JP2018126313A - Biopharmaceutical container, article containing biopharmaceutical, method for storing biopharmaceutical and method for producing article containing biopharmaceutical in container - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a biopharmaceutical container that has excellent transparency even after heating, and also can keep a high drug action, and an article containing a biopharmaceutical using the same, a method for storing a biopharmaceutical and a method for producing an article containing the biopharmaceutical in a container.SOLUTION: A biopharmaceutical container 1 for storing a protein-derived medicinal component 4, has a layer (X) containing at least one of polyolefin resins as the main component and a layer (Y) containing a polyamide resin (A) as the main component, where the polyamide resin (A) has a diamine-derived constitutional unit and a dicarboxylate-derived constitutional unit, where 70 mol% or more of the diamine-derived constitutional unit is derived from m-xylylenediamine, and 30-60 mol% of the dicarboxylate-derived constitutional unit is derived from C4-20 α,ω-linear aliphatic dicarboxylate and 70-40 mol% of it is derived from isophthalic acid.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a biopharmaceutical container, and an article containing the biopharmaceutical using the biopharmaceutical container, a method for storing the biopharmaceutical, and a method for producing the article containing the biopharmaceutical in the container.

Conventionally, containers such as glass ampoules, vials, and prefilled syringes have been used as medical packaging containers for filling and storing medicines in a sealed state. However, these glass containers have a problem that a fine glass substance called flakes is generated during use, and is easily broken by an impact such as dropping. Further, since glass has a relatively large specific gravity, there is also a problem that the container itself is heavy.
On the other hand, plastics are lighter than glass and, depending on the material, are excellent in impact resistance, heat resistance, transparency, etc., plastic containers are being considered as substitutes for glass containers. For example, Patent Document 1 discloses a medical container made of a polyester resin. In addition, cycloolefin polymers (hereinafter sometimes abbreviated as “COP”) are excellent in impact resistance, heat resistance, and transparency, and are generally used as glass substitute materials in medical containers.

  As a plastic container as an alternative container for a glass container, for example, Patent Document 2 discloses a medical multilayer container in which an innermost layer and an outermost layer are made of a polyolefin resin, and an intermediate layer is a resin layer having excellent barrier properties. It is disclosed.

  In addition, plastic containers using polymetaxylylene adipamide (hereinafter sometimes abbreviated as “N-MXD6”) are also known (Patent Documents 3 to 6). However, since N-MXD6 crystallizes very quickly at a thermoforming temperature of polyolefin resin, for example, COP of 250 to 320 ° C., N-MXD6 was used as a gas barrier layer and COP was used as an innermost layer and an outermost layer. In the multilayer container, the N-MXD6 layer is damaged, uneven in thickness, and whitened during molding. Moreover, it may whiten after heat sterilization (sterilization) processing, and transparency may be impaired.

As means for suppressing whitening of N-MXD6, a method of adding a specific fatty acid metal salt as a whitening inhibitor and a method of adding a specific diamide compound or diester compound are known. The whitening suppression using these additives is, for example, PET / N-MXD6 / PET using a single layer film directly exposed to water or polyethylene terephthalate (hereinafter sometimes abbreviated as “PET”). It is known that the stretched use is effective like a stretch bottle having a layer structure. However, the whitening suppression effect after the heat sterilization treatment in a multilayer container having a layer structure of COP / N-MXD6 / COP is not satisfactory.
Also known are a method of adding a crystallization nucleating agent to N-MXD6 and a method of blending with N-MXD6 a crystalline polyamide resin such as nylon 6 that acts as a crystallization nucleating agent during heat sterilization treatment. . However, even by these methods, the whitening suppression effect after the heat sterilization treatment in the multilayer container having the layer configuration of COP / N-MXD6 / COP is not satisfactory.

JP 08-127641 A JP 2004-229750 A JP 2012-201412 A JP 2012-30556 A JP 2014-69829 A JP 2014-68767 A

In recent years, biopharmaceuticals have been utilized. Containers for storing biopharmaceuticals are required to have a high medicinal effect in addition to excellent transparency (inhibition of whitening) even after heat sterilization.
The problem to be solved by the present invention is to solve the above-mentioned problem. In addition to being excellent in transparency even after the heat sterilization treatment, the container for biopharmaceuticals that can maintain high medicinal effect, and An object of the present invention is to provide an article containing a biopharmaceutical using the same, a method for preserving the biopharmaceutical and a method for producing an article containing the biopharmaceutical in a container.

As a result of investigations based on the above problems, the present inventors have found that the above problems can be solved by the following means.
Specifically, the above problem has been solved by the following means <1>, preferably <2> to <18>.
<1> It has a layer (X) mainly composed of at least one polyolefin resin and a layer (Y) mainly composed of a polyamide resin (A), and the polyamide resin (A) is a structural unit derived from diamine. And 70 mol% or more of the structural unit derived from dicarboxylic acid is derived from metaxylylenediamine, and 30 to 60 mol% of the structural unit derived from dicarboxylic acid has 4 carbon atoms. A container for biopharmaceuticals for preserving protein-derived medicinal ingredients derived from -20 α, ω-linear aliphatic dicarboxylic acids and 70-40 mol% derived from isophthalic acid.
<2> The biopharmaceutical container according to <1>, wherein the polyamide resin (A) contains a calcium atom.
<3> The biopharmaceutical container according to <2>, wherein the calcium atom contained in the polyamide resin (A) is derived from calcium hypophosphite.
<4> The biopharmaceutical container according to any one of <1> to <3>, wherein the polyamide resin (A) contains phosphorus atoms in a proportion of 3 to 300 ppm by mass.
<5> The polyamide resin (A) contains phosphorus atoms in a proportion of 20 to 200 ppm by mass, and contains calcium atoms in a proportion of a molar ratio of phosphorus atoms to calcium atoms of 1: 0.3 to 0.7. The container for biopharmaceuticals according to <1> or <3>.
<6> The biopharmaceutical container according to any one of <1> to <5>, wherein the polyolefin resin is at least one selected from the group consisting of a cycloolefin polymer and a polypropylene polymer.
<7> The biopharmaceutical container according to any one of <1> to <6>, wherein 30 to 60 mol% of the structural unit derived from dicarboxylic acid is a structural unit derived from adipic acid.
<8> The biopharmaceutical container is composed of at least three layers, the inner layer and the outer layer are the layer (X), and at least one of the intermediate layers is the layer (Y), <1> to <7 > The container for biopharmaceuticals as described in any one of>.
<9> The biopharmaceutical container according to any one of <1> to <8>, wherein the thickness of the layer (Y) is 2 to 40% with respect to the total thickness of the biopharmaceutical container.
<10> The biopharmaceutical container according to any one of <1> to <9>, wherein the biopharmaceutical container is a vial.
<11> The biopharmaceutical container according to any one of <1> to <10>, wherein the protein-derived medicinal component is selected from the group consisting of an antibody, a hormone, an enzyme, and a complex containing these.
<12> An article comprising the biopharmaceutical container according to any one of <1> to <11> and the biopharmaceutical in the biopharmaceutical container.
<13> It has a layer (X) mainly composed of at least one kind of polyolefin resin and a layer (Y) mainly composed of polyamide resin (A),
The polyamide resin (A) is composed of a structural unit derived from a diamine and a structural unit derived from a dicarboxylic acid, 70 mol% or more of the structural unit derived from the diamine is derived from metaxylylenediamine, and derived from the dicarboxylic acid. 30 to 60 mol% of the structural unit is derived from an α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70 to 40 mol% is derived from isophthalic acid, using a protein derived from protein A method for preserving a biopharmaceutical comprising storing the biopharmaceutical containing the ingredient.
<14> The method for storing a biopharmaceutical according to <13>, wherein the container is the biopharmaceutical container according to any one of <2> to <10>.
<15> The method for preserving a biopharmaceutical according to <13> or <14>, wherein the protein-derived medicinal component is selected from the group consisting of an antibody, a hormone, an enzyme, and a complex containing these.
<16> It has a layer (X) mainly composed of at least one polyolefin resin and a layer (Y) mainly composed of polyamide resin (A),
The polyamide resin (A) is composed of a structural unit derived from a diamine and a structural unit derived from a dicarboxylic acid, 70 mol% or more of the structural unit derived from the diamine is derived from metaxylylenediamine, and derived from the dicarboxylic acid. 30 to 60 mol% of the structural unit is derived from α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70 to 40 mol% is derived from isophthalic acid, and a protein-derived medicinal component is added to the container. A method for producing an article containing a biopharmaceutical in a container, comprising enclosing the biopharmaceutical containing.
<17> The production method according to <16>, wherein the container is the biopharmaceutical container according to any one of <2> to <10>.
<18> The method according to <16> or <17>, wherein the protein-derived medicinal component is selected from the group consisting of an antibody, a hormone, an enzyme, and a complex containing these.

