JPH03187853A - Plastic container to be filled with dispersion liquid - Google Patents

Abstract

PURPOSE:To provide a plastic container in which fat balls of charged liquid does not cause phase separation easily and which is safety and well-operative by a method wherein at least a part of an inner face of the container in contact with at least content liquid is subjected to hydrophilic treatment. CONSTITUTION:A container 1 to be filled with dispersion system liquid is sealed with a peripheral seal 3 on an periphery of a pair of sheets 2 forming a container wall 21 wherein the inner face of a container 1 has been subjected to hydrophilic treatment as well as a port 4 for putting in or exhausting the dispersion system liquid is attached. The dispersion system liquid, that is, fat emulsion is subjected to conditions severe to the fat emulsion which has a nature to be easily phase-separated naturally such that it is exposed to a high temperature at the time of autoclave sterilization, or left for a long time to cause aging, etc. since it is filled in the container 1 until it is used for a patient. Therefore, while some normal plastic cases wherein an inner face has not been subjected to hydrophilic treatment may cause phase separation of the fat emulsion so that such cases cannot be used, by making the inner face of the plastic case hydrophilic, the container to be filled with dispersed system liquid can be obtained wherein the fat emulsion is not likely to cause phase separation.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention relates to a plastic container for filling a dispersion liquid, and more specifically, a dispersion of liposome-like dispersoids or a plastic container typified by a fat emulsion. The present invention relates to a container for filling a dispersion liquid such as an oil-in-water emulsion preparation, and a container that improves the stability of the filled dispersion or emulsion preparation.

[Prior Art] When lipids are administered as nutritional supplements through blood vessels, they cannot be administered in their original form, that is, in their oil form. This is because lipids do not dissolve in water, so they do not disperse uniformly in the blood and flow through blood vessels in an oily state, which can adhere to blood vessel walls and cause blood clots.
This is because it binds with oily substances in the membranes of blood cells and causes hemolysis. Even if no problems occur as a result, it is difficult to pass through blood vessel walls in that form, so it is difficult for the body to pass through. This is because it is difficult for cells to utilize it as nutrients. Incidentally, within the body of an animal, lipids move through blood vessels as minute lipid globules (hereinafter referred to as fat globules), are taken up by cells, and are utilized.

For this reason, high-calorie lipids have traditionally been administered as nutritional infusions after surgery, etc., and fat emulsions, which are oil-in-water emulsion preparations, have been used as formulations for this purpose.

However, although general high-calorie infusions are packaged in safe and easy-to-use plastic containers that do not break easily even if dropped, fat emulsions are still packaged in plastic containers. It is not commercially available and is packed in glass containers.

Fat emulsion is a state in which fat globules with a diameter of 1 μm or less are suspended in water containing electrolytes, that is, in an emulsion state, and is susceptible to temperature changes and external stimuli. It is easily destroyed, and the slightest thing can cause phase separation such as fusion of fat globules with each other or adhesion of fat globules to the wall of the container, and the stability of the emulsion state is lost just by filling and storing it in a plastic container. This caused phase separation.

One of the reasons for this is that while the surface of a glass container that comes into contact with the fat emulsion is hydrophilic, the inner surface of a plastic container is generally hydrophobic, so the hydrophobic surface and fat globules interact with each other. It is thought that the stability of the fat globules is impaired, and the fat globules fuse with each other, further losing stability and adhering to the container wall, eventually breaking the emulsion and causing phase separation.

Since high-calorie infusions are medications that are administered continuously over a long period of time, patients often move around, urinate, and defecate while taking the medication. Despite the demand for safe plastic containers, the reality is that they have not yet been developed.

[Problems to be Solved by the Invention] Therefore, the present invention seeks to eliminate the drawbacks of the prior art. In other words, the aim is to provide a plastic container that is safe and easy to operate because the fat globules of the filled drug solution undergo phase separation like in glass containers. It is an object of the present invention to provide a container that is less contaminated by adhesion of microorganisms, etc., and manufactured by a process that can easily guarantee that less contamination occurs.

[Means for Solving the Problems] In order to achieve the above objectives, the present inventors investigated the difference between a plastic container in which fat globules are easily damaged and a glass container in which fat globules are not easily damaged, that is, the surface of the plastic container is strongly hydrophobic. The present invention was developed as a result of focusing on the fact that the surface of the glass container is hydrophilic, whereas the surface of the glass container is hydrophilic. That is, the present inventors have discovered that the above-mentioned problems can be solved by using a plastic container for filling a dispersion liquid, in which at least a portion of the inner surface of the container that comes into contact with the content liquid has been treated to make it hydrophilic. It is something.

[Specific description of the structure] Hereinafter, a case will be described with reference to the drawings, taking as an example a case in which a plastic container for filling a dispersion liquid according to the present invention is filled with a fat emulsion, which is a medical liquid.

