copolymers, olefin-acrylic acid copolymers, or a mixture thereof. It is done.

  (Ii) As a co-catalyst that can be activated to a stable ionic state by reacting with a metallocene compound, an organoaluminum oxy compound (for example, an aluminoxane compound), an ion-exchange layered silicate, a Lewis acid, a boron-containing compound, an ionic compound And fluorine-containing organic compounds.

  (Iii) Examples of organoaluminum compounds include trialkylaluminum such as triethylaluminum, triisopropylaluminum, triisobutylaluminum, dialkylaluminum halide, alkylaluminum sesquihalide, alkylaluminum dihalide, alkylaluminum hydride, organoaluminum alkoxide. Can be mentioned.

Propylene-based polymers can be produced by a slurry method using an inert solvent, a solution method, a gas phase method substantially using no solvent, or a bulk polymerization using a polymerization monomer as a solvent in the presence of the above catalyst. Legal etc. are mentioned.
For example, in the case of slurry polymerization, it can be carried out in an inert hydrocarbon or liquid monomer such as n-butane, isobutane, n-pentane, isopentane, hexane, heptane, octane, cyclohexane, benzene, toluene, xylene and the like. . The polymerization temperature is usually −80 to 150 ° C., preferably 40 to 120 ° C. The polymerization pressure is preferably 1 to 60 atmospheres, and the molecular weight of the resulting propylene polymer can be adjusted with hydrogen or other known molecular weight regulators. The polymerization is carried out by a continuous or batch reaction, and the conditions may be those usually used. Furthermore, the polymerization reaction may be performed in one stage or in multiple stages.

  Moreover, when the polymer manufactured using the metallocene catalyst is mixed with the propylene polymer (A), the propylene polymer (A) is more compatible with the one manufactured using the metallocene catalyst. Good and more preferable.

[Hindered phenolic compound (B)]
The hindered phenol compound (B) used in the present invention is a hindered phenol compound represented by the following (B1) to (B6).
(B1): 1,3,5-tris (3,5-di-tert-butyl-4-hydroxybenzyl) -s-triazine-2,4,6 (1H, 3H, 5H) -trione (CAS No. 27676-62-6)
(B2): Octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid ester (CAS No. 2082-79-3)
(B3): Ethylene bis [3,3-bis [3- (1,1-dimethylethyl) -4-hydroxyphenyl] butyric acid ester] (CAS No. 32509-66-3)
(B4): 2,2 ′, 2 ″, 6,6 ′, 6 ″ -hexa-tert-butyl-4,4 ′, 4 ″-[(2,4,6-trimethyl-1,3,5- Benzenetolyl) trismethylene] triphenol (CAS No. 1709-70-2)
(B5): 2- [1- (2-hydroxy-3,5-di-tert-pentylphenyl) ethyl] -4,6-di-tert-pentylphenyl acrylate (CAS No. 123968-25-2)
(B6): 1,3,5-tris (4-t-butyl-3-hydroxy-2,6-dimethylbenzyl) -isocyanuric acid (CAS No. 40601-76-1)

  The hindered phenol compound (B) used in the present invention is excellent in processing stability and long-term stability, and even if the propylene polymer contains a specific amount or more of an aluminum metal compound, the acceptance criteria are severe. It is one of the few hindered phenol compounds that can pass the 16th revised Japanese Pharmacopoeia test.

  The content of the hindered phenol compound (B) is in the range of 0.001 to 1.0 part by weight with respect to 100 parts by weight of the propylene polymer (A). If it is less than 0.001 part by weight, it is difficult to obtain sufficient processing stability and long-term stability, and if it exceeds 1.0 part by weight, further improvement in performance cannot be expected, which is uneconomical. The content of the hindered phenol compound (B) is preferably 0.01 to 0.2 parts by weight, and more preferably 0.01 to 0.1 parts by weight. You may use a hindered phenol type compound (B) individually by 1 type or in combination of multiple types.

[Neutralizer]
The propylene-based resin composition for medical kit preparations of the present invention includes “16th revision Japanese Pharmacopoeia General Test 7.02 Test Method for Plastic Drug Containers 2 Standard of Water-soluble Plastic Injection Container 2.1” A neutralizing agent can be blended within a range that does not adversely affect the test items and mechanical properties of the “polypropylene aqueous injection container”.
Specific examples of such a neutralizing agent include metal fatty acid salts such as calcium stearate, zinc stearate, and magnesium stearate, hydrotalcite (trade name, manufactured by Kyowa Chemical Industry Co., Ltd., represented by the following general formula (1). Magnesium aluminum composite hydroxide salt), Mizukarak (trade name, manufactured by Mizusawa Chemical Industry Co., Ltd., lithium aluminum composite hydroxide salt represented by the following general formula (2)), and the like. In particular, when used as a member that is in contact with the liquid for a long period of time, such as a prefilled syringe, a kit preparation, or an infusion bag, hydrotalcite or mizucarac that does not elute into the liquid that comes into contact is advantageous.

