JPH0549673A - Container for liquid drug - Google Patents

Abstract

PURPOSE:To provide the container for liquid drugs which has a high gas barrier property, does not generate pinholes, etc., is strong to friction, impact and bending and prevents the deterioration in the properties of the liquid drugs to be enclosed therein. CONSTITUTION:This container for the liquid drugs consists of a composite sheet or film consisting of a ceramic layer as an intermediate layer and org. polymer layers as an inside layer and outside layer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug solution container suitable for preventing the drug solution contained therein from being altered by oxygen, carbon dioxide gas or the like.

[0002]

2. Description of the Related Art Some infusions and other medicinal liquids are modified by air such as amino acid preparations, but the material for the container for storing and storing the medicinal liquid is lightweight, easy to handle, etc. From the viewpoint of soft polyvinyl chloride,
In many cases, soft polymers having excellent flexibility and transparency such as polyethylene and ethylene-vinyl acetate copolymer are desired, and these polymers do not have sufficient barrier properties against gas, particularly oxygen, and some measures are required. As a conventional measure or attempted countermeasure, a reducing agent such as sulfite is added to the liquid medicine, and the liquid medicine container is further wrapped with a gas barrier outer packaging material (film, sheet, blister, etc.). ,
Further, in order to enhance the effect of wrapping with the packaging material, there is a presence of a deoxidizer such as a reducing iron compound between the drug solution container and the outer package, and the drug solution container itself has a gas barrier property. is there. However, since the introduction amount of the reducing agent is limited due to consideration of the living body to be introduced, the effect is temporary and it is not suitable for long-term storage. In the current situation, there is no packaging material with sufficient performance and practicability in the case of packaging with the gas barrier packaging material of (as is the case). In order to deal with the presence of the oxygen scavenger in the packaging material, there is a problem that a step of inserting the oxygen scavenger separately is required and the manufacturing process becomes complicated. In the case where the liquid medicine container itself, which is considered to be the most ideal form, has gas barrier properties, so-called barrier materials such as vinylidene chloride-based polymers, acrylonitrile-based polymers, ethylene vinyl alcohol copolymers, polymethaxylylene adipamide, etc. A single-layer film (sheet) or a multi-layer film (sheet) of soft polyvinyl chloride, polyethylene, etc. has been proposed for pharmaceutical liquid medicines, but with vinylidene chloride-based polymers, pinholes (barrier property) due to bending are formed. However, it is fatal that the polymers of the latter three types have reduced barrier properties due to water absorption (it is inevitable that water will be absorbed by contact with pharmaceutical liquids or by high-pressure steam sterilization). It is a drawback.

In addition, as a technique which has been attracting attention in recent years, there is the use of a ceramic layer having a high gas barrier property. For example, in Japanese Patent Laid-Open No. 3-4870, "Transparent with a thin ceramic layer provided on one or both sides of a plastic film. "Container for infusion agent using a laminated film" is described.
When this was actually tried, it was pointed out that the ceramic layer is brittle, and cracks and pinholes are easily generated in the ceramic layer due to external forces such as friction, bending, and impact, and the gas barrier property cannot be maintained. The reality is that there are restrictions on conversion.

[0004]

DISCLOSURE OF THE INVENTION The present invention is intended to provide a container which solves the above-mentioned various problems in performance or production associated with prevention of alteration of the contained pharmaceutical liquid agent.

[0005]

Means for Solving the Problems The present invention is achieved by a container for a medicinal solution which comprises a composite sheet or film comprising at least three layers having a ceramic layer as an intermediate layer and an organic polymer layer as an inner layer and an outer layer.

In the present invention, the ceramic layer is 0.00
1 to 1.0 μm thick silicon oxide layer, the outer layer is biaxially oriented polyethylene terephthalate or polybutylene terephthalate film, and the inner layer sheet or film is high pressure low density polyethylene, linear low density polyethylene, ethylene. It is preferably made of at least one material selected from the group of vinyl acetate copolymer, polypropylene or polybutene-1.

As a result of further studies on the effective use of the ceramic layer, the inventors have found that the presence of the ceramic layer between the layers of the organic polymer significantly reduces the adverse effect of external force. Came to.