FIG. 1 is a front view of a container for filling a dispersion liquid filled with the fat emulsion of the present invention, and FIG. 2 is a cross-sectional view taken along line XX.

In the container 1 for filling a dispersion liquid of the present invention, the periphery of a pair of sheets 2 forming a container wall 21 whose inner side (hereinafter referred to as the inner surface) of the container 1 has been subjected to a hydrophilic treatment is sealed by a periphery seal 3. At the same time, a boat 4 for filling or discharging the dispersion liquid is attached.

The container 1 receives the dispersion liquid from the boat 4, namely:
After being filled with the fat emulsion 5, the opening 6 of the boat 5 is sealed with a convenient structure for dripping or mixing, such as a plastic molding assembly 7 with a rubber stopper 8 inside. Ru.

The fat emulsion in a container for filling a dispersion liquid of the present invention produced by the above method is sterilized, packaged, and used by a patient under the supervision of a doctor.

After the fat emulsion is filled into the container and before it is used by a patient, it may be exposed to high temperatures during autoclave sterilization, left for a long time and change over time, or the fat emulsion may be prone to phase separation. However, since the fat emulsion is exposed to harsh conditions, it has been impossible to use ordinary plastic containers, that is, plastic containers whose inner surfaces are not made hydrophilic, because the fat emulsion will undergo phase separation.
By making the inner surface of the plastic container hydrophilic as described above, it is possible to obtain a container for filling a dispersion liquid in which the fat emulsion is less likely to undergo phase separation.

By the way, even though hydrophilicity generally occurs, there are different levels of hydrophilicity, so the level of hydrophilicity will be explained using parameters.

In addition, as a parameter for recognizing hydrophilicity and hydrophobicity,
In general, the contact angle (θ) when water is dropped onto the surface of a substance is known, and it is known that the smaller the contact angle, the more hydrophilic it is. The contact angle with water is used as the parameter expressed by .

The inventors noticed that there is a relationship between the size of fat globules in the dispersion liquid filled in the container, that is, the fat emulsion, and the hydrophilicity of the inner surface of the plastic container. That is, when the diameter of the fat globules in the fat emulsion was measured, the average diameter was about 0.5 μm or less.

If the average diameter of the fat globules is 0.158 m or less, the effect is obtained when the contact angle (θ) with water on the inner surface of the container is 80” or less, preferably when the water contact angle (θ) is 64° or less. Things are better able to achieve their purpose.

To make a plastic surface hydrophilic, i.e. to reduce the contact angle of the surface with water, the surface can be polarized, for example by imparting an electric dipole to the surface, or by making small scratches on the surface. It is known that it is good to apply it and roughen it. Specific methods include methods of bringing the plastic surface into contact with plasma, such as electric discharge treatment or flame treatment.
Other methods include irradiation with ultraviolet rays generated from a low-pressure mercury lamp, etc., irradiation with radiation such as electron beams, immersion treatment in a sulfuric acid chromic acid mixture, coating with hydrophilic resin, and sandblasting. be.

If the contact angle on the inner surface of the container becomes 80° or less by treating with each of the above treatment methods, or by treating with a combination of two or more methods, no matter which method is used, However, in order to maintain favorable results, the contact angle should be 64° or less.

When considering whether the treatment method is appropriate for medical containers, at least the methods of coating with a hydrophilic resin, the method of immersion in a sulfuric acid chromic acid mixture, and the method of sandblasting are not recommended. This is not a desirable method.

Mercury lamps include low-pressure mercury lamps, high-pressure mercury lamps, and ultra-high-pressure mercury lamps, but the most effective ultraviolet lamp is a low-pressure mercury lamp, and the most effective lamps are high-output or high-input types. It was a low-pressure mercury lamp. However, even with other ultraviolet rays, effects were observed by experimenting with conditions that would not melt the irradiated object, increasing the illumination intensity, and increasing the total irradiation time.

The mechanism of ozone generation and active oxygen generation by ultraviolet lamps is generally considered as follows. At the beginning 2
Ultraviolet rays with wavelengths of 53.7 nm and 184.9 nm oxidize oxygen in gas, producing ozone (O3). When the generated ozone is further irradiated with ultraviolet rays having wavelengths of 253°7 nm and 184.9 nm, activated oxygen (0) is generated.

The activated oxygen generated here is generally said to oxidize and decompose organic matter on the surface of the plastic, causing the surface of the plastic to evaporate as a gas. However, evaporation alone cannot completely explain the decrease in contact angle with an aqueous solution.

In other words, while the generated ozone and activated oxygen exhibit the above-mentioned behavior, when they come into contact with the plastic surface, they add oxygen to the molecules on the plastic surface, oxidizing the plastic surface and interacting with the water on the plastic surface. This is thought to reduce the contact angle of It is expected that the latter case is likely to cause a decrease in the contact angle of the plastic surface with water due to ultraviolet irradiation.