Mg _1-x Al _x (OH) ₂ (CO ₃ ) _{x / 2} · mH ₂ O (1)
[Wherein x is 0 <x ≦ 0.5, and m is a number of 3 or less. ]
[Al ₂ Li (OH) ₆ ] _n X · mH ₂ O (2)
[Wherein, X is an inorganic or organic anion, n is the valence of the anion (X), and m is 3 or less. ]

  The blending amount of the neutralizing agent is preferably in the range of 0.005 to 0.2 parts by weight and more preferably in the range of 0.01 to 0.05 parts by weight with respect to 100 parts by weight of the polymer mixture.

[Lubricant]
The propylene-based resin composition for medical kit preparations of the present invention includes “16th revision Japanese Pharmacopoeia General Test 7.02 Test Method for Plastic Drug Containers 2 Standard of Water-soluble Plastic Injection Container 2.1” Lubricants can be blended within a range that does not adversely affect the test items and mechanical properties of the “polypropylene aqueous injection container”.

Examples of the lubricant include known lubricants, but butyl stearate and silicone oil are preferable. Specific silicone oils include dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrodienepolysiloxane, α-ωbis (3-hydroxypropyl) polydimethylsiloxane, polyoxyalkylene (C ₂ -C ₄ ) dimethylpolysiloxane. And a polyorgano (C ₁ -C ₂ alkyl group and / or phenyl group) siloxane and polyalkylene (C ₂ -C ₃ ) glycol condensate. Of these, dimethylpolysiloxane and methylphenylpolysiloxane are preferred.
When silicone such as dimethylpolysiloxane is added, not only can scratches that occur during molding be prevented, but also burns that can occur in cylinders and hot runners can be prevented.

The blending amount of the lubricant is preferably 0.001 to 0.5 parts by weight, more preferably 0.01 to 0.15 parts by weight, and 0.03 to 0.1 parts by weight with respect to 100 parts by weight of the polymer mixture. Particularly preferred. If the amount is less than 0.001 part by weight, the effect cannot be expected. On the other hand, if the amount exceeds 0.5 part by weight, not only a further effect cannot be expected, but also economically undesirable.
A single lubricant or a plurality of lubricants may be used.

[Other additives]
In addition to the above-described components, a phosphorus-based antioxidant additive used as a propylene-based polymer stabilizer or the like can be added to the propylene-based resin composition for medical kit preparations of the present invention.

  Specifically, as the antioxidant, bis (2,6-di-t-butyl-4-methylphenyl) pentaerythritol-di-phosphite, di-stearyl-pentaerythritol-di-phosphite, bis ( 2,4-di-t-butylphenyl) pentaerythritol-diphosphite, tris (2,4-di-t-butylphenyl) phosphite, tetrakis (2,4-di-t-butylphenyl) -4 Phosphorus-based antioxidants such as 4,4′-biphenylene-diphosphonite, tetrakis (2,4-di-t-butyl-5-methylphenyl) -4,4′-biphenylene-diphosphonite Can be mentioned.

[Producing method of propylene-based resin composition]
The propylene resin composition for a medical kit preparation of the present invention comprises a propylene polymer (A), a hindered phenol compound (B), and other additives as necessary, a Henschel mixer, a super mixer, a ribbon. Obtained by melting and kneading in a normal single-screw extruder, twin-screw extruder, Banbury mixer, plastic bender, roll, etc., preferably at a temperature range of 170 to 260 ° C. after being put into a blender or the like and mixed. Can do.

[Molded article / Medical kit preparation]
The propylene-based resin composition of the present invention is formed into a molded product by injection molding with a known injection molding machine, film molding, sheet molding, blow molding, or the like with a known extruder.
The obtained molded product has a strict acceptance standard "16th revision Japanese Pharmacopoeia General Test 7.02
Test method for plastic drug containers 2 Standards for water-soluble plastic injection containers 2.1 Since it can satisfy all the test items of “Polyethylene or polypropylene aqueous injection containers”, it is particularly useful as a kit preparation. Suitable for syringes and storage containers filled with liquids, and particularly suitable for prefilled syringes, infusion bags, infusion bottles, and infusion port members among kit formulations.
The molded article of the present invention may be subjected to a known sterilization process such as high-pressure steam sterilization (autoclave sterilization), radiation sterilization, ethylene oxide gas sterilization (EOG sterilization), and ultraviolet sterilization.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to a following example, unless the summary is exceeded.
The evaluation methods, resins and additives used in Examples and Comparative Examples are as follows.