  According to the present invention, in addition to being excellent in transparency even after heat treatment, a biopharmaceutical container that can maintain a high medicinal effect, an article containing a biopharmaceutical using the same, a biopharmaceutical storage method, and a bio in the container It has become possible to provide a method for manufacturing an article including a pharmaceutical product.

It is the schematic which shows an example of the container for biopharmaceuticals in this invention.

  Hereinafter, the contents of the present invention will be described in detail. In the present specification, “to” is used to mean that the numerical values described before and after it are included as a lower limit and an upper limit.

The biopharmaceutical container of the present invention is a biopharmaceutical container for storing protein-derived medicinal ingredients, and mainly comprises a layer (X) mainly composed of at least one polyolefin resin and a polyamide resin (A). It has a layer (Y) as a component, and the polyamide resin (A) is composed of a structural unit derived from diamine and a structural unit derived from dicarboxylic acid, and 70 mol% or more of the structural unit derived from diamine is metaxylline. 30-60 mol% of the structural unit derived from range amine is derived from α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70-40 mol% is derived from isophthalic acid. It is derived from.
The polyamide resin (A) is usually an amorphous polyamide resin. By using such a polyamide resin, a biopharmaceutical container having excellent gas barrier properties and transparency even after heat sterilization treatment is used. be able to. Furthermore, it is possible to maintain a high medicinal effect of a pharmaceutical product having a protein-derived medicinal component.
Here, the amorphous polyamide resin is a resin having no clear melting point. Specifically, it means that the crystal melting enthalpy ΔHm is less than 5 J / g, preferably 3 J / g or less, preferably 1 J / g. g or less is more preferable.

<Layer structure>
The layer structure in the biopharmaceutical container of the present invention is not particularly limited, and the number and type of layers (X) and layers (Y) are not particularly limited.
The number of layers constituting the biopharmaceutical container is preferably composed of at least three layers, more preferably 3 to 10 layers, and even more preferably 3 to 5 layers.
The number of layers (X) in the biopharmaceutical container is preferably 1 to 5 layers, and more preferably 2 to 4 layers. The number of layers (Y) in the biopharmaceutical container is preferably 1 to 3 layers, more preferably 1 layer or 2 layers.
For example, a biopharmaceutical container has an X / Y configuration (layer (X) is an inner layer) or Y / X configuration (layer (Y) is composed of one layer (X) and one layer (Y). It may be an inner layer) or may be a three-layer structure of X / Y / X composed of two layers (X) and one layer (Y). Furthermore, in the biopharmaceutical container of the present invention, the layer (X) and the layer (Y) may be in contact with each other, but may include any layer such as an adhesive layer (AD).
In the biopharmaceutical container of the present invention, the inner layer and the outer layer are preferably the layer (X), and at least one of the intermediate layers is preferably the layer (Y) (X / Y / X configuration). In the present embodiment, the layer (X) that is the inner layer and the outer layer may be in contact with the (Y) layer that is an intermediate layer (X / Y / X), or the layer (Y) and the layer (X) may be bonded to each other via an adhesive layer (AD) (X / AD / Y / AD / X). Moreover, in this invention, it is possible to further have various thermoplastic resin layers according to the purpose, not limited to these.
Here, the inner layer refers to a layer located inside the (Y) layer that is one intermediate layer among the layers constituting the biopharmaceutical container, and the outer layer refers to a layer that constitutes the biopharmaceutical container. Among these, the layer located outside the (Y) layer which is one intermediate layer is said. The inner layer and the outer layer may be the innermost layer and the outermost layer, respectively, or may have an innermost layer and an outermost layer separately.

In the multilayer container of the present invention, it is preferable that the thickness of at least one outer layer is thicker than the thickness of at least one inner layer. The difference in thickness between the outer layer and the inner layer is preferably 200 μm or more, more preferably 300 μm or more, and more preferably 300 to 900 μm.
The lower limit of the total thickness of the multilayer container of the present invention is preferably 0.5 mm or more, more preferably 0.8 mm or more, and further preferably 1.0 mm or more. The total thickness is preferably 2.5 mm or less, and more preferably 2.0 mm or less.

<Layer (X)>
The layer (X) constituting the biopharmaceutical container of the present invention is a layer mainly composed of at least one polyolefin resin, and usually functions as a water vapor barrier layer. Here, “main component” means that the layer (X) contains a polyolefin resin (water vapor barrier polymer) in the layer (X) of 70% by mass or more, preferably 80% by mass or more, more preferably 90%. It means that -100 mass% is contained. Layer (X) may contain only 1 type of polyolefin resin, or may contain 2 or more types. When 2 or more types are included, the total amount of the polyolefin resin falls within the above range.
In addition to the polyolefin resin, the layer (X) includes an antioxidant, a matting agent, a weather resistance stabilizer, an ultraviolet absorber, a crystallization nucleating agent, and the like within a range that does not impair the effects of the present invention, depending on the desired performance and the like. Additives such as plasticizers, flame retardants and antistatic agents may be included.
The biopharmaceutical container of the present invention may have a plurality of layers (X), and the configurations of the plurality of layers (X) may be the same or different. Although the thickness of layer (X) is not specifically limited, From a viewpoint of intensity | strength and cost, 20-2000 micrometers is preferable and 50-1500 micrometers is more preferable.

<< Polyolefin resin >>
The polyolefin resin used in the present invention is not particularly defined, and a known polyolefin resin can be used.

  The polyolefin resin is preferably at least one selected from the group consisting of a cycloolefin polymer and a polypropylene polymer (PP), and more preferably at least one cycloolefin polymer. The cycloolefin polymer may be a cycloolefin polymer (COP) or a cycloolefin copolymer (COC). COP and COC have chemical properties such as heat resistance and light resistance and chemical resistance, which are characteristic of polyolefin resins, and physical properties such as mechanical properties, melting, flow properties, and dimensional accuracy are amorphous resins. It is preferable because it shows the characteristics as follows. On the other hand, PP is preferable from the viewpoint of oil resistance.

  COP is, for example, a polymer obtained by ring-opening polymerization of norbornene and hydrogenation. COP is described in, for example, Japanese Patent Application Laid-Open No. 5-317411, and ZEONEX (registered trademark) or ZEONOR (registered trademark) manufactured by Nippon Zeon Co., Ltd. or Daikyo Resin CZ manufactured by Daikyo Seiko Co., Ltd. It is marketed as (registered trademark).

  COC is, for example, a copolymer made from olefins such as norbornene and ethylene, and a copolymer made from olefins such as tetracyclododecene and ethylene. COC is commercially available, for example, as Apel (registered trademark) manufactured by Mitsui Chemicals.

  As PP, well-known polymers, such as a propylene homopolymer, a propylene-ethylene block copolymer, a propylene-ethylene random copolymer, can be used. As a commercial item, Boredalis company make, Bormed RB845MO etc. are mentioned.

  In addition to the above, polyolefin resins described in paragraphs 0101 to 0103 of JP-A-2014-068767 can also be used, and the contents thereof are incorporated herein.

<Layer (Y)>
The layer (Y) constituting the biopharmaceutical container of the present invention is a layer mainly composed of at least one kind of the predetermined polyamide resin (A), and usually functions as a gas barrier layer.
The layer (Y) usually has a role of blocking oxygen entering from the outside of the container and preventing oxidative deterioration of the contents in the container. From the viewpoint of good gas barrier properties, the oxygen permeability coefficient of the layer (Y) in an environment of 23 ° C. and a relative humidity of 60% is preferably 1.0 mL · mm / (m ² · day · atm) or less. It is more preferable that it is 0.05-0.8mL * mm / (m < ² > * day * atm). The oxygen permeability coefficient can be measured according to ASTM D3985, and can be measured using, for example, “OX-TRAN (registered trademark) 2/61” (manufactured by MOCON).