Here, to simplify the explanation, 253.7 nm, 1
Although the explanation was limited to ultraviolet light with two wavelengths of 84.9 nm,
The wavelengths of ultraviolet rays that have the effect of reducing the contact angle with water on plastic surfaces are not limited to the two wavelengths mentioned above, but wavelengths close to these or other wavelengths can also reduce the contact angle, regardless of the degree of oxidizing power. Since there is an effect of reducing the surface area, it is thought that the contact angle with water on the plastic surface is reduced even when UV irradiation is performed using a lamp other than a low-pressure mercury lamp.

Examples of the discharge treatment include glow discharge treatment, corona discharge treatment, high frequency discharge treatment, treatment using microwave discharge, CASING treatment, plasma jet treatment, and the like. Furthermore, examples of the type of plasma include argon, helium, N2.02, and the like.

The above method is also suitable for manufacturing medical containers, but if the purpose-0 container is a medical container
In cases other than containers, coating with cellulose resin, vinyl acetate resin, methacrylate hydrophilic resin, etc., acid treatment, etc. are also effective.

The material forming the container wall of the plastic container for filling a dispersion liquid of the present invention may be a single layer or a multilayer, and the resin forming them may be a linear low density polyethylene resin. , polyester resin, vinyl chloride resin,
Polyurethane resin, low density polyethylene resin, high density polyethylene resin, ethylene-vinyl acetate copolymer resin,
Examples include polypropylene resin, polycarbonate resin, etc., and resin mixtures thereof. In particular, when the dispersion liquid is an injectable drug, polyolefin resin,
That is, linear low-density polyethylene resin, low-density polyethylene resin, high-density polyethylene resin, ethylene-vinyl acetate copolymer resin, polypropylene resin, etc. are preferable.

Note that although the dispersion liquid material is explained using a fat emulsion, which is a medical liquid, as an example, the use of the plastic container for filling the dispersion liquid material of the present invention is not necessarily limited to medical use. Instead, it may be a storage container for food or other items.

Further, in order to simplify the explanation, the shape of the plastic container for filling a dispersion liquid of the present invention was explained using the shape of FIG. 1 or 2 as an example, but the plastic container of the present invention for filling a dispersion liquid The shape of the container is not necessarily limited to the shape described above, and various structures can be considered.

[Example] Next, a detailed description will be given based on an example.

Example 1 Extruded linear low density polyethylene resin with a thickness of about 250 μm (L-LDPE: contact angle with water θ = 95°)
When the sheet was irradiated with ultraviolet rays from a distance of 25+u+ using a high-output low-pressure mercury lamp (250 watts) intermittently for 6 seconds at a time for a total irradiation time of 48 seconds, the contact angle (θ) with water was A sheet with a 70° surface made hydrophilic was obtained.

These two sheets were stacked one on top of the other with the irradiated sides facing each other, and three sides were sealed with an impulse sealer to create a bag-shaped container. Next, a commercially available fat emulsion for doctors (Indralipos 10% manufactured by Midori Juji Co., Ltd.) is filled.
It was replaced with nitrogen and sealed.

Next, the four samples prepared above were heated in a constant temperature bath at 60°C for 1 hour, and then shaken for 1 hour in a shaker that moves up and down at 10 cm 150 times per minute to check for destruction of fat globules. Ta.

To evaluate the destruction of fat globules, place the sample in a precise glass test tube with a diameter of 13 mm, centrifuge it in a centrifuge for blood collection at 3000 rpm for 2 hours, and then measure the thickness of the oily liquid layer released in the upper layer of the test tube. When the thickness was measured using a caliper, the results shown in Table 1 were obtained.

In addition, as another evaluation method, we took the fat emulsion from the container that had undergone the above treatment into a dropper, put a drop on a slide glass, and observed the state of the fat globules under a microscope with a magnification of 800 times.The results shown in Table 2 were obtained. Obtained.

Furthermore, as another evaluation method, the degree of coloring of the fat emulsion subjected to the above treatment was observed, and the results shown in Table 3 were obtained. Regarding the coloring of fat emulsions, in general, when the fat globules of a fat emulsion, that is, spherical particles, undergo oil-water separation or when giant particles are formed, the initially white appearance of the fat emulsion may change to yellow. Are known.

Example 2 An extruded sheet of linear low-density polyethylene resin (L-LDPE) with a thickness of approximately 250 μm was subjected to glow discharge using a glow discharge device at a frequency of 5 kHz, a degree of vacuum of 0.6 Torr, and a discharge time of 1 second. When subjected to electric discharge treatment, a sheet with a hydrophilic surface having a contact angle (θ) with water of 74° was obtained.