1. Evaluation method (1) Ethylene content
The ethylene content in the copolymer was measured by infrared spectroscopy using a characteristic absorber of 733 cm ⁻¹ with an ethylene-propylene copolymer whose composition was verified by ¹³ C-NMR as a reference substance. The pellets were formed into a film having a thickness of about 500 microns by press molding.
(2) MFR
According to JIS K7210: 1999, the measurement was performed at a heating temperature of 230 ° C. and a load of 21.18 N.

(3) Measurement of aluminum content in propylene polymer After the resin pellets were melted at a pressure of 0 kg / cm ² G for 7 minutes using an electric press at a temperature of 200 ° C., the pressure was 70 kg / cm ² G for 3 minutes. Compressed. Thereafter, the sample is quickly moved to a cooling press at 30 ° C., cooled at a pressure of 120 kg / cm ² G for 3 minutes, a test piece having a thickness of 3 mm and 30 mmΦ is prepared, and aluminum is subjected to the following conditions of the fluorescent X-ray analyzer. The concentration was quantified.

X-ray device: ZSX 100e manufactured by Rigaku Denki Kogyo Co., Ltd.
Tube: Rh
Spectral crystal: PET (pentaerythritol)
Counter: PC (proportional counter)
Tube voltage: 50 kv
Tube current: 50 mA
2θKα: 144.79 °
Peak count: 20 sec (2θ peak irradiation time)
B. G. 1-B. G. 2: 143.250-146.60 ° (background)
B. G. Count: 10 sec (irradiation time for each background)
A calibration curve of aluminum concentration and X-ray intensity was prepared in advance using a standard sample, and the aluminum concentration in the sample was quantified from the measured X-ray intensity using the calibration curve (standard sample concentration: 0.0004- 0.0473 wt%).

(4) 16th revision Japanese Pharmacopoeia General Examination (Japanese Pharmacopoeia Exam):
In accordance with the test method in “7.02 Test methods for plastic drug containers 2 Standards for water-soluble plastic injection containers 2.1 Water-based injection containers made of polyethylene or polypropylene”, transparency, heavy metals, lead, cadmium, strong Thermal residue, foaming, pH, potassium permanganate reducing substance, ultraviolet absorption spectrum, and evaporation residue were measured.
However, in the sample preparation, resin pellets were melted at a pressure of 0 kg / cm ² G for 7 minutes using an electric press at a temperature of 230 ° C. and then compressed at a pressure of 70 kg / cm ² G for 3 minutes. Thereafter, the sample was quickly moved to a cooling press at 30 ° C. and cooled at a pressure of 120 kg / cm ² G for 3 minutes to produce a test piece having a thickness of 0.5 mm and a surface area of 1200 cm ^2. The sample was cut into a size of centimeter and width of about 0.5 centimeter, washed with water, and dried at room temperature. Put this in a hard glass container with an internal volume of about 300 ml, add exactly 200 ml of water, seal it with an appropriate stopper, heat it at 121 ° C for 1 hour using a high-pressure steam sterilizer, and leave it to room temperature. Then, this solution was used as a test solution, and separately with water, a blank test solution was prepared in the same manner.

(5) Processing stability Resin pellets are granulated twice using a 30 mmφ single screw extruder at a temperature of 250 ° C., a screw rotation speed of 100 rpm, an extrusion rate of about 7 kg / hr, and a sample supply hopper under air atmosphere. Went. When the MFR of the resin pellet after two repetitions was MFR3 and the MFR of the resin pellet before repeated extrusion was MFR1, the processing stability was evaluated from ΔMFR represented by the following general formula. Further, ΔMFR of 20 or more was regarded as no processing stability (x), and less than 20 was regarded as processing stability (◯).
ΔMFR = MFR3-MFR1

(6) Heat Aging Test The resin pellets were melted at a pressure of 0 kg / cm ² G for 7 minutes using an electric press at a temperature of 230 ° C. and then compressed at 70 kg / cm ² G for 3 minutes. Thereafter, the sample was quickly moved to a cooling press at 30 ° C. and cooled at a pressure of 120 kg / cm ² G for 3 minutes to produce a test piece having a width of 35 mm, a length of 65 mm, and a thickness of 0.5 m. Thereafter, the test piece was sandwiched between clips with glass tape and attached to a rotating drum in an oven set at 130 ° C. in advance. Thereafter, the time when the crack area on the sheet surface reached 20% was recorded, and long-term stability was evaluated. When the crack area reached 20% within 100 hours, no long-term stability was indicated (x), and when it exceeded 100 hours, long-term stability was indicated (◯).