In addition, the above “main component” means that the polyamide resin (A) (gas barrier polymer) in the layer (Y) is 70 to 100% by mass, preferably 80 to 100% by mass, more preferably 90 to 100%. It means that it is contained by mass%, more preferably 95-100 mass%, and still more preferably 98-100 mass%. The layer (Y) may contain only 1 type of polyamide resin (A), or may contain 2 or more types. When 2 or more types are included, the total amount of the polyamide resin (A) falls within the above range.
The biopharmaceutical container of the present invention may have a plurality of layers (Y), and the configurations of the plurality of layers (Y) may be the same as or different from each other. Although the thickness of a layer (Y) is not specifically limited, 1-800 micrometers is preferable from a viewpoint of gas barrier property, transparency, and cost, and 100-700 micrometers is more preferable. In addition, the thickness of the layer (Y) in the biopharmaceutical container of the present invention is preferably in the range of 2 to 40% with respect to the total thickness of the biopharmaceutical container from the viewpoint of gas barrier properties, transparency, and cost. More preferably, it is 5-38%, More preferably, it is 10-35%. The thickness of the layer (Y) in the biopharmaceutical container can be measured by cutting the container and peeling it from the layer (X). In addition, when there are two or more layers (Y), the total is calculated as the thickness of the layer (Y).
In addition to the polyamide resin (A), the layer (Y) may contain additives in a range that does not impair the effects of the present invention, depending on the desired performance and the like. Specifically, pigments (such as inorganic pigments), lubricants (such as sodium stearate and calcium stearate), matting agents, heat stabilizers (such as antioxidants, more preferably phosphorous antioxidants), weathering stabilizers, Examples thereof include ultraviolet absorbers, crystallization nucleating agents, plasticizers, flame retardants, antistatic agents, anti-coloring agents, and anti-gelling agents. One type of additive may be used, or a combination of two or more types may be used. The content of the additive in the layer (Y) is preferably 10% by mass or less, more preferably 5% by mass or less, although it depends on the type of additive. Details of the additive can be referred to the descriptions in paragraphs 0071 to 0099 of JP-A-2014-068767, the contents of which are incorporated herein.
The following are illustrated as preferable embodiment of the layer (Y) in this invention.
(1) A layer consisting essentially of only one or two or more polyamide resins (A) (2) Substantially other than one or two or more polyamide resins (A) and a polyamide resin (A) Layer consisting only of polyamide resin (3) Layer consisting essentially of one or more polyamide resins (A) and antioxidants (4) One or more polyamide resins (A) and polyamide A layer consisting only of a polyamide resin other than the resin (A) and an antioxidant (5) One or two or more types of polyamide resins (A) and a layer consisting only of a lubricant (6) One or more types of polyamide resins ( A layer consisting only of a polyamide resin and a lubricant other than A) and the polyamide resin (A) (7) A layer consisting of only one or more polyamide resins (A), an antioxidant and a lubricant (8) One or two More than species polya A layer consisting only of a polyamide resin (A) and a polyamide resin (A), an antioxidant and a lubricant. (9) In the above, a layer wherein the polyamide resin other than the polyamide resin (A) is an amorphous polyamide resin.

<Polyamide resin (A)>
The polyamide resin (A) used in the present invention is composed of a structural unit derived from diamine and a structural unit derived from dicarboxylic acid, and 70 mol% or more of the structural unit derived from diamine is derived from metaxylylenediamine, Of the structural unit derived from acid, 30 to 60 mol% is derived from α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70 to 40 mol% is derived from isophthalic acid. The polyamide resin (A) used in the present invention is an amorphous resin. Transparency can be improved by using an amorphous resin. Furthermore, the polyamide resin (A) used in the present invention is also excellent in barrier properties after the heat sterilization treatment.
The polyamide resin (A) used in the present invention preferably contains calcium atoms. By including calcium atoms, the transparency after the heat treatment can be further improved.
The polyamide resin (A) used in the present invention contains phosphorus atoms in a proportion of 20 to 200 ppm by mass, and contains calcium atoms in a proportion such that the molar ratio of phosphorus atoms: calcium atoms is 1: 0.3 to 0.7. It is more preferable. With such a configuration, a biopharmaceutical container having higher transparency after heat treatment and lower YI value (yellowness) after heat treatment can be obtained. The calcium atom is preferably derived from calcium hypophosphite.

  When a polyamide resin synthesized from metaxylylenediamine, an α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and isophthalic acid is used, the yellowness may increase. Therefore, it is conceivable to add a phosphorus-containing compound that is a coloring inhibitor during polycondensation. However, when the proportion of isophthalic acid in all dicarboxylic acids constituting the structural unit derived from dicarboxylic acid increases to 40 mol% or more, sodium hypophosphite, which is generally used as a phosphorus-containing compound, was used. In this case, it was found that although the yellowness is improved, the transparency may be inferior. Furthermore, when sodium hypophosphite was used, even if the obtained polyamide resin was transparent, it was found that transparency may deteriorate when subjected to water immersion treatment or the like. As a result of further investigation, by adding calcium hypophosphite instead of sodium hypophosphite as the phosphorus-containing compound, the transparency (haze) is further improved and the transparency is further improved after the water immersion treatment. It was found that it can be improved. However, calcium salts such as calcium hypophosphite have low solubility in α, ω-linear aliphatic dicarboxylic acids and isophthalic acids having 4 to 20 carbon atoms, and white foreign matter is generated when the amount of calcium salt added increases. It turns out that it may end up. Based on the above knowledge, the present invention succeeded in providing a polyamide resin with higher transparency by setting the ratio of the phosphorus atom and the calcium atom of the polyamide resin as described above. It has succeeded in improving sex.

In the present invention, 70 mol% or more of the structural unit derived from diamine is derived from metaxylylenediamine. The structural unit derived from diamine is preferably 80 mol% or more, more preferably 90 mol% or more, still more preferably 95 mol% or more, still more preferably 98 mol% or more, and even more preferably 99 mol% or more. Derived from range amine.
Examples of diamines other than metaxylylenediamine include aromatic diamines such as paraphenylenediamine and paraxylylenediamine, 1,3-bis (aminomethyl) cyclohexane, 1,4-bis (aminomethyl) cyclohexane, and tetramethylenediamine. And aliphatic diamines such as pentamethylenediamine, hexamethylenediamine, octamethylenediamine, and nonamethylenediamine. These other diamines may be used alone or in combination of two or more.

In the present invention, 30 to 60 mol% of the structural unit derived from dicarboxylic acid is derived from α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70 to 40 mol% is derived from isophthalic acid.
Of all dicarboxylic acids constituting the structural unit derived from dicarboxylic acid, the lower limit of the proportion of isophthalic acid is preferably 41 mol% or more, more preferably 43 mol% or more, and even more preferably 45 mol% or more. The upper limit of the proportion of isophthalic acid is preferably 68 mol% or less, and more preferably 66 mol% or less. By setting it as such a range, it exists in the tendency for the haze after the heat processing of the container for biopharmaceuticals to fall more, and it is preferable.

Of all dicarboxylic acids constituting the structural unit derived from dicarboxylic acid, the lower limit of the proportion of α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms is preferably 32 mol% or more, and 34 mol% or more. More preferred. 59 mol% or less is preferable, as for the upper limit of the ratio of a C4-C20 linear aliphatic dicarboxylic acid, 57 mol% or less is more preferable, and 55 mol% or less is more preferable. By setting it as such a range, it exists in the tendency for the oxygen barrier property of the container for biopharmaceuticals, especially the oxygen barrier property after heat processing to improve more.
Examples of the α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms include fats such as succinic acid, glutaric acid, pimelic acid, suberic acid, azelaic acid, adipic acid, sebacic acid, undecanedioic acid, and dodecanedioic acid. Adipic acid and sebacic acid are preferable, and adipic acid is more preferable. The α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms may be one type or two or more types.

  Of all dicarboxylic acids constituting the structural unit derived from dicarboxylic acid, the total proportion of isophthalic acid and α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms is preferably 90 mol% or more, More preferably, it is 95 mol% or more, More preferably, it is 98 mol% or more, and 100 mol% may be sufficient. By setting it as such a ratio, it exists in the tendency for the transparency of the container for biopharmaceuticals to improve, and for yellowness to fall more.

  Examples of dicarboxylic acids other than isophthalic acid and α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms include terephthalic acid, 2,6-naphthalenedicarboxylic acid, and alicyclic dicarboxylic acids having 6 to 12 carbon atoms. Illustrated. Specific examples thereof include 1,4-cyclohexanedicarboxylic acid and 1,3-cyclohexanedicarboxylic acid.

  In addition, although the polyamide resin (A) used by this invention is comprised from the structural unit derived from dicarboxylic acid and the structural unit derived from diamine, structural units other than the structural unit derived from dicarboxylic acid and the structural unit derived from diamine, and the terminal Other sites such as groups may be included. Examples of other structural units include structural units derived from lactams such as ε-caprolactam, valerolactam, laurolactam, and undecanalactam, and aminocarboxylic acids such as 11-aminoundecanoic acid and 12-aminododecanoic acid. It is not limited to these. Furthermore, the polyamide resin (A) used in the present invention contains trace components such as additives used in the synthesis. The polyamide resin (A) used in the present invention is usually 95% by mass or more, preferably 98% by mass or more of a structural unit derived from a dicarboxylic acid or a structural unit derived from a diamine.

