JP2018201887A - Pharmaceutical container - Google Patents

Abstract

To provide a pharmaceutical container having excellent oxygen barrier properties.SOLUTION: A pharmaceutical container has (A) a mold container, and (B) a cap. The (A) mold container has an oxygen permeability of 0.001 mL/(0.21 atm day package) or less, and the (B) cap is made from materials with an oxygen permeability coefficient of 300 mL mm/(mday atm) or less.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical container, and more particularly to a pharmaceutical container having excellent oxygen barrier properties.

  2. Description of the Related Art Conventionally, glassy vials and the like have been used as medical packaging containers for filling and storing medicinal solutions in a sealed state at medical sites and the like. However, such a glass container is colored when using a light-shielding glass container colored with metal, in which a sodium ion or the like elutes in the content liquid in the container during storage, or a fine substance called flakes is generated. There is a problem that the metal for use is mixed into the contents and is easily broken by an impact such as dropping. Further, since the specific gravity is relatively large, there is a problem that the medical packaging container is heavy. Therefore, development of alternative materials is expected. Specifically, plastics that are lighter than glass, for example, polyester, polycarbonate, polypropylene, cycloolefin polymer (hereinafter may be abbreviated as “COP”), and the like are being studied as glass substitute materials.

  In particular, as a pharmaceutical container with excellent oxygen barrier performance and oxygen absorption performance under a wide range of humidity conditions from low to high humidity, an oxygen-absorbing resin containing a polymer having a predetermined tetralin ring and a transition metal catalyst (patented) Documents 1), polymetaxylylene adipamide (hereinafter sometimes abbreviated as “N-MXD6”) (Patent Documents 2 to 5) and the like have been developed.

International Publication No. 2013/077436 JP 2012-201412 A JP 2012-30556 A JP 2014-69829 A JP 2014-68767 A

  However, the medical container described in Patent Document 1 may have a problem in oxygen barrier performance depending on the cap material used. This invention is made | formed in view of the said subject, The objective is to provide the container for pharmaceuticals excellent in oxygen barrier property.

  As a result of intensive studies on pharmaceutical containers, the present inventors have found that the above problems can be solved by using a cap having excellent oxygen barrier performance, and have completed the present invention.

That is, the present invention is as follows.
<1>
(A) Molded container, (B) A pharmaceutical container provided with a cap, wherein the oxygen permeability of the molded container (A) is 0.001 mL / (0.21 atm · day · package) or less, B) The container for pharmaceuticals whose oxygen permeability coefficient of the material of a cap is 300 mL * mm / (m < ² > * day * atm) or less.
<2>
The pharmaceutical container according to <1>, wherein the (A) molded container is a multilayer.
<3>
The pharmaceutical container according to <1> or <2>, wherein the (B) cap contains butyl rubber.
<4>
An article comprising the pharmaceutical container according to any one of the above items <1> to <3> and a chemical solution contained in the container.

  The pharmaceutical container of this embodiment includes (A) a molded container and (B) a cap. ADVANTAGE OF THE INVENTION According to this invention, the container for pharmaceuticals excellent in oxygen barrier property can be provided by (A) molded container and (B) cap which have the outstanding oxygen barrier property. Moreover, it can preserve | save for a long period of time, suppressing oxidation of the chemical | medical solution etc. to accommodate.

  Embodiments of the present invention will be described below. In addition, the following embodiment is an illustration for demonstrating this invention, and this invention is not limited only to the embodiment.

[(A) Molded container]
The molded container used in the present embodiment can be a general resin molded container and is not limited at all. However, from the viewpoint of ensuring the oxygen barrier performance of the pharmaceutical container, the molded container is 0.001 mL / (0.21 atm). (Day / package) It is preferable to have an oxygen permeability equal to or lower than that.

  The molded container is not limited in the form of a single layer or a multilayer, but it is preferable to use a multilayer container because it is easy to improve oxygen barrier performance and to provide functions other than oxygen barrier performance.

<Multilayer container>
Although the layer structure of the multilayer container is not particularly limited, a resin layer (layer B) containing the thermoplastic resin composition (b), a resin layer (layer A) comprising the barrier thermoplastic resin composition (a), The thing which has at least 3 layer in this order with the resin layer (layer B) containing a thermoplastic resin composition (b) is preferable.