(7) Japanese Pharmacopoeia UV absorption spectrum (220nm-240nm)
In accordance with the Japanese Pharmacopoeia 2.24 UV-Visible Absorbance Measurement Method, using the test solution prepared in accordance with the evaluation procedure of the 16th revision Japanese Pharmacopoeia General Test and the blank test station in (4) above, using the blank test solution as a control. The test solution was evaluated and the maximum absorbance in the 240-220 nm interval was recorded.
In addition, as for the specification of the Japanese Pharmacopoeia 2.1 polyethylene or polypropylene aqueous injection container, the maximum absorbance at 220 nm to 220 nm is 0.08 or less.

2. Materials used [propylene polymer]
Propylene polymers PP1 to PP6 produced according to the following Production Examples 1 to 6 were used.

(Production Example 1: Production of PP1)
1) Preparation of solid component A 10 L autoclave equipped with a stirrer was sufficiently substituted with nitrogen, and 2 L of purified toluene was introduced. To this, 200 g of Mg (OEt) ₂ and 1 L of TiCl ₄ were added at room temperature. The temperature was raised to 90 ° C. and 50 ml of di-n-butyl phthalate was introduced. Thereafter, the temperature was raised to 110 ° C. to carry out a reaction for 3 hours. The reaction product was thoroughly washed with purified toluene. Subsequently, the refined toluene was introduce | transduced and the whole liquid quantity was adjusted to 2L. 1 L of TiCl ₄ was added at room temperature, the temperature was raised to 110 ° C., and the reaction was performed for 2 hours. The reaction product was thoroughly washed with purified toluene. Subsequently, the refined toluene was introduce | transduced and the whole liquid quantity was adjusted to 2L. 1 L of TiCl ₄ was added at room temperature, the temperature was raised to 110 ° C., and the reaction was performed for 2 hours. The reaction product was thoroughly washed with purified toluene. Further, using purified n-heptane, toluene was replaced with n-heptane to obtain a slurry of the solid component (a1). A portion of this slurry was sampled and dried. As a result of analysis, the Ti content of the solid component (a1) was 2.7 wt%. Next, a 20 L autoclave equipped with a stirrer was sufficiently replaced with nitrogen, and 100 g of the slurry of the solid component (a1) was introduced as the solid component (a1). Purified n-heptane was introduced to adjust the concentration of the solid component (a1) to 25 g / L. 50 ml of SiCl ₄ was added and a reaction was performed at 90 ° C. for 1 hr. The reaction product was thoroughly washed with purified n-heptane. Thereafter, purified n-heptane was introduced to adjust the liquid level to 4 L. To this, 30 ml of dimethyldivinylsilane, 30 ml of (i-Pr) ₂ Si (OMe) ₂ and 80 g of Et ₃ Al in an n-heptane diluted solution were added as Et ₃ Al, and a reaction was carried out at 40 ° C. for 2 hours. The reaction product was thoroughly washed with purified n-heptane, and a portion of the resulting slurry was sampled and dried. As a result of analysis, the solid component contained 1.2 wt% Ti and 8.8 wt% (i-Pr) ₂ Si (OMe) ₂ .

2) Prepolymerization Prepolymerization was performed by the following procedure using the solid component obtained above. Purified n-heptane was introduced into the slurry, and the solid component concentration was adjusted to 20 g / L. After cooling the slurry to 10 ° C., 10 g was added n- heptane dilution of _Et 3 Al as _Et 3 Al, were fed over 4hr of propylene 280 g. After the supply of propylene was completed, the reaction was further continued for 30 minutes. Next, the gas phase was sufficiently replaced with nitrogen, and the reaction product was thoroughly washed with purified n-heptane. The obtained slurry was extracted from the autoclave and vacuum dried to obtain a solid catalyst component (i). This solid catalyst component (i) contained 2.5 g of polypropylene per 1 g of the solid component. As a result of analysis, the portion of the solid catalyst component (i) excluding polypropylene was 1.0 wt% Ti, 17.5 wt% Mg, and 8.2 wt% (i-Pr) ₂ Si (OMe) _2. It was included.

[Production of propylene homopolymer]
After thoroughly replacing the inside of the stirred autoclave with an internal volume of 3 L with propylene, at room temperature, 2.25 ml of triethylaluminum heptane solution (10 wt%) was added, and 5000 ml of hydrogen was introduced, followed by 750 g of liquid propylene, The temperature in the tank was raised to 70 ° C. While maintaining the temperature in the tank at 70 ° C., 2.2 ml of the prepolymerized catalyst normal heptane slurry (7 mg-catalyst / ml) obtained above and 15.4 mg as the catalyst (excluding the weight of the prepolymerized polymer) Was injected with argon and polymerized at 70 ° C. for 1 hour. After polymerization for a specified time, 10 ml of ethanol was injected into the autoclave with argon and the remaining gas was purged. The obtained polymer (PP1) was dried at 110 ° C. for 1 hour. As a result, 602.6 g of polymer was obtained. The catalytic activity was 39,130 g-PP / g-catalyst · hour, MFR = 22.0 (g / 10 min), and the aluminum content in the polymer was 0.0064 (wt%).