As described above, the polyamide resin (A) used in the present invention preferably contains phosphorus atoms at a rate of 3 to 300 ppm by mass, more preferably 4 to 250 ppm by mass, and more preferably 20 to 200 ppm by mass. More preferably, it is contained at a ratio of Moreover, it is preferable to contain a calcium atom in the ratio from which the molar ratio of a phosphorus atom: calcium atom will be 1: 0.3-0.7.
The lower limit of the phosphorus atom concentration in the polyamide resin (A) used in the present invention is preferably 3 mass ppm or more, more preferably 4 mass ppm or more, further preferably 20 mass ppm or more, and 22 mass. More preferably, it is more than ppm, 50 mass ppm or more may be sufficient, 100 mass ppm or more may be sufficient, and especially 150 mass ppm or more may be sufficient. By increasing the phosphorus atom concentration in the polyamide resin (A), the upper limit of the phosphorus atom concentration that enables the yellowness (YI value) to be more effectively reduced is 300 ppm by mass or less. Preferably, it is 250 ppm by mass or less, more preferably 230 ppm by mass or less, still more preferably 200 ppm by mass or less, still more preferably 190 ppm by mass or less, and 180 ppm by mass. It is even more preferable that: By setting the phosphorus atom concentration in the polyamide resin to the lower limit value or more, the yellowness of the biopharmaceutical container can be lowered, and the color tone is further improved. Moreover, it exists in the tendency which the transparency of the container for biopharmaceuticals obtained improves more by making the phosphorus atom concentration in a polyamide resin below into an upper limit.
The molar ratio of phosphorus atom: calcium atom in the polyamide resin (A) used in the present invention is preferably a ratio of 1: 0.3 to 0.7, and a ratio of 1: 0.4 to 0.6 is preferred. More preferably, the ratio is 1: 0.45 to 0.55, and particularly preferably the ratio is 1: 0.48 to 0.52. The phosphorus atom and calcium atom contained in the polyamide resin (A) used in the present invention are preferably derived from calcium hypophosphite, respectively. By setting the molar ratio of phosphorus atom: calcium atom in the polyamide resin to the lower limit value or more, the haze of the resulting biopharmaceutical container tends to be lower. Moreover, it exists in the tendency for the haze of the biopharmaceutical container obtained to become lower by making the molar ratio of the phosphorus atom: calcium atom in a polyamide resin below an upper limit.
The measurement method of a phosphorus atom concentration and a calcium atom concentration follows the method as described in the Example mentioned later, respectively. However, when the device used in the embodiment is an abandoned number or the like, other devices having the same performance can be used. Hereinafter, the same applies to other measurement methods.

<< Physical properties of polyamide resin (A) >>
Relative viscosity is generally used as an index of the degree of polymerization of polyamide resin. The relative viscosity of the polyamide resin (A) used in the present invention is preferably 1.5 to 3.0 from the viewpoint of the melt viscosity of the layer (X) and the co-injection moldability. The lower limit of the relative viscosity is more preferably 1.6 or more, further preferably 1.8 or more, and particularly preferably 1.9 or more. The upper limit value of the relative viscosity is more preferably 2.8 or less, further preferably 2.5 or less, still more preferably 2.3 or less, and even more preferably 2.0 or less. By setting it as such a range, co-injection moldability improves and the effect that the container for biopharmaceuticals with high interlayer adhesiveness is obtained is exhibited.
The relative viscosity referred to here means that 0.2 g of polyamide resin is precisely weighed, dissolved in 20 mL of 96 mass% sulfuric acid aqueous solution at 25 ° C. with stirring, completely dissolved, and immediately, 5 mL of the solution is immediately added to the viscometer. Take the sample for 10 minutes in a constant temperature bath at 25 ° C., and then measure the drop time (t). Further, the dropping time (t0) of the 96% by mass sulfuric acid aqueous solution itself is measured in the same manner. The relative viscosity is calculated from t and t0 according to the following equation. More specifically, the method described in the examples is followed.
Relative viscosity = t / t0

<Method for producing polyamide resin (A)>
Next, an example of the manufacturing method of the polyamide resin (A) used by this invention is described. The polyamide resin (A) used in the present invention is preferably a polyamide resin produced by the method described below, but it goes without saying that the present invention is not limited to this.

In the method for producing the polyamide resin (A) used in the present invention, a diamine and a dicarboxylic acid are used in the presence of hypophosphite (for example, sodium hypophosphite and / or calcium hypophosphite, preferably calcium hypophosphite). Including 70% by mole of the diamine is metaxylylenediamine, and 30 to 60% by mole of the dicarboxylic acid is an α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms. 70 to 40 mol% is isophthalic acid.
In particular, by synthesizing in the presence of calcium hypophosphite, the phosphorus atom concentration in the obtained polyamide resin can be set to a predetermined value, the yellowness can be further reduced, and the calcium atom concentration is set to a predetermined range. And transparency can be further improved. In addition, a part or all of hypophosphite is phosphite (for example, calcium phosphite), phosphate (for example, calcium phosphate), polyphosphate (due to oxidation during polycondensation or secondary processing) For example, it changes to calcium polyphosphate). The ratio varies depending on the polycondensation conditions, the oxygen concentration during the polycondensation, and the like. Therefore, for example, even if the polyamide resin (A) used in the present invention contains a calcium atom or a phosphorus atom, calcium hypophosphite may not exist at all.
The polycondensation is usually a melt polycondensation method, in which a raw material diamine is added dropwise to a molten raw material dicarboxylic acid, the temperature is increased under pressure, and polymerization is performed while removing condensed water, or the raw material diamine and the raw material dicarboxylic acid. A method is preferred in which a salt composed of is heated in the presence of water under pressure and polymerized in a molten state while removing added water and condensed water.
In the present invention, hypophosphorous acid salt (for example, sodium hypophosphite and / or calcium hypophosphite, preferably calcium hypophosphite), and the concentration of phosphorus atoms contained in the polyamide resin (A) is 3 to 300 masses. It is preferable to add at a ratio of ppm. A more preferable range is a range in which the ratio is the same as the preferable range of the ratio of phosphorus atoms contained in the polyamide resin (A).

Further, at the time of polycondensation, another alkali metal compound may be added in combination with hypophosphite (for example, sodium hypophosphite and / or calcium hypophosphite, preferably calcium hypophosphite). By adding an alkali metal compound, it becomes possible to adjust the amidation reaction rate. An example of the alkali metal compound is sodium acetate. When blending an alkali metal compound, the molar ratio of alkali metal compound / hypophosphite (for example, sodium hypophosphite and / or calcium hypophosphite, preferably calcium hypophosphite) is 0.5 to 2.0. It is preferable that
Regarding other polymerization conditions, descriptions in JP-A-2015-098669 and International Publication WO2012 / 140785 can be referred to, and the contents thereof are incorporated in the present specification.
The details of diamine, dicarboxylic acid and the like are the same as those described in the above-mentioned polyamide resin, and the preferred ranges are also the same.

The layer (Y) in the present invention may contain a polyamide resin other than the polyamide resin (A). The polyamide resin other than the polyamide resin (A) may be an amorphous resin or crystalline. A resin may be used, but an amorphous resin is preferred.
Moreover, the layer (Y) in this invention can also be set as the structure which does not contain polyamide resins other than the said polyamide resin (A) substantially. “Substantially free” means, for example, that the amount of the polyamide resin other than the polyamide resin (A) in the layer (Y) is 1% by mass or less of the polyamide resin (A).

<Arbitrary layer>
In addition to the layer (X) and the layer (Y), the biopharmaceutical container of the present invention may contain any layer depending on the desired performance and the like. Examples of such an arbitrary layer include the above-mentioned adhesive layer.

<< Adhesive layer >>
In the biopharmaceutical container of the present invention, when a practical interlayer adhesive strength cannot be obtained between two adjacent layers, it is preferable to provide an adhesive layer between the two adjacent layers.
The adhesive layer preferably contains a thermoplastic resin having adhesiveness. Examples of the thermoplastic resin having adhesiveness include an acid-modified polyolefin obtained by modifying a polyolefin resin such as polyethylene or polypropylene with an unsaturated carboxylic acid such as acrylic acid, methacrylic acid, maleic acid, maleic anhydride, fumaric acid, and itaconic acid. Examples thereof include polyester-based thermoplastic elastomers mainly composed of a 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 polyolefin resin used as the layer (X) 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.