(Layer structure)
As long as these layers are arranged in the order of B / A / B, the number and types of the resin layer (layer A) and the resin layer (layer B) are not particularly limited. For example, a three-layer five-layer configuration of B1 / B2 / A / B2 / B1 composed of one layer A, two layers B1, and two layers B2 may be used, and one layer A and layers B1 and B2 A B3 / A3 / B2 three-layer structure may be used. Moreover, the pharmaceutical container of the present embodiment may include an arbitrary layer such as an adhesive layer (layer AD) as necessary, for example, four types 7 of B1 / AD / B2 / A / B2 / AD / B1. A layer structure may be used.

(Barrier thermoplastic resin composition (a))
As the barrier thermoplastic resin composition (a), a resin composition (a-1) or an oxygen-absorbing resin composition (a-2) having a low oxygen permeability can be used.

As the resin composition (a-1) having a small oxygen permeability, a resin having an oxygen permeability coefficient of 0.5 mL · mm / (m ² · day · atm) or less obtained by a method based on JIS K 7126 is preferable. , Polyolefin, polyester, polyamide, ethylene-vinyl alcohol copolymer, plant-derived resin and chlorine-based resin. Moreover, it is preferable that it is an amorphous resin from a transparency viewpoint so that the contents can be easily recognized.

  No matter how the gas replacement operation is performed at the time of filling the chemical solution, there is a possibility that oxygen contained in bubbles mixed at the time of filling or oxygen dissolved in the liquid of the contents cannot be completely removed. When the oxygen-absorbing resin composition (a-2) is used as the barrier thermoplastic resin composition (a), it is possible to suppress the permeation of trace amounts of oxygen that permeate through the wall of the container and enter from the outside. In addition, oxygen contained in bubbles mixed at the time of filling the chemical solution and dissolved oxygen in the chemical solution can be absorbed, which is preferable. As a preferable oxygen-absorbing resin composition (a-2), for example, an oxygen-absorbing resin composition containing a polyester compound and a transition metal catalyst described in International Publication No. 2013/0777436 can be given.

  In addition to the resin layer (layer A) and the resin layer (layer B) containing a thermoplastic resin, the multilayer container of the present embodiment may include an arbitrary layer depending on the desired performance. Examples of such an arbitrary layer include an adhesive layer.

  In the multilayer container of this embodiment, when practical interlayer adhesive strength cannot be obtained between two adjacent layers, it is preferable to provide an adhesive layer (layer AD) between the two layers. The adhesive layer preferably contains a thermoplastic resin having adhesiveness. As the thermoplastic resin having adhesiveness, for example, an acid modification in which a polyolefin resin such as polyethylene or polypropylene is modified with an unsaturated carboxylic acid such as acrylic acid, methacrylic acid, maleic acid, maleic anhydride, fumaric acid, itaconic acid, etc. Examples thereof include polyester-based thermoplastic elastomers mainly composed of a polyolefin resin and a polyester-based block copolymer. As the adhesive layer, it is preferable to use a modified resin of the same type as the thermoplastic resin used as the layer B from the viewpoint of adhesiveness. The thickness of the adhesive layer is preferably 2 to 100 μm, more preferably 5 to 90 μm, and still more preferably 10 to 80 μm, from the viewpoint of ensuring molding processability while exhibiting practical adhesive strength.

(Thermoplastic resin composition (b))
A well-known thing can be used suitably as a thermoplastic resin composition (b). For example, low density polyethylene, medium density polyethylene, high density polyethylene, linear low density polyethylene, linear ultra low density polyethylene, polypropylene, poly-1-butene, poly-4-methyl-1-pentene, or ethylene, propylene, Polyolefins such as random or block copolymers of α-olefins such as 1-butene and 4-methyl-1-pentene; acid-modified polyolefins such as maleic anhydride grafted polyethylene and maleic anhydride grafted polypropylene; ethylene-vinyl acetate copolymer Polymers, ethylene-vinyl alcohol copolymers, ethylene-vinyl chloride copolymers, ethylene- (meth) acrylic acid copolymers and their ionic cross-linked products (ionomers), ethylene-methyl methacrylate copolymers and other ethylene- Vinyl compound copolymer; Police Styrene resins such as Len, acrylonitrile-styrene copolymer, α-methylstyrene-styrene copolymer; polyvinyl compounds such as polymethyl acrylate and polymethyl methacrylate; nylon 6, nylon 66, nylon 610, nylon 12, Polyamides such as nylon 6IT and polymetaxylylene adipamide (MXD6); polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT), polyethylene naphthalate (PEN), glycol-modified polyethylene terephthalate (PETG) ), Polyethylene succinate (PES), polybutylene succinate (PBS), polyesters such as polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxyalkanoate; Polycarbonate such as polyethylene carbonate; cycloolefin copolymer (COC) which is a copolymer made from olefins such as norbornene and ethylene, and a copolymer made from olefins such as tetracyclododecene and ethylene In addition, cycloolefin polymer (COP), which is a polymer obtained by ring-opening polymerization of norbornene and hydrogenation, or a mixture thereof can be used. In addition, a thermoplastic resin composition (b) can be used individually by 1 type or in combination of 2 or more types.