(Production Example 2: Production of PP2)
[Production of propylene homopolymer]
After fully replacing the inside of the stirred autoclave with an internal volume of 3 L with propylene, at room temperature, 11.0 ml of a triethylaluminum heptane solution (10 wt%) was added, and then 5000 ml of hydrogen and then 750 g of liquid propylene were introduced. The temperature in the tank was raised to 70 ° C. While maintaining the temperature in the tank at 70 ° C., 1.6 ml of the normal polymerization heptane slurry (7 mg-catalyst / ml) of the prepolymerized catalyst obtained in Production Example 1 and 11.2 mg as the catalyst (the weight of the prepolymerized polymer is Excluded with argon, and polymerized at 70 ° C. for 1 hour. After polymerization for a specified time, 10 ml of ethanol was injected into the autoclave with argon and the remaining gas was purged. The obtained polymer (PP2) was dried at 110 ° C. for 1 hour. As a result, 384.5 g of polymer was obtained. The catalytic activity was 34330 g-PP / g-catalyst · hour, MFR = 37.0 (g / 10 min), and the aluminum content in the polymer was 0.0492 (wt%).

(Production Example 3: Production of PP3)
[Production of propylene-ethylene copolymer]
After thoroughly replacing the inside of the stirred autoclave with an internal volume of 3 L with propylene, at room temperature, 1.65 ml of triethylaluminum heptane solution (10 wt%) was added, 6000 ml of hydrogen, 8 g of ethylene, and then 750 g of liquid propylene were added. The temperature inside the tank was raised to 70 ° C. While maintaining the internal temperature at 70 ° C., 0.7 ml of the normal polymerization heptane slurry (10 mg-catalyst / ml) of the prepolymerized catalyst obtained in Production Example 1 and 4.9 mg as the catalyst (the weight of the prepolymerized polymer is Excluded with argon, and polymerized at 70 ° C. for 1 hour. After polymerization for a specified time, 10 ml of ethanol was injected into the autoclave with argon and the remaining gas was purged. The obtained polymer was dried at 110 ° C. for 1 hour. As a result, 351 g of polymer (PP3) was obtained. The catalyst activity was 71630 g-PP / g-catalyst · hour, MFR = 29.1 (g / 10 min), ethylene content = 2.32 (wt%), and the aluminum content in the polymer was 0.0081 ( % By weight).

(Production Example 4: Production of PP4)
[Production of propylene-ethylene copolymer]
After fully replacing the inside of the stirred autoclave with an internal volume of 3 L with propylene, at room temperature, 2.25 ml of triethylaluminum heptane solution (10 wt%) was added, 6000 ml of hydrogen, 8 g of ethylene, and then 750 g of liquid propylene were added. The temperature inside the tank was raised to 70 ° C. While maintaining the internal temperature at 70 ° C., 0.7 ml of the normal polymerization heptane slurry (10 mg-catalyst / ml) of the prepolymerized catalyst obtained in Production Example 1 and 4.9 mg as the catalyst (the weight of the prepolymerized polymer is Excluded with argon, and polymerized at 70 ° C. for 1 hour. After polymerization for a specified time, 10 ml of ethanol was injected into the autoclave with argon and the remaining gas was purged. The obtained polymer was dried at 110 ° C. for 1 hour. As a result, 365 g of polymer (PP4) was obtained. The catalytic activity was 74,490 g-PP / g-catalyst.hour, MFR = 27.9 (g / 10 min), ethylene content = 2.26 (wt%), and the aluminum content in the polymer was 0.00. 0106 (% by weight).

(Production Example 5: Production of PP5)
[Production of propylene-ethylene copolymer]
After fully replacing the interior of the stirred autoclave with a volume of 3 L with propylene, add 11 ml of triethylaluminum heptane solution (10 wt%) at room temperature, introduce 6000 ml of hydrogen, 8 g of ethylene, and then 750 g of liquid propylene. The bath temperature was raised to 70 ° C. While maintaining the internal temperature at 70 ° C., 0.7 ml of the normal polymerization heptane slurry (10 mg-catalyst / ml) of the prepolymerized catalyst obtained in Production Example 1 and 4.9 mg as the catalyst (the weight of the prepolymerized polymer is Excluded with argon, and polymerized at 70 ° C. for 1 hour. After polymerization for a specified time, 10 ml of ethanol was injected into the autoclave with argon and the remaining gas was purged. The obtained polymer was dried at 110 ° C. for 1 hour. As a result, 346 g of polymer (PP5) was obtained. The catalyst activity is 70694 g-PP / g-catalyst · hour, MFR = 35.6 (g / 10 min), ethylene content = 2.26 (wt%), and the aluminum content in the polymer is 0.0547 ( % By weight).