<Physical properties of containers for biopharmaceuticals>
The container for biopharmaceuticals of the present invention preferably has the following ranges for the physical properties of haze, total light transmittance, YI, and oxygen transmission rate (OTR), and particularly preferably has both of these physical properties.

<< Haze >>
In the biopharmaceutical container of the present invention, the haze (%) after heat treatment at 121 ° C. for 30 minutes is preferably 6% or less, more preferably 5% or less, and more preferably 4% or less. More preferably. The lower limit of the haze is preferably 0%, but even if it is 2% or more, and further 3% or more, it is a practical level. The method for measuring haze (%) after heat treatment at 121 ° C. for 30 minutes is measured according to the method described in the examples described later.

<< Total light transmittance >>
The total light transmittance (%) after heat treatment at 121 ° C. for 30 minutes of the biopharmaceutical container of the present invention is preferably 71% or more, more preferably 73% or more, and 75% or more. More preferably, it is 80% or more, more preferably 85% or more. The upper limit of the total light transmittance is preferably 100%, but is 95% or less, more preferably 93% or less, and particularly 90% or less is a practical level. The measuring method of the total light transmittance (%) after the heat treatment at 121 ° C. for 30 minutes is measured according to the method described in Examples described later.

<< YI >>
In the biopharmaceutical container of the present invention, the YI value after heat treatment at 121 ° C. for 30 minutes is preferably 8 or less, more preferably 6 or less, and even more preferably 5 or less. The lower limit value of the YI value is preferably 0, but is 2 or more, further 3 or more, and particularly 4 or more is sufficiently practical. The measurement method of the YI value after the heat treatment at 121 ° C. for 30 minutes is measured according to the method described in Examples described later.

<< Oxygen transmission rate (OTR) >>
The oxygen permeability (OTR) of the biopharmaceutical container of the present invention at 23 ° C., 100% relative humidity inside the biopharmaceutical container, and 50% relative humidity outside the biopharmaceutical container is 0.00030 mL / (0.21 atm · day · package) or less. The lower limit value of the oxygen permeability is preferably 0 mL / (0.21 atm · day · package), but it is sufficiently practical even at 0.00025 mL / (0.21 atm · day · package) or more. The measuring method of the said oxygen permeability is measured according to the method as described in the Example mentioned later.
The oxygen permeability (mL / (0.21 atm · day · package)) after heat treatment at 121 ° C. for 30 minutes of the biopharmaceutical container of the present invention is 0.00030 mL / (0.21 atm · day · package) or less. It is preferably 0.00028 mL / (0.21 atm · day · package) or less. The lower limit value of the oxygen permeability is preferably 0 mL / (0.21 atm · day · package), but it is sufficiently practical even at 0.00025 mL / (0.21 atm · day · package) or more. The method for measuring the oxygen transmission rate after the heat treatment is measured according to the method described in Examples described later.
In addition, the oxygen permeability of the biopharmaceutical container of the present invention at 23 ° C., relative humidity of 100% inside the biopharmaceutical container and 50% relative humidity outside the biopharmaceutical container, and the biopharmaceutical container of the present invention The difference in oxygen permeability after heat treatment at 121 ° C. for 30 minutes is preferably 0.00005 mL / (0.21 atm · day · package) or less, and 0.00003 mL / (0.21 atm · day · package) or less. More preferably, it is 0.00002 mL / (0.21 atm · day · package) or less.

<Method for producing biopharmaceutical container>
For the biopharmaceutical container of the present invention, a preferable molding method is selected depending on the use, and it is preferably produced by injection (injection) molding or injection blow (injection blow) molding.
By performing injection blow (injection blow) molding, the resulting biopharmaceutical container (injection blow molded product) can be hardly deformed even when sterilized under high-pressure steam, effectively suppressing whitening, and further barriering Sex can be kept high. In injection blow molding, a test tubular preform (parison) is first molded by injection molding, and then the preform is fitted in a final mold (blow mold) while being heated to some extent, and air is passed through the mouth. Can be formed into a bottle shape by inflating the preform, inflating the preform, closely contacting the mold, and solidifying by cooling.

A normal injection molding method can be applied to the preform molding.
For example, using a molding machine equipped with two or more injection machines and an injection mold, the material constituting the layer (X) and the material constituting the layer (Y) are passed from each injection cylinder through a mold hot runner. By injecting into the cavity, a multilayer preform corresponding to the shape of the injection mold can be manufactured.
First, the material constituting the layer (X) is injected from the injection cylinder, and then the material constituting the layer (Y) is injected simultaneously from the resin constituting the layer (X) from another injection cylinder. A multilayer preform having a three-layer structure X / Y / X can be manufactured by injecting a necessary amount of the resin constituting X) to fill the cavity.
Alternatively, first, the material constituting the layer (X) is injected, then the material constituting the layer (Y) is injected alone, and finally the necessary amount of the material constituting the layer (X) is injected. By filling the mold cavity, a multilayer preform with a five-layer structure X / Y / X / Y / X can be produced.
The biopharmaceutical container used in the present invention may be stretched, but is usually an unstretched body.

  The mold corresponding to the final shape described above is preferably heated to 120 to 170 ° C., more preferably 130 to 160 ° C., and at the time of blowing, the outer wall of the molded body is brought into contact with the inner surface of the mold for a predetermined time.

  As another method for producing a blow molded article, the multilayer preform is formed into a primary blow molded article having a size larger than that of the final blow molded article using a primary stretch blow mold, and then the primary blow molded article is heated and shrunk. Then, a two-stage blow molding may be employed in which a stretch blow molding is performed using a secondary mold to obtain a final blow molded body. According to this blow molded article manufacturing method, the bottom of the blow molded article is sufficiently stretched and thinned to obtain a blow molded article excellent in hot filling, deformation of the bottom during heat sterilization, and impact resistance. .

The biopharmaceutical container of the present invention may be coated with an inorganic or inorganic oxide vapor-deposited film or an amorphous carbon film.
Examples of the inorganic substance or inorganic oxide include aluminum, alumina, silicon oxide, and the like. The vapor deposition film of an inorganic substance or an inorganic oxide can shield eluents such as acetaldehyde and formaldehyde from the biopharmaceutical container of the present invention. The formation method of a vapor deposition film is not specifically limited, For example, physical vapor deposition methods, such as a vacuum evaporation method, sputtering method, and an ion plating method, Chemical vapor deposition methods, such as PECVD, etc. are mentioned. The thickness of the deposited film is preferably 5 to 500 nm, more preferably 5 to 200 nm, from the viewpoints of gas barrier properties, light shielding properties, bending resistance, and the like.
The amorphous carbon film is a diamond-like carbon film, which is a hard carbon film also called i-carbon film or hydrogenated amorphous carbon film. Examples of the method for forming the film include a method in which the inside of the hollow molded body is evacuated by evacuation, a carbon source gas is supplied thereto, and plasma generating energy is supplied by supplying plasma generating energy, Thereby, an amorphous carbon film can be formed on the inner surface of the biopharmaceutical container. The amorphous carbon film not only can remarkably reduce the permeability of low-molecular inorganic gases such as oxygen and carbon dioxide, but can also suppress the sorption of various low-molecular organic compounds having an odor. The thickness of the amorphous carbon film is preferably 50 to 5000 nm from the viewpoint of the effect of suppressing the sorption of the low-molecular organic compound, the effect of improving the gas barrier property, the adhesion to plastic, the durability and the transparency.

<Specific examples of biopharmaceutical containers>
The type of the biopharmaceutical container of the present invention is not particularly defined, and may be a known one such as a vial, a syringe, an ampoule or the like. The biopharmaceutical container in the present invention is preferably a vial.