Suitable ceramics used in the present invention are silicon oxide and alumina (aluminum oxide Al ₂ O ₃ ), particularly the former in terms of processability, adhesion to organic polymer, gas barrier property, transparency and the like. It shows a good balance and is optimal. Silicon oxide (Si
In the case of O _x ), silicon monoxide (X
= 1) and silicon dioxide (X = 2) are both conceivable, but either is acceptable. For example, when vapor deposition processing is performed using silicon monoxide, X is often about 1.5, and it is not possible to specify dioxide and monoxide.

Next, the organic polymer in the present invention means an organic polymer capable of forming a sheet (film) and is not particularly limited. Preferred specific examples include soft polyvinyl chloride containing a plasticizer such as di (2-ethylhexyl) phthalate, high-pressure low-density polyethylene, butene-1, hexene-1, octene-1,4-methylpentene-1. Linear low-density polyethylene, high-density polyethylene containing α-olefins such as
Propylene, polybutene-1, poly-4-methylpentene-1, ethylene vinyl acetate copolymer, ethylene methyl methacrylate copolymer, ethylene vinyl alcohol copolymer, polyvinylidene chloride, polyvinylidene fluoride, polyacrylonitrile, 1,2-polybutadiene, polystyrene Block copolymer of ethylene propylene copolymer, block copolymer of polystyrene and ethylene butylene copolymer, nylon 6, nylon 8, nylon 11, nylon 12, nylon 46,
Nylon 66, Nylon 610, Polymethaxylylene adipamide, Polyurethane, Polyethylene terephthalate, Polybutylene terephthalate, Polyethylene-2,
6-naphthalate, poly-1,4-cyclohexylene dimethylene terephthalate, polycarbonate, polyphenylene sulfide, polyarylate, polysulfone, polyether sulfone, etc. and melt-molding into sheets and films such as organic polymers based on these Such organic polymers can be used, and one or more selected from these organic polymer groups can be used in an appropriate combination.

As a method for producing the composite sheet or film in the present invention, a ceramic layer is formed on one side or both sides of the organic polymer film or sheet by vacuum deposition method, ion plating method, sputtering method, sol-gel method, chemical vapor deposition method and the like. After being formed by a technique, it is common to laminate it on the surface of the ceramic layer, that is, with another organic polymer film so that the ceramic layer serves as an intermediate layer. With such a configuration, the ceramic layer becomes resistant to friction, bending, impact and the like. Here, the ceramic layer varies depending on the required gas barrier property and transparency and the type of the organic polymer sheet (film) used, but in general, it is preferably 0.001 to 1.0 μm per surface, and more preferably 0.005 per side. 0.8
μm is suitable. The thickness of this ceramic layer is 0.00
When it is less than 1 μm, the gas barrier property is not effective.
If it is thicker than 0 μm, it becomes inflexible. There is a risk that resistance to shock will be lost. Furthermore, as the organic polymer sheet (film) on which the ceramic layer is first formed, it is preferable that it has excellent heat resistance and dimensional stability due to the processability and stability when forming the ceramic layer or during high-pressure steam sterilization, and it is also flexible. Considering the transparency and transparency, it is 0.
A biaxially stretched film made of polyethylene terephthalate or polybutylene terephthalate having a thickness of 5 to 20 μm, preferably 1 to 15 μm is most suitable. On the other hand, as an organic polymer sheet (film) to be attached to this film, especially the innermost layer of the composite sheet (film) (inner wall of the container) has flexibility, transparency, bag-making property (heat sealing property), etc. The most suitable is a non-stretched sheet (film) made of an olefin polymer such as high-pressure low-density polyethylene, linear low-density polyethylene, ethylene vinyl acetate copolymer, polypropylene, and polybutene-1. The total thickness of the composite sheet (film) is 20-
The thickness is preferably 100 to 500 μm, more preferably 1000 μm. If it is less than 20 μm, flexibility and bag-making properties cannot be maintained,
If it exceeds 1000 μm, the transparency may deteriorate.

Here, as the adhesive used for bonding, an ordinary laminating adhesive can be used,
An isocyanate type, an acid-modified polyolefin type copolyester type, or the like is applied. The adhesive may be in a form of being directly bonded without using an adhesive.

Further, the processing (bag-making) from the composite sheet (film) to the container for medical liquid agent is usually a known hot plate sealing method,
It can be performed by a known technique such as an impulse sealing method, a high frequency sealing method, an ultrasonic sealing method, or the like. In addition to the above-mentioned amino acid preparations, the medical liquid preparations of the present invention include physiological saline, electrolyte solution, dextran preparation, mannitol preparation, saccharide preparation and the like.