(Production Example 6: Production of PP6)
[Production of propylene-ethylene copolymer]
I. Production of transition metal compound component (1) Synthesis of metallocene compound:
The synthesis of (r) -dichloro [1,1′-dimethylsilylenebis {2-methyl-4- (4-chlorophenyl) -4H-azurenyl}] zirconium is described in the examples of JP-A-11-240909. Synthesized by the method.

(2) Preparation of chemically treated ion exchange layered silicate:
To a 10-liter glass separable flask equipped with a stirring blade, 3.75 liters of distilled water was added slowly followed by 2.5 kg of concentrated sulfuric acid (96%). At 50 ° C., 1 kg of montmorillonite (trade name “Benclay SL” manufactured by Mizusawa Chemical Co., Ltd.) was further dispersed, heated to 90 ° C., and maintained at that temperature for 6.5 hours. After cooling to 50 ° C., the slurry was filtered under reduced pressure to recover the cake. 7 liters of distilled water was added to this cake, and after reslurry, it was filtered. This washing operation was performed until the pH of the washing liquid (filtrate) exceeded 3.5.
The collected cake was dried at 110 ° C. overnight under a nitrogen atmosphere. The weight after drying was 705 g.
The composition (molar) ratio of the obtained ion-exchanged layered silicate was Al / Si = 0.129, Mg / Si = 0.018, Fe / Si = 0.133.
The silicate previously chemically treated was further dried by a kiln dryer. The specifications and conditions of the dryer are as follows.
Rotating cylinder: cylindrical, inner diameter 50 mm, humidification zone 550 mm (electric furnace), with lifting blades Rotation speed: 2 rpm, tilt angle: 20/520, silicate feed rate; 2.5 g / min gas flow rate: nitrogen, 96 Liter / hour, countercurrent drying temperature: 200 ° C (powder temperature)

(3) Preparation of solid catalyst Into a metal reactor equipped with a stirrer having an internal volume of 13 liters, a mixture of 0.20 kg of the dried silicate obtained above and 0.74 liters of heptane was introduced, and tri-normal octyl aluminum was further introduced. 1.26 liters of a heptane solution (0.04M) was added to maintain the system temperature at 25 ° C. After the reaction for 1 hour, it was thoroughly washed with heptane to prepare 2.0 liters of a silicate slurry.
0.80 liters of heptane was added to 2.18 g (3.30 mmol) of (r) -dichloro [1,1′-dimethylsilylenebis {2-methyl-4- (4-chlorophenyl) -4H-azulenyl}] zirconium. Then, 33.1 ml of a heptane solution of triisobutylaluminum (0.71 M) was added, and the mixture reacted at room temperature for 1 hour was added to the silicate slurry. After stirring for 1 hour, heptane was added to add 5.0. Adjusted to liters.
Subsequently, propylene was supplied at a rate of 100 g / hour at a temperature of 40 ° C., and prepolymerization was performed for 4 hours. Further polymerization was carried out for 1 hour.
After completion of the prepolymerization, the residual monomer was purged, and the catalyst was thoroughly washed with heptane. Subsequently, 0.17 L of a heptane solution of triisobutylaluminum (0.71 M / L) was added, followed by drying at 45 ° C. under reduced pressure. By this operation, 0.60 kg of a dried prepolymerized catalyst was obtained.

[Catalyst synthesis]
1 kg of commercially available montmorillonite was dispersed in 6.3 liters of demineralized water in which 1.25 kg of magnesium chloride was dissolved, and the mixture was stirred at 80 ° C. for 1 hour. This solid was washed with water, then dispersed in 7 liters of an 8% aqueous hydrochloric acid solution, stirred at 90 ° C. for 2 hours, and washed with demineralized water. The montmorillonite water slurry was adjusted to a solid content concentration of 15% and spray granulated with a spray dryer to obtain spherical particles. Thereafter, the particles were dried under reduced pressure at 200 ° C. for 2 hours.