Next, the structure of the biopharmaceutical container will be described with reference to FIG. 1, taking a vial as an example. It goes without saying that the biopharmaceutical container in the present invention is not limited to that shown in FIG.
FIG. 1 is a schematic view showing the structure of a vial as an example of the container of the present invention, wherein 1 is a vial, 2 is a packing, 3 is a cap, and 4 is a pharmaceutical product. In the present invention, by using the container having the above-described layer configuration for the vial 1, it is possible to prevent whitening even after the medicine is stored and stored for a certain period of time, and the medicinal effect of the stored medicine can be maintained high. it can.
The height (H) of the vial 1 of the present invention is preferably 10 to 80 mm, and more preferably 20 to 60 mm. The length (H) of the vial in the present invention refers to the height from the bottom to the opening as shown in FIG.
It is preferable that the main body of the vial 1 of the present invention (portion where the pharmaceutical product is stored) is cylindrical. When the main body of the vial 1 of the present invention is cylindrical, the outer diameter (D) is preferably 2 to 40 mm, and more preferably 5 to 30 mm. The outer diameter (D) of the vial in the present invention refers to the outer diameter of a cylinder when the body is cylindrical, for example.
The portion of the biopharmaceutical container of the present invention other than the pharmaceutical is preferably filled with nitrogen.
The packing 2 is not particularly defined as long as it can seal the vial. Examples of the material include rubber.
The cap 3 holds the packing and is usually formed from metal. Further, by adopting a valve seal structure, it is possible to adopt a structure that does not use packing.
In addition, the biopharmaceutical container of the present invention may be provided with a structure having a screw opening at the opening of the vial, and a corresponding cap may be used.

The biopharmaceutical container of the present invention is preferably sterilized. The sterilization treatment is preferably a sterilization treatment using high energy radiation (for example, gamma rays and electron beams) or a sterilization treatment using ethylene oxide gas (EOG). In addition, the biopharmaceutical container of the present invention is preferably subjected to a heat sterilization treatment.
The heat sterilization temperature is preferably 100 ° C. or higher, more preferably 110 ° C. or higher. The upper limit of the heat sterilization temperature may be, for example, 150 ° C. or less. The heat sterilization treatment is preferably 10 minutes to 1 hour.

<Biopharmaceuticals>
The biopharmaceutical in the present invention is not particularly defined as long as it contains protein-derived medicinal ingredients, and biopharmaceuticals known to those skilled in the art can be widely used. Specifically, it is preferably a biopharmaceutical selected from the group consisting of antibodies, hormones, enzymes, and complexes containing these.
Specific examples of biopharmaceuticals include adrenergic antagonists, analgesics, anesthetics, angiotensin antagonists, anti-inflammatory drugs, anxiolytics, antiarrhythmic drugs, anticholinergics, anticoagulants, antiepileptics, antipruritics, anti Histamine, anti-neoplastic and antimetabolite, anti-neoplastic and antimetabolite, antiplastic, anti-ulcer, bisphosphonate, bronchodilator, cardiotonic, cardiovascular, centrally acting α2 stimulant, contrast agent , Converting enzyme inhibitors, skin drugs, diuretics, drugs for erectile dysfunction, drugs for abuse, endothelin antagonists, hormones and cytokines, hypoglycemic drugs, drugs for promoting uric acid excretion and gout, immunosuppressants, lipids Descent drugs, various drugs, psychotherapeutic drugs, renin inhibitors, serotonin antagonists, steroids, sympathomimetics, thyroid and antithyroid drugs, and vasodilators, vasopeptida Inhibitor, insulin, blood factor, thrombolytic drug, hormone, hematopoietic growth factor, interferon, interleukin product, vaccine, monoclonal antibody, tumor necrosis factor, therapeutic enzyme, antibody-drug complex, biosimilar, Erythropoietin, immunoglobulins, somatic cells, gene therapy, tissues, and therapeutic recombinant proteins are included.
The biopharmaceutical may be liquid, solid, or a mixture of liquid and solid.

<Preservation method of biopharmaceuticals>
The present invention also includes a layer (X) mainly composed of at least one polyolefin resin and a layer (Y) mainly composed of a polyamide resin (A), wherein the polyamide resin (A) is derived from a diamine. And 70 mol% or more of the structural unit derived from dicarboxylic acid is derived from metaxylylenediamine, and 30 to 60 mol% of the structural unit derived from dicarboxylic acid is composed of Using a container derived from an α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms and 70 to 40 mol% derived from isophthalic acid, storing a biopharmaceutical containing a protein-derived medicinal component A method for preserving biopharmaceuticals is disclosed.
The details of the container are the same as those of the biopharmaceutical container described above. The details of the biopharmaceutical are the same as described above.

  The biopharmaceutical is preferably filled and stored in a container so that the filling rate is more than 0% by volume and 70% by volume or less. The container is preferably filled with nitrogen together with the biopharmaceutical. The storage temperature of the biopharmaceutical can be appropriately determined depending on the type of the biopharmaceutical, but can be set to 2 to 8 ° C., for example.

<Articles containing biopharmaceuticals in containers for biopharmaceuticals>
The present invention also discloses a biopharmaceutical container of the present invention and an article containing the biopharmaceutical in the biopharmaceutical container. Being in a container means a state in which a biopharmaceutical is stored or enclosed in the container. The details of the biopharmaceutical container and the biopharmaceutical are the same as described above. The container is preferably filled with nitrogen along with the biopharmaceutical. The biopharmaceutical is preferably sealed in the container so that the amount of the biopharmaceutical is more than 0% by volume and 70% by volume or less.

<Production method for articles containing biopharmaceuticals in containers>
The present invention also includes a layer (X) mainly composed of at least one polyolefin resin and a layer (Y) mainly composed of a polyamide resin (A), wherein the polyamide resin (A) is derived from a diamine. And 70 mol% or more of the structural unit derived from dicarboxylic acid is derived from metaxylylenediamine, and 30 to 60 mol% of the structural unit derived from dicarboxylic acid is composed of Encapsulating a biopharmaceutical containing a protein-derived medicinal ingredient in a container derived from an α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms and 70 to 40 mol% derived from isophthalic acid, Disclosed is a method for manufacturing an article containing a biopharmaceutical in a container.

  The details of the container are the same as those of the biopharmaceutical container described above. The details of the biopharmaceutical are the same as described above.

When enclosing the biopharmaceutical in the container, it is preferable to enclose the biopharmaceutical so that the amount of the biopharmaceutical is more than 0% by volume and 70% by volume or less. The container is preferably filled with nitrogen together with the biopharmaceutical. The temperature at the time of encapsulating the biopharmaceutical can be appropriately determined depending on the type of the biopharmaceutical, but can be set to 2 to 8 ° C., for example. When encapsulating the biopharmaceutical in the container, it is preferably performed under aseptic conditions. In addition, it is preferable to sterilize the container before enclosing the biopharmaceutical in the container.
Furthermore, the article containing the biopharmaceutical in the container according to the present invention may be stored in the case together with the article. Cases include paper and plastic boxes. As the case, a case for storing at a temperature different from the outside, such as a cold insulation case or a constant temperature case, is also preferably used.

  The present invention will be described more specifically with reference to the following examples. The materials, amounts used, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention is not limited to the specific examples shown below.

(1) Relative viscosity 0.2 g of polyamide resin was precisely weighed and dissolved in 20 mL of 96 mass% sulfuric acid aqueous solution at 25 ° C with stirring. After the polyamide resin was completely dissolved, 5 mL of the solution was quickly taken into a Cannon Fenceke viscometer, and allowed to stand in a constant temperature bath at 25 ° C. for 10 minutes, and then the drop time (t) was measured. The drop time (t0) of the 96 mass% sulfuric acid aqueous solution itself was also measured in the same manner. The relative viscosity was calculated from t and t0 according to the following formula.
Relative viscosity = t / t0

(2) Heat treatment The container for biopharmaceuticals was heat-treated (retort) at 121 ° C. for 30 minutes using an autoclave (product name: “SR-240” manufactured by Tommy Seiko Co., Ltd.). The heat treatment time does not include the temperature raising time and the cooling time.

(3) Oxygen permeability (OTR) of biopharmaceutical containers
For the biopharmaceutical container before the heat treatment, the oxygen transmission rate (OTR) at 23 ° C., relative humidity 100% inside the biopharmaceutical container, and relative humidity 50% outside the biopharmaceutical container is in accordance with ASTM D3985. The oxygen permeability was measured using an oxygen permeability measuring device (manufactured by MOCON, product name: “OX-TRAN (registered trademark) 2/61”). It shows that oxygen barrier property is so favorable that a measured value is low.
The oxygen permeability of the biopharmaceutical container after the heat treatment was also measured.

(4) Transparency of biopharmaceutical containers (haze and total light transmittance)
The side part of the biopharmaceutical container after the heat treatment was cut out to measure haze and total light transmittance. The haze was measured according to JIS K7136. Moreover, the measurement of the total light transmittance was performed according to JIS K7375. A color / turbidity measuring device (manufactured by Nippon Denshoku Industries Co., Ltd., product name: “COH-300A”) was used as a measuring device. The thickness of the side part of the biopharmaceutical container at the measurement location was measured and shown as a value converted to a thickness of 300 μm.