Further, the thermoplastic resin composition (b) preferably has properties excellent in chemical resistance, elution resistance and impact resistance for the convenience of storing a chemical solution. Further, it is more preferable to have a water vapor barrier property, and it is preferable to select from resins having a water vapor transmission coefficient of 1.0 g · mm / m ² · day or less obtained by a method based on JIS K 7126. Particularly preferred are copolymers of norbornene and olefins such as ethylene as raw materials, cycloolefin copolymer (COC) which is a copolymer of tetracyclododecene and olefins such as ethylene as raw materials, and norbornene. A cycloolefin polymer (COP) which is a polymer obtained by ring polymerization and hydrogenation is also preferable. Such COC and COP are described in, for example, JP-A-5-300939 or JP-A-5-317411.

<Single layer container>
As the resin used in the single-layer container, the same one as the thermoplastic resin composition (b) can be mentioned as a preferred example.

  The thickness of the container is not particularly limited regardless of whether it is a single layer or multiple layers, but is preferably about 0.5 to 5 mm from the viewpoint of long-term storage stability, moldability and strength of the chemical solution. Further, another gas barrier layer may be formed on the surface for the purpose of long-term storage stability. As such a layer and a method for forming the layer, a method described in JP-A-2004-323058 can be employed.

[Container manufacturing method]
The manufacturing method of the multilayer container of this embodiment is not particularly limited, and can be manufactured by a normal injection molding method. For example, a manufacturing method described in International Publication No. 2013/0777436 (Patent Document 1) can be used.

[Coating container manufacturing method]
In this embodiment, a multilayer container can be produced by coating other materials on the single-layer container. The material used for the coating is not particularly limited. From the viewpoint of ensuring oxygen barrier performance, the composition of the barrier film of the coat is preferably a film based on silicon oxide. Such a film is desirably made of a volatile organosilicon compound or gas. There is no limit to the number of coat layers. There is no limitation on the method of coating the barrier film.

[(B) Cap]
The cap is fitted and attached to the opening of the molded container. The material of the cap is not particularly limited. For example, various rubber materials such as natural rubber, butyl rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, silicone rubber, polyurethane, polyester, polyamide, olefin, styrene Examples thereof include elastic materials such as various thermoplastic elastomers or mixtures thereof. From the viewpoint of ensuring the oxygen barrier performance of pharmaceutical containers, the material used for the cap has good oxygen barrier properties, such as butyl rubber made of a copolymer of isobutylene and a small amount of isoprene, chlorobutyl rubber or bromobutyl rubber halogenated from butyl rubber. Bromobutyl rubber and chlorobutyl rubber are preferred. The cap material preferably has an oxygen permeability coefficient of 300 mL · mm / (m ² · day · atm) or less, more preferably 200 mL · mm / (m ² · day · atm) or less, and 100 mL · mm / (M ² · day · atm) or less is particularly preferable.

[Pharmaceutical containers]
As one aspect of the use of the present invention, a form in which a chemical solution is accommodated in the above-described molded container and a cap is attached may be mentioned.

  Although there is no restriction | limiting in particular as a chemical | medical solution to contain, From the point of the effect of this embodiment, vitamin agents, such as vitamin A, vitamin B2, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, atropine, etc. Hormonal agents such as alkaloids, adrenaline and insulin, sugars such as glucose and maltose, antibiotics such as ceftriaxone, cephalosporin and cyclosporine, hormonal agents such as insulin and adrenaline, benzodiazepines such as oxazolam, flunitrazepam, clothiazepam and clobazam Examples include drugs. The container for pharmaceuticals of this embodiment can suppress the deterioration by oxidation, when the chemical | medical solution etc. containing these compounds are accommodated.