[Adjustment of catalyst components]
The chemically treated montmorillonite (5.04 g) obtained above was introduced into a glass reactor equipped with a stirring blade having an internal volume of 0.3 liter, and toluene and a toluene solution of triethylaluminum (30.2 mmol) were added, followed by stirring at room temperature. did. After 1 hour, it was washed with toluene (residual liquid ratio: less than 1%).
Next, in a 100 ml flask, 30 ml of a toluene slurry solution of 0.0752 mmol of (r) -dimethylsilylenebis (2-methyl-4-phenyldihydroazurenyl) zirconium dichloride and a toluene solution of triisobutylaluminum (0.75 mmol) were added. 0.93 ml was added at room temperature and stirred.
Subsequently, 400 ml of normal heptane was introduced into a stirring autoclave having an internal volume of 1.0 liter sufficiently substituted with propylene and kept at 40 ° C. Thereto was added 6.3 ml of a toluene solution of triisobutylaluminum (5.08 mmol), and then the previously prepared montmorillonite was further adjusted to the above-prepared (r) -dimethylsilylenebis (2-methyl-4-phenyldihydroazurenyl). ) A mixed solution of zirconium dichloride and triisobutylaluminum was introduced. The pressure was increased to 5 kg · f / cm ² to maintain the temperature and pressure. After 30 minutes, propylene was purged, and the prepolymerized catalyst slurry was collected with a siphon and dried under reduced pressure at room temperature. By this operation, a prepolymerized catalyst containing 1.47 g of polypropylene per 1 g of catalyst was obtained.

II. Propylene random copolymer production: Stirring autoclave with an internal volume of 270 L, liquid propylene at 38 kg / hr, ethylene at 1.4 kg / hr, hydrogen at 0.2 g / hr, and triisobutylaluminum (TIBA) at 9 g / hr Continuously. An internal temperature is maintained at 60 ° C., and a constant amount of slurry of liquid paraffin (trade name “White Rex 335”, manufactured by TonenGeneral Sekiyu KK) of the above catalyst is continuously supplied, and 11 kg / hr of propylene-ethylene random copolymer (PP6) was obtained.
The MFR was 7.0 (g / 10 min), the ethylene content was 3.4 (wt%), and the aluminum content in the polymer was 0.0005 (wt%).

The physical properties of the propylene polymers PP1 to PP6 are summarized in Table 1 below.

[Hindered phenol antioxidant (B)]
(B1) 1,3,5-tris (3,5-di-tert-butyl-4-hydroxybenzyl) -s-triazine-2,4,6 (1H, 3H, 5H) -trione:
“AO-20” (trade name, manufactured by Asahi Denka Co., Ltd.)
(B2) Octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid ester:
"Irganox 1076" (trade name, manufactured by BASF)
(B3) Ethylene bis [3,3-bis [3- (1,1-dimethylethyl) -4-hydroxyphenyl] butyric acid ester]:
"HOSTANOXO3" (trade name, manufactured by Clariant)
(B4) 2,2 ′, 2 ″, 6,6 ′, 6 ″ -hexa-tert-butyl-4,4 ′, 4 ″-[(2,4,6-trimethyl-1,3,5-benzene Tolyl) trismethylene] triphenol:
"Irganox 1330" (trade name, manufactured by BASF)
(B5) 2- [1- (2-Hydroxy-3,5-di-tert-pentylphenyl) ethyl] -4,6-di-tert-pentylphenyl acrylate:
"Sumilyzer GS" (trade name, manufactured by Sumitomo Chemical Co., Ltd.)
(B6) 1,3,5-tris (4-t-butyl-3-hydroxy-2,6-dimethylbenzyl) -isocyanuric acid:
"Irganox 3790" (trade name, manufactured by BASF)

[Phenolic antioxidants other than hindered phenolic antioxidants (B)]
(BX1) Tetrakis [methylene-3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate] methane:
"Irganox 1010" (trade name, manufactured by BASF)
(BX2) 6- [3- (3-t-Butyl-4-hydroxy-5-methyl) propoxy] -2,4,8,10-tetra-t-butyldibenz [d, f] [1,3,2 ] -Dioxaphosphepine:
"Sumilyzer GP" (trade name, manufactured by Sumitomo Chemical Co., Ltd.)

[Phosphorus antioxidant]
(C1) Tris (2,4-di-tert-butylphenol) phosphite:
“Irgafos168” (trade name, manufactured by BASF)

[Neutralizer]
(D1) DHT-4A:
"Hydrotalcite" (trade name, manufactured by Kyowa Chemical Industry Co., Ltd.)

(Examples 1-8, Comparative Examples 1-8)
Propylene polymer and additives (antioxidant, neutralizing agent) were prepared in the blending ratios (parts by weight) shown in Tables 2-3, and after dry blending with a super mixer, using a 30 mmΦ single screw extruder. The temperature was 250 ° C., the screw rotation speed was 100 rpm, the amount of extrusion was about 7 kg / hr, and the sample supply hopper was melt-kneaded under conditions in an air atmosphere. Extrusion was performed from the die at a die outlet temperature of 250 ° C., and the resin was pelletized. Thereafter, various evaluations were performed.
The results are shown in Tables 2-3.