(5) Color tone of the biopharmaceutical container after the heat treatment The side part of the biopharmaceutical container after the heat treatment was cut out to measure the yellowness (YI value). A color / turbidity measuring device (manufactured by Nippon Denshoku Industries Co., Ltd., product name: “COH-300A”) was used as a measuring device.

(6) Oil resistance test of biopharmaceutical container 10 mL of Nissin MCT oil (100% medium chain fatty acid triglyceride (fatty acid glyceride having 8 to 12 carbon chains)) is poured into the biopharmaceutical container before the heat treatment, Stored at 40 ° C. for 6 months. The case where there was no change in the appearance of the biopharmaceutical container was marked with ○, and the case where oil leaked from the biopharmaceutical container was marked with x.

(7) Measuring method of phosphorus atom concentration and calcium atom concentration Put 0.2 g of polyamide resin and 8 mL of 35 mass% nitric acid aqueous solution in a TFM-modified PTFE (manufactured by 3M) container and use ETHOS One by Milestone General Microwave decomposition was performed at a temperature of 230 ° C. for 30 minutes. The decomposition solution was made up to volume with ultrapure water to obtain an ICP measurement solution. The phosphorus atom concentration and calcium atom concentration were measured using ICPE-9000 manufactured by Shimadzu Corporation.

(8) Biopharmaceutical storage test (antibody activity retention rate)
(Coupling ratio measurement method)
Using an isothermal titration calorimeter, 5 μM of an antigen solution (manufactured by Biologic Industries Ltd., FGF1-Mouse) was filled on the cell side, and the binding ratio at 25 ° C. was measured while 10 μL of the antibody solution was dropped into the cell.
(Preservation test)
The biopharmaceutical container before the heat treatment is filled with 1 cc (1 mL) of ANTI FGF1, Monoclonal Antibody (mAb1), manufactured by Wako Pure Chemical Industries, Ltd., adjusted to 50 μM as an antibody solution, and 8 ° C. and 50% relative humidity. The sample was stored for 180 days under the following conditions. As a solvent, a phosphate buffer (pH 7.4) manufactured by Inbiogen was used. The binding ratio of the antibody solution before storage test and after storage for 180 days was measured by the above method, and the antibody activity retention before and after storage was determined by the following formula.
Antibody activity retention rate (%)
= (Binding ratio of antibody solution after storage for 180 days / Binding ratio of antibody solution before storage test) × 100

<Example 1>
A polyamide resin shown in Table 1 was synthesized according to the following method.
In a reaction vessel equipped with a stirrer, a partial condenser, a full condenser, a thermometer, a dropping funnel and a nitrogen introduction tube, and a strand die, 6,000 g (41.06 mol) of adipic acid and 6,821 g of isophthalic acid were precisely weighed ( 41.06 mol), 10.04 g of calcium hypophosphite (Ca (H ₂ PO ₂ ) ₂ ) (175 mass ppm as the phosphorus atom concentration in the polyamide resin), 7.26 g of sodium acetate, and after sufficient nitrogen substitution, Nitrogen was charged to an internal pressure of 0.4 MPa, and the system was heated to 190 ° C. with stirring in a small amount of nitrogen. The molar ratio of sodium acetate / calcium hypophosphite was 1.50.
To this, 11,185 g (82.12 mol) of metaxylylenediamine was added dropwise with stirring, and the inside of the system was continuously heated while removing the condensed water to be produced. After the addition of metaxylylenediamine was completed, the internal temperature was raised, and when the temperature reached 265 ° C., the pressure in the reaction vessel was reduced, and the internal temperature was further raised to continue the melt polycondensation reaction at 270 ° C. for 10 minutes. Thereafter, the inside of the system was pressurized with nitrogen, and the obtained polymer was taken out from the strand die and pelletized to obtain about 21 kg of polyamide resin (A1) pellets. The relative viscosity of the polyamide resin (A1) was 1.95.

Next, under the following conditions, the material constituting the layer (X) is injected from the injection cylinder, and the material constituting the layer (Y) is injected from another injection cylinder simultaneously with the resin constituting the layer (X). Further, a required amount of resin constituting the layer (X) was injected to fill the cavity, thereby obtaining a multilayer preform (5.1 g) having a three-layer structure of X / Y / X.
In addition, as a resin constituting the layer (X), a cycloolefin polymer (manufactured by Nippon Zeon Co., Ltd., product name: “ZEONEX (registered trademark) 690R”) was used. As the resin constituting the layer (Y), the polyamide resin (A1) 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 biopharmaceutical container.

<< Biopharmaceutical container shape >>
Total length 45mm, outer diameter 24mmφ, wall thickness (total thickness of biopharmaceutical container, outer layer (X), inner layer (X) and intermediate layer (Y) total thickness) 1.0mm, outer layer (X) thickness 600μm, inner layer ( X) The thickness was 200 μm, and the intermediate layer (Y) thickness was 200 μm. In the production of the biopharmaceutical container, injection blow molding was performed using an injection blow integrated molding machine (manufactured by Nissei ASB Machine Co., Ltd., model: “ASB12N / 10T”, 4 pieces).
(Molding conditions for biopharmaceutical containers)
Injection cylinder temperature for layer (X): 300 ° C
Injection cylinder temperature for layer (Y): 280 ° C
Injection resin flow path temperature: 300 ° C
Blow temperature: 150 ° C
Blow mold cooling water temperature: 40 ° C

<Example 2>
In Example 1, it adjusted so that the molar ratio of adipic acid and isophthalic acid might be set to 40:60, and others performed similarly and obtained the polyamide resin pellet (A2). The relative viscosity of the polyamide resin (A2) was 1.94.

  A biopharmaceutical container was produced in the same manner as in Example 1 except that the polyamide resin (A2) was used instead of the polyamide resin (A1).

<Example 3>
In Example 1, it adjusted so that the molar ratio of adipic acid and isophthalic acid might be set to 60:40, and others performed similarly and obtained the polyamide resin pellet (A3). The relative viscosity of the polyamide resin (A3) was 1.94.

  A biopharmaceutical container was produced in the same manner as in Example 1 except that the polyamide resin (A3) was used instead of the polyamide resin (A1).

<Example 4>
In Example 1, sodium hypophosphite was used as the hypophosphite, and others were performed in the same manner to obtain polyamide resin (A4) pellets. The relative viscosity of the polyamide resin (A4) was 1.95.

  A biopharmaceutical container was produced in the same manner as in Example 1 except that the polyamide resin (A4) was used instead of the polyamide resin (A1).

<Example 5>
In Example 1, the amount of calcium hypophosphite added was changed as shown in Table 1, and the others were performed in the same manner to obtain polyamide resin (A5) pellets. The relative viscosity of the polyamide resin (A5) was 1.93.

  A biopharmaceutical container was produced in the same manner as in Example 1 except that the polyamide resin (A5) was used instead of the polyamide resin (A1).

<Example 6>
In Example 1, the amount of calcium hypophosphite added was changed as shown in Table 1, and the others were carried out in the same manner to obtain polyamide resin (A6) pellets. The relative viscosity of the polyamide resin (A6) was 1.93.

  A biopharmaceutical container was produced in the same manner as in Example 1 except that the polyamide resin (A6) was used instead of the polyamide resin (A1).

<Examples 7 to 9>
The resin constituting the layer (X) was changed to a cycloolefin polymer (manufactured by Nippon Zeon Co., Ltd., product name: “ZEONEX (registered trademark) 690R”) and a cycloolefin copolymer (TOPAS ADVANCED POLYMERS GmbH, product name: A biopharmaceutical container was produced in the same manner as in Examples 1 to 3, except that "TOPAS (registered trademark) 6013S-04") was used.

<Examples 10 to 12>
The resin constituting the layer (X) was changed to a cycloolefin polymer (manufactured by ZEON Corporation, product name: “ZEONEX (registered trademark) 690R”), and a polypropylene polymer (manufactured by BOREALIS, product name: “Bormed RB845MO”). “)” Was used in the same manner as in Examples 1 to 3, except that a biopharmaceutical container was produced.

<Comparative Example 1>
In Example 1, it adjusted so that the molar ratio of adipic acid and isophthalic acid might be set to 94: 6, and others were performed similarly and the polyamide resin pellet (A7) of the comparative example 1 was obtained. The relative viscosity of the polyamide resin (A8) was 2.65.

  A biopharmaceutical container was produced in the same manner as in Example 1 except that the polyamide resin (A7) was used instead of the polyamide resin (A1).