Using this sheet, a container-packed fat emulsion was prepared in the same manner as in Example 1, and evaluated in the same manner as in Example 1, and the results shown in Tables 1, 2, and 3 were obtained.

Example 3 Example 2 was performed except that the discharge treatment was performed under the same conditions as in Example except that the discharge time was 3 seconds, and a sheet whose surface was made hydrophilic and whose contact angle with water (θ) was 64° was used. Regarding the fat emulsion in a container prepared in the same manner as in Example 1, the state of destruction of fat globules was evaluated in the same manner as in Example 1, and the results shown in Tables 1, 2, and 3 were obtained.

Example 4 An extruded sheet of linear low-density polyethylene resin (L-LDPE) with a thickness of approximately 250 μm was heated using a corona discharge device (frequency: 40 kHz to 50 kHz) with an interelectrode distance of 1.5 mm and a current. 6.5A, line speed 5
When corona discharge treatment was performed at 00mm/min and 10 times, the contact angle (θ) with water was 56°.
A sheet whose surface was made hydrophilic was obtained. Using this sheet, a containerized fat emulsion was prepared in the same manner as in Example 1, and evaluated in the same manner as in Example 1.
The results shown in Table 3 were obtained.

Example 5 Discharge treatment was performed under the same conditions as Example 2 except that ultraviolet rays were irradiated in the same manner as Example 1 before glow discharge treatment, and the surface with a contact angle (θ) with water of 56° was made hydrophilic. The state of destruction of fat globules was evaluated in the same manner as in Example 1 for a containerized fat emulsion prepared in the same manner as in Example 2, except that a sheet was used. I can't get the results shown.

Comparative Example A fat emulsion prepared in the same manner as in Example 1 except that it was not irradiated with ultraviolet rays was evaluated for the fractured layer of fat globules in the same manner as in Example 1. Tables 1, 2, and 3 The results shown are obtained.

Table 3. It is possible to provide a container manufactured by a process that can easily guarantee that there is little contamination due to observation of yellowing of the fat emulsion and that there is little contamination on the inner surface of the manufactured container.

[Brief explanation of drawings]

FIG. 1 is a front view of a container for filling a dispersion liquid filled with the fat emulsion of the present invention, and FIG. 2 is a sectional view taken along line XX'. [Effects of the Invention] As described above, according to the present invention, if at least a part of the inner surface of the container that comes into contact with the content liquid is hydrophilized, it is possible to The objective is to provide a plastic container that is safe and easy to operate because the fat globules of the drug solution undergo phase separation like in glass containers. It can be adopted from among various methods that can be continuous without contact, such as treatment and glow discharge treatment, so that it can prevent fine particles, microorganisms, etc. from adhering to the inner surface of the container. Molded assembly rubber stopper, container wall

Claims (12)

[Claims] (1) A plastic container for filling a dispersion liquid, characterized in that at least a portion of the inner surface of the container that comes into contact with the filled dispersion liquid has been subjected to a hydrophilic treatment. (2) The dispersion system for filling a liquid according to claim 1, wherein the contact angle (θ) of distilled water with at least the hydrophilized inner surface of the container is 80° or less. plastic container. (3) The hydrophilicity of at least the hydrophilic-treated inner surface of the container is obtained by irradiating ultraviolet rays, as set forth in claim 1 or 2. A plastic container for filling dispersion liquids. (4) Claim 1, characterized in that the hydrophilicity of at least the hydrophilic-treated inner surface of the container is obtained by bringing the inner surface into contact with plasma;
Alternatively, the plastic container for filling a dispersion liquid according to item 2. (5) The plastic container for filling a dispersed liquid material according to claim 4, wherein the treatment for bringing the inner surface into contact with plasma is a discharge treatment. (6) Claim 1, wherein the hydrophilicity of at least the hydrophilic-treated inner surface of the container is obtained by applying both ultraviolet irradiation and discharge treatment, or The plastic container for filling a dispersion liquid according to item 2. (7) The plastic container for filling a dispersion liquid according to claim 3 or 6, wherein the source of the ultraviolet rays to be irradiated is a low-pressure mercury lamp. (8) The plastic container for filling a dispersion liquid according to claim 5 or 6, wherein the discharge treatment is a glow discharge treatment. (9) The plastic container for filling a dispersion liquid according to claim 5 or 6, wherein the discharge treatment is a corona discharge treatment. (10) A plastic container for filling a liquid dispersion according to any one of claims 1 to 9, wherein the liquid dispersion filled in the container is a medicinal solution for injection. (11) A plastic container for filling a dispersion liquid according to claims 1 to 9, characterized in that it is filled with an emulsion in which the average particle diameter of at least the dispersoid is 0.5 μm or less. . (12) A plastic container for filling a dispersion liquid according to claims 10 and 11, characterized in that it is filled with at least a fat emulsion.