Although the container for a medicinal solution of the present invention is mainly intended for a container for directly accommodating a medicinal solution, it goes without saying that it may be used as an outer packaging material as described in the section of the prior art. Nor.

[0014]

The present invention will be described in more detail with reference to the following examples.

Examples 1 to 4 Preparation of base material vapor-deposited composite sheet (Table 1 shows film thickness and vapor-deposited surface): Biaxially stretched polybutylene terephthalate (hereinafter referred to as PBT) film having a thickness of 5 μm. Then, a silicon oxide (SiO ₁ .5) film having each thickness was provided by continuous vacuum deposition using an electron beam heating method. Next, a sheet made of a linear low-density polyethylene resin (hereinafter LLDPE) containing butene-1 as a copolymerization component (density 0.91) is provided on the ceramic layer side.
3 g / cm ³ ) 100 μm with an isocyanate-based adhesive 5 μ
m coating was used and laminated to obtain a highly transparent composite base material sheet.

Preparation of container for medicinal liquid agent: This base sheet was heat-sealed so that the LLDPE layer was located inside, and a plastic container having a size of 40 × 180 × 130 mm in the form of a flat mold was prepared. Further, a rigid cylindrical drainage port made of high-density polyethylene resin, to which a rubber stopper is attached, is fixed to one end of this container. Next, 500 ml of an infusion solution consisting of an aqueous solution containing about 12 w / v% amino acid was dispensed into this container.

Sterilization: Place the container in the autoclave,
Sterilization was performed at a temperature of 115 ° C. and a gauge pressure of 1.8 kg / cm ² for 30 minutes.

Impact Test and Gas Barrier Property Evaluation The following experiment was conducted on the container manufactured as described above.

The container was naturally dropped from a height of 150 cm to a concrete floor in an atmosphere of 10 ° C. and 40% RH. Place this container in an atmosphere of 23 ° C and 60% RH for 1
After standing for 00 days, the color change of the content liquid was observed. This experiment was performed on 20 vessels per example. Table 1 shows the ratio of yellowed containers.

Comparative Examples 1 and 2 The same as Examples 2 and 4 except that the side on which the LLDPE layer is laminated is the PBT layer side (that is, the vapor deposition surface forms the outer surface of the container) in Examples 2 and 4. I conducted an experiment.

Comparative Example 3 The same experiment was carried out on a non-deposited PBT film laminated with LLDPE.

[0022]

[Table 1]

[0023]

[Experimental results] as silicon oxide shown in Table 1 (SiO 1 · ₅₎
The container having the vapor-deposited layer as the intermediate layer does not have the problem of gas barrier property deterioration due to impact. On the other hand, when the vapor-deposited layer forms an outer layer, there is a case where a pinhole is apt to be generated due to impact and the gas barrier property is deteriorated and the infusion agent inside is discolored. The oxygen permeability (measured at 23 ° C. and 75% RH) of the sheets of Examples 1 to 4 and Comparative Examples 1 and 2 before the impact test was 1.5 to 6 cc / m ² · day · atm.
This performance was maintained even after the impact test in Examples 1 to 4, but in Comparative Examples 1 and 2, the transfusion agents with discoloration were 50 to 200 cc / m ² · day · atm (directly. Measure the point where the shock is applied).

[0024]

As described above, according to the present invention, a container made of a composite sheet having a ceramic layer as an intermediate layer and an organic polymer layer as an inner layer and an outer layer is a ceramic sheet from an external force such as friction, bending and impact. It has a structure capable of preventing the generation of cracks or pinholes in the layer, and its gas barrier property is not affected by moisture. Therefore, it is excellent in long-term stable storage, transportation and handling of the drug. Further, it has advantages such as transparency, and its industrial value is high.

Claims (2)

[Claims] 1. A container for a medicinal solution comprising a composite sheet or film comprising at least three layers having a ceramic layer as an intermediate layer and an organic polymer layer as an inner layer and an outer layer. 2. The ceramic layer is 0.001 to 1.0 μm.
m-thick silicon oxide layer, the outer layer is a biaxially oriented polybutylene terephthalate film, and the inner layer sheet or film is at least one selected from the group consisting of linear low-density polyethylene and polybutene-1. The container for medicinal liquid agent according to claim 1, which is made of two materials.