As is apparent from Table 2, Examples 1 to 8 are those using the propylene-based resin composition of the present invention, excellent in processing stability and long-term stability, and including all ultraviolet absorption spectra. An excellent molded product that conforms to the items of the Japanese Pharmacopoeia can be obtained.
Examples 1, 2, 5, and 8 use resin powders having different aluminum metal contents in the propylene polymer, but are defined in the Japanese Pharmacopoeia as long as they are within the scope of the claims of the present invention. The measured value of the ultraviolet absorption spectrum is within the standard range, and it is found that it conforms to all Japanese Pharmacopoeia items and is excellent in processing stability and long-term stability.

On the other hand, Comparative Examples 1 and 6 are obtained by replacing the phenolic antioxidants of Examples 1 and 3-7 with conventional phenolic antioxidants outside the scope of the present patent claims. It can be seen that the value of the specified ultraviolet absorption spectrum exceeds the upper limit of the standard and does not conform to the Japanese Pharmacopoeia.
Further, as is clear from Comparative Examples 1 to 5, when a conventional phenolic antioxidant is blended with a propylene polymer having a specific amount of aluminum content, it exceeds the upper limit of the standard value of the Japanese Pharmacopeia. It turns out that it does not conform to the pharmacopoeia. It can also be seen that there is a relationship between the aluminum content and the measured value of the ultraviolet absorption spectrum defined by the Japanese Pharmacopoeia.
On the other hand, Comparative Example 6 was obtained by replacing the phenolic antioxidant of Example 7 with a conventional phenolic antioxidant which is outside the scope of the present patent claim. It can be seen that the spectrum value exceeds the upper limit of the standard and does not conform to the Japanese Pharmacopoeia.
Moreover, in the comparative example 7, it is a propylene polymer simple substance which does not mix | blend antioxidant. Although it is compatible with the Japanese Pharmacopoeia, it is clear that processing stability and long-term stability are poor.
Furthermore, in Comparative Example 8, no phenolic antioxidant is blended. It is clear that it conforms to the Japanese Pharmacopoeia and has excellent processing stability but poor long-term stability.

  The propylene-based resin composition of the present invention is excellent in processing stability, long-term stability, and low elution, and more specifically, since it passes the 16th revision Japanese Pharmacopoeia general test with strict acceptance criteria, particularly low elution is required. It is very suitable for medical kit formulations, and can be used particularly suitably for syringes and containers filled with drug solutions, specifically prefilled syringes, infusion bags, infusion bottles, infusion port materials, kit formulations, etc. It is.

Claims (5)

1 selected from the group consisting of the following (B1) to (B6) with respect to 100 parts by weight of the propylene polymer (A) containing 0.0001 to 0.1% by weight of aluminum metal detected by fluorescent X-ray analysis A propylene-based resin composition for medical kit preparations, comprising 0.001 to 1.0 part by weight of at least one kind of hindered phenol compound (B).
(B1): 1,3,5-tris (3,5-di-tert-butyl-4-hydroxybenzyl) -s-triazine-2,4,6 (1H, 3H, 5H) -trione (B2): Octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid ester (B3): ethylenebis [3,3-bis [3- (1,1-dimethylethyl) -4-hydroxyphenyl ] Butyric acid ester]
(B4): 2,2 ′, 2 ″, 6,6 ′, 6 ″ -hexa-tert-butyl-4,4 ′, 4 ″-[(2,4,6-trimethyl-1,3,5- Benzenetolyl) trismethylene] triphenol (B5): 2- [1- (2-hydroxy-3,5-di-tert-pentylphenyl) ethyl] -4,6-di-tert-pentylphenyl acrylate (B6) : 1,3,5-tris (4-t-butyl-3-hydroxy-2,6-dimethylbenzyl) -isocyanuric acid   The aluminum metal is derived from any aluminum-containing compound of trialkylaluminum, dialkylaluminum halide, alkylaluminum sesquihalide, alkylaluminum dihalide, alkylaluminum hydride, organoaluminum alkoxide, aluminum hydroxide, or aluminum oxide. The propylene-based resin composition for a medical kit preparation according to claim 1.   A medical kit preparation using the propylene-based resin composition according to claim 1.   The medical kit preparation according to claim 3, wherein the kit preparation is a prefilled syringe, an infusion bag, an infusion bottle, or an infusion port member.   The medical kit preparation according to claim 3 or 4, which has been subjected to radiation sterilization, ethylene oxide gas sterilization, or high-pressure steam sterilization.