[Sterilization treatment]
It should be noted that the container and the chemical solution can be sterilized before and after the storage of these chemical solutions in a form suitable for the chemical solution. Examples of the sterilization method include heat sterilization such as hot water treatment at 100 ° C. or lower, pressurized hot water treatment at 100 ° C. or higher, and ultrahigh temperature heat treatment at 130 ° C. or higher; electromagnetic sterilization such as ultraviolet rays, microwaves, and gamma rays; Gas treatment of ethylene oxide and the like; chemical sterilization such as hydrogen peroxide and hypochlorous acid; and the like.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto. Unless otherwise stated, NMR measurements were performed at room temperature.

Example 1
[Monomer synthesis]
An autoclave with an internal volume of 18 L was charged with 2.20 kg of dimethyl naphthalene-2,6-dicarboxylate, 11.0 kg of 2-propanol, and 350 g of a catalyst in which 5% by mass of palladium was supported on activated carbon (50 wt% water-containing product). Next, after the air in the autoclave was replaced with nitrogen, and further nitrogen was replaced with hydrogen, hydrogen was supplied until the pressure in the autoclave reached 0.8 MPa. Next, the agitator was started, the rotation speed was adjusted to 500 rpm, the internal temperature was raised to 100 ° C. over 30 minutes, and hydrogen was further supplied to make the pressure 1 MPa. Thereafter, the supply of hydrogen was continued to maintain 1 MPa in accordance with the pressure drop due to the progress of the reaction. Since the pressure drop disappeared after 7 hours, the autoclave was cooled, unreacted residual hydrogen was released, and then the reaction solution was taken out from the autoclave. The reaction solution was filtered to remove the catalyst, and then 2-propanol was evaporated from the separated filtrate with an evaporator. To the obtained crude product, 4.40 kg of 2-propanol was added and purified by recrystallization to obtain dimethyl tetralin-2,6-dicarboxylate in a yield of 80%. The NMR analysis results are as follows. 1H-NMR (400 MHz CDCl ₃ ) δ 7.76-7.96 (2H m), 7.15 (1H d), 3.89 (3H s), 3.70 (3H s), 2.70-3. 09 (5H m), 2.19-2.26 (1H m), 1.80-1.95 (1H m).

[Polymer production example]
Tetralin-2,6-dicarboxylate dimethyl ester in 0.03 cubic meter polyester resin production equipment equipped with packed tower type rectification tower, partial condenser, total condenser, cold trap, stirrer, heating device and nitrogen introduction pipe 18.15 kg, 7.26 kg of ethylene glycol, and 2.86 g of tetrabutyl titanate were charged, and the temperature was raised to 230 ° C. in a nitrogen atmosphere to perform a transesterification reaction. After setting the reaction conversion rate of the dicarboxylic acid component to 85% or more, 2.86 g of tetrabutyl titanate was added, the temperature was increased and the pressure was gradually reduced, polycondensation was performed at 245 ° C. and 0.1 kPa or less, and the polyester compound ( 1) was obtained. The obtained polyester compound (1) has a weight-average molecular weight in terms of polystyrene of 8.5 × 10 ⁴ , a number-average molecular weight of 3.0 × 10 ⁴ , a glass transition temperature of 67 ° C., and a melting point of amorphous. There wasn't.

[Production example of resin composition]
A biaxial extrusion having two screws with a diameter of 37 mm, obtained by dry blending cobalt stearate (II) with a cobalt content of 0.00025 parts by mass with respect to 100 parts by mass of the polyester compound (1) The oxygen-absorbing resin composition (1) is supplied to the machine at a rate of 15 kg / h, melt kneaded at a cylinder temperature of 290 ° C., extruding a strand from the extruder head, cooling, and pelletizing. Obtained.

[Manufacture of containers]
Under the following conditions, the material constituting the layer (B) is injected from the injection cylinder, and the material constituting the layer (A) is injected from another injection cylinder simultaneously with the resin constituting the layer (B). Furthermore, a multilayer preform (5.1 g) having a three-layer structure of B / A / B was obtained by injecting a necessary amount of the resin constituting the layer (B) to fill the cavity.
In addition, as a resin constituting the layer (B), a cycloolefin polymer (manufactured by Zeon Corporation, product name: “ZEONEX (registered trademark) 5000”) was used. As the resin constituting the layer (A), the oxygen-absorbing resin composition (1) was used.
After the obtained preform is cooled to a predetermined temperature, it is transferred to a blow mold as secondary processing, air is blown from the mouth, the preform is inflated and brought into close contact with the mold, and blown by cooling and solidifying. Molding was performed to produce a multilayer container.