<Comparative example 2>
Instead of polyamide resin (A1), N-MXD6 (Mitsubishi Gas Chemical Co., Ltd., product name: “MX nylon S6007”, relative viscosity = 2.65) consisting of a metaxylylenediamine unit and an adipic acid unit is used. A biopharmaceutical container was produced in the same manner as in Example 1 except that.

<Comparative Example 3>
Polyhexamethylene isophthalamide / polyhexamethylene terephthalamide copolymer (manufactured by DSM Japan Engineering Plastics Co., Ltd., product name: “Novamid (registered trademark) X21”) instead of polyamide resin (A1) A biopharmaceutical container was produced in the same manner as in Example 1 except that was used.

<Comparative example 4>
A biopharmaceutical container in the same manner as in Example 11 except that an ethylene-vinyl alcohol copolymer (manufactured by Kuraray Co., Ltd., product name: “EVAL (registered trademark) F171B”) was used instead of the polyamide resin (A1). Manufactured.

<Comparative Example 5>
In Example 1, a single-layer biopharmaceutical container consisting only of the layer (X) was produced. The thickness of the layer (X) was 1000 μm.

About the biopharmaceutical container obtained in Examples 1-12 and Comparative Examples 1-5, the oxygen transmission rate (OTR) was measured by the said method. Further, haze, total light transmittance, color tone (YI), and oxygen transmittance (OTR) after the heat treatment were measured. Furthermore, the oil resistance test was implemented about the obtained container for biopharmaceuticals. In addition, antibody activity retention was measured.
The results are shown in Tables 1 to 3.

In Tables 1 to 3, abbreviations and the like are as follows.
* 1: Amount in diamine unit (mol%)
* 2: Amount in dicarboxylic units (mol%)
COP: cycloolefin polymer COC: cycloolefin copolymer PP: polypropylene polymer N-6I / 6T: polyhexamethylene isophthalamide / polyhexamethylene terephthalamide copolymer EVOH: ethylene-vinyl alcohol copolymer

The biopharmaceutical containers of Comparative Examples 1 and 2 had high haze after heat treatment and low total light transmittance, resulting in poor transparency after heat treatment.
Moreover, in the comparative example 3 using a polyhexamethylene isophthalamide / polyhexamethylene terephthalamide copolymer, when a biopharmaceutical was preserve | saved, the fall of the medicinal effect after storage was recognized. Also, the oxygen barrier property was insufficient before and after the heat treatment.
Furthermore, in Comparative Example 4 using an ethylene-vinyl alcohol copolymer, when the biopharmaceutical was stored, a decrease in medicinal effect after storage was observed. In addition, the oxygen barrier property after the heat treatment was insufficient.
Furthermore, in Comparative Example 5 in which only the cycloolefin polymer was used, when the biopharmaceutical was stored, a decrease in medicinal effect after storage was observed. In addition, both before and after heat treatment results in insufficient oxygen barrier properties,

On the other hand, when biopharmaceuticals were preserve | saved using the container for biopharmaceuticals of Examples 1-12, it turned out that the fall of the medicinal effect after storage is suppressed.
Furthermore, it turned out that the container for biopharmaceuticals of Examples 1-12 is excellent in transparency also after heat processing. In the examples, oxygen barrier properties were also excellent.
In particular, when the polyamide resin contains phosphorus atoms in a proportion of 20 to 200 ppm by mass and calcium atoms in a proportion of a molar ratio of phosphorus atoms: calcium atoms of 1: 0.3 to 0.7, after heat treatment Was obtained, and a biopharmaceutical container having a lower YI value after the heat treatment was obtained.
In addition, Examples 10 to 12 resulted in slightly inferior transparency after heat treatment as compared to other examples, but the content is sufficiently visible, and even after heat treatment, It was excellent in oxygen barrier properties. In addition, the container was found to be excellent in oil resistance.
In addition, the polyamide resins (A1) to (A6) used in Examples 1 to 12 were found to be amorphous with a crystal melting enthalpy ΔHm of approximately 0 J / g during the temperature rising process.

  The biopharmaceutical container of the present invention has transparency suitable as a biopharmaceutical container for preserving protein-derived medicinal ingredients. In addition, a decrease in drug efficacy after storage of biopharmaceuticals is suppressed. In addition, it has excellent oxygen barrier properties. Therefore, the biopharmaceutical can be stored for a long period of time, and the contents can be visually recognized even after the heat sterilization treatment, and the convenience of the customer can be improved as a substitute for the glass container.

1 Vial 2 Packing 3 Cap 4 Pharmaceutical

Claims (18)

It has a layer (X) mainly composed of at least one kind of polyolefin resin and a layer (Y) mainly composed of polyamide resin (A),
The polyamide resin (A) is composed of a structural unit derived from a diamine and a structural unit derived from a dicarboxylic acid, 70 mol% or more of the structural unit derived from the diamine is derived from metaxylylenediamine, and derived from the dicarboxylic acid. Preserving protein-derived medicinal ingredients, in which 30 to 60 mol% of the structural unit is derived from α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms and 70 to 40 mol% is derived from isophthalic acid. For biopharmaceuticals. The container for biopharmaceuticals according to claim 1, wherein the polyamide resin (A) contains a calcium atom. The container for biopharmaceuticals according to claim 2, wherein the calcium atom contained in the polyamide resin (A) is derived from calcium hypophosphite. The container for biopharmaceuticals of any one of Claims 1-3 in which the said polyamide resin (A) contains a phosphorus atom in the ratio of 3-300 mass ppm. The said polyamide resin (A) contains a phosphorus atom in the ratio of 20-200 mass ppm, and contains a calcium atom in the ratio from which the molar ratio of a phosphorus atom: calcium atom will be 1: 0.3-0.7. The biopharmaceutical container according to 1 or 3. The biopharmaceutical container according to any one of claims 1 to 5, wherein the polyolefin resin is at least one selected from the group consisting of a cycloolefin polymer and a polypropylene polymer. The biopharmaceutical container according to any one of claims 1 to 6, wherein 30 to 60 mol% of the structural unit derived from dicarboxylic acid is a structural unit derived from adipic acid. The biopharmaceutical container is composed of at least three layers, the inner layer and the outer layer are the layer (X), and at least one of the intermediate layers is the layer (Y). The biopharmaceutical container according to item. The biopharmaceutical container according to any one of claims 1 to 8, wherein a thickness of the layer (Y) is 2 to 40% with respect to a total thickness of the biopharmaceutical container. The biopharmaceutical container according to any one of claims 1 to 9, wherein the biopharmaceutical container is a vial. The biopharmaceutical container according to any one of claims 1 to 10, wherein the protein-derived medicinal component is selected from the group consisting of an antibody, a hormone, an enzyme, and a complex containing these. An article comprising the biopharmaceutical container according to any one of claims 1 to 11 and the biopharmaceutical in the biopharmaceutical container. It has a layer (X) mainly composed of at least one kind of polyolefin resin and a layer (Y) mainly composed of polyamide resin (A),
The polyamide resin (A) is composed of a structural unit derived from a diamine and a structural unit derived from a dicarboxylic acid, 70 mol% or more of the structural unit derived from the diamine is derived from metaxylylenediamine, and derived from the dicarboxylic acid. 30 to 60 mol% of the structural unit is derived from an α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70 to 40 mol% is derived from isophthalic acid, using a protein derived from protein A method for preserving a biopharmaceutical comprising storing the biopharmaceutical containing the ingredient. The biopharmaceutical storage method according to claim 13, wherein the container is the biopharmaceutical container according to any one of claims 2 to 10. The method for preserving a biopharmaceutical according to claim 13 or 14, wherein the protein-derived medicinal component is selected from the group consisting of an antibody, a hormone, an enzyme, and a complex containing these. It has a layer (X) mainly composed of at least one kind of polyolefin resin and a layer (Y) mainly composed of polyamide resin (A),
The polyamide resin (A) is composed of a structural unit derived from a diamine and a structural unit derived from a dicarboxylic acid, 70 mol% or more of the structural unit derived from the diamine is derived from metaxylylenediamine, and derived from the dicarboxylic acid. 30 to 60 mol% of the structural unit is derived from α, ω-linear aliphatic dicarboxylic acid having 4 to 20 carbon atoms, and 70 to 40 mol% is derived from isophthalic acid, and a protein-derived medicinal component is added to the container. A method for producing an article containing a biopharmaceutical in a container, comprising enclosing the biopharmaceutical containing. The manufacturing method according to claim 16, wherein the container is the biopharmaceutical container according to any one of claims 2 to 10. The production method according to claim 16 or 17, wherein the protein-derived medicinal component is selected from the group consisting of an antibody, a hormone, an enzyme, and a complex containing these.

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