<Shape of multilayer container>
The total length was 45 mm, the outer diameter was 24 mmφ, the thickness (total thickness of the multilayer container) was 1.0 mm, the outer layer (B) thickness was 600 μm, the inner layer (A) thickness was 200 μm, and the intermediate layer (B) thickness was 200 μm. The multilayer container was manufactured by injection blow molding using an injection blow integral molding machine (manufactured by Nissei ASB Machine Co., Ltd., model: “ASB12N / 10T”, 4 pieces).
(Molding conditions for multilayer containers)
Injection cylinder temperature for layer (A): 260 ° C
Injection cylinder temperature for layer (B): 260 ° C
Resin channel temperature in injection mold: 260 ° C
Blow temperature: 150 ° C
Blow mold cooling water temperature: 40 ° C

<Measurement of oxygen permeability of molded container>
The oxygen permeability on the 30th day from the start of measurement was measured in an atmosphere of 23 ° C., 50% relative humidity outside the container, and 100% relative humidity inside the container. For the measurement, an oxygen permeability measuring device (manufactured by MOCON, trade name “OX-TRAN 2-21ML”) was used. The lower the measured value, the better the oxygen barrier property. The lower limit of detection of the measurement was an oxygen transmission rate of 5 × 10 ⁻⁴ mL / (0.21 atm · day · package).

[Evaluation of container]
The oxygen barrier properties of the obtained pharmaceutical container were measured and evaluated according to the following methods and standards.

<Methylene blue gel oxygen barrier test>
5.0 g of sucrose fatty acid ester was dissolved in 5.0 L of water at 90 ° C. To this aqueous solution, 75 g of agar powder, 2.4 g of sodium hydroxide, 300 g of D-glucose and 0.75 g of methylene blue were added and dissolved to prepare a methylene blue gel. The gel was then boiled for 10 minutes to remove dissolved oxygen. The color of the gel after boiling is yellow, and when it reacts with oxygen, it turns blue. A container made of this gel was filled, and a cap made of chlorobutyl rubber (Sumitomo Rubber Industries, Ltd., L10-2, oxygen transmission coefficient: 45 mL · mm / (m ² · day · atm)) was attached to the container. The opening was sealed. The changes after storage at 23 ° C. for 1 month and 6 months were observed. The oxygen barrier performance after storage was evaluated by gel color according to the following criteria. The evaluation results are shown in Table 1.
<Gel color evaluation criteria>
A: Yellow just after filling B: Light blue near the opening C: Light blue overall D: Blue near the opening E: Blue overall

(Example 2)
Instead of the oxygen-absorbing resin composition (1), an aromatic polyamide resin (Mitsubishi Gas Chemical Co., Ltd., trade name “MX Nylon S6007”) is used, and a cycloolefin polymer (manufactured by Nippon Zeon Co., Ltd., product name: “ In place of ZEONEX (registered trademark) 5000 "), a cycloolefin polymer (manufactured by Nippon Zeon Co., Ltd., product name:" ZEONEX (registered trademark) 690R ") was used in the same manner as in Example 1, except that Manufactured. Performance evaluation of the obtained container was performed in the same manner as in Example 1. The evaluation results are shown in Table 1.

(Comparative Example 1)
A test was performed in the same manner as in Example 1 except that nylon 6IT (DSM Japan Engineering Plastics, Novamid (registered trademark)) was used instead of the oxygen-absorbing resin composition (1). The evaluation results are shown in Table 1.

(Comparative Example 2)
In Example 1, a single-layer container consisting only of the layer (B) was produced. The thickness of the layer (B) was 1000 μm. Performance evaluation of the obtained container was performed in the same manner as in Example 1. The evaluation results are shown in Table 1.

  Table 1 shows the evaluation results of the containers obtained in Examples 1-2 and Comparative Examples 1-2.

  As is apparent from Table 1, it was confirmed that the pharmaceutical containers of Examples 1 and 2 were excellent in oxygen barrier properties.

Claims (4)

(A) Molded container, (B) A pharmaceutical container provided with a cap, wherein the oxygen permeability of the molded container (A) is 0.001 mL / (0.21 atm · day · package) or less, B) The container for pharmaceuticals whose oxygen permeability coefficient of the material of a cap is 300 mL * mm / (m < ² > * day * atm) or less. The pharmaceutical container according to claim 1, wherein the molded container (A) is a multilayer container. The pharmaceutical container according to claim 1 or 2, wherein the material of the (B) cap contains butyl rubber. The article | item provided with the container for pharmaceuticals as described in any one of Claims 1-3, and the chemical | medical solution accommodated in the said container.