JPS60236651A - Drug container - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Background of the Technology Technical Field The present invention relates to a drug container. More specifically, the present invention relates to a drug container that has extremely high gas barrier properties, good transparency, and does not cause the drugs inside to deteriorate over a long period of time.

Furthermore, the present invention relates to a drug container containing a drug solution that has been sterilized by high-pressure steam.

PRIOR ART Conventionally, various types of synthetic resin containers have been used in various fields. Some of these containers contain medical solutions, such as infusions such as fat infusions, nutritional supplements containing amino acids, etc.
There are medical solution containers that store medical solutions such as glucose aqueous solutions and physiological saline.

Conventionally, glass containers have been used as such chemical liquid containers because the container body has no gas permeability and has good transparency. However, glass containers are easily damaged during storage, transportation, or use.
Another drawback was that it was heavy. For this reason, we investigated the use of lightweight and transparent containers made of synthetic resin. However, since synthetic resins are more or less gas permeable, during long-term storage, surrounding atmospheric gases, such as air (oxygen There was a drawback that gases) permeated through the device, resulting in deterioration of the chemical solution inside. For example, if a drug that is easily oxidized, such as a fat infusion or an amino acid, is stored inside a synthetic resin container, the drug may be oxidized by oxygen (contained in the surrounding air that passes through the container and flows in). If you try to use a container made of synthetic resin, as it will oxidize and cause deterioration.
It was necessary to store the synthetic resin container in a vacuum packaging container.

However, storage in a reduced pressure packaging container has the disadvantage that, since the packaging container is a reduced pressure container, it is extremely expensive and requires considerable time and effort to seal and open the can, resulting in high costs. On the other hand, when storing an aqueous solution such as a glucose aqueous solution or physiological saline, there is a drawback that the water inside evaporates and passes through the synthetic resin container as water vapor, resulting in a change in its concentration.

Further, as in the past, such plastic containers containing chemical solutions need to be sterilized before use. This sterilization is generally performed by so-called high-pressure steam sterilization, which is performed in saturated steam at high temperatures. However, even plastic materials such as polyvinyl chloride, which have low gas permeability at room temperature, become highly gas permeable during high-pressure steam sterilization, allowing oxygen present in the atmosphere to enter the container through the container wall made of plastic material. and alters the content of the liquid. There is a particularly high risk of deterioration when the content liquid contains components that are easily deteriorated by oxygen, such as high-concentration amino acid infusions containing tryptophan or fat emulsions for infusion. In addition, plastic containers were sometimes damaged under normal high-pressure steam sterilization conditions.

(9) Purpose of the Invention Therefore, the purpose of the present invention is to provide a novel drug container. Another object of the present invention is to provide a drug solution container containing a drug solution such as an infusion solution, a nutrient, an electrolyte, etc., which has a high gas barrier property and good transparency, and which does not cause the internal drug solution to deteriorate over a long period of time. . Still another object of the present invention is to provide a chemical liquid container that is free from damage and has extremely high gas barrier properties.

A further object of the present invention is to provide a high-pressure steam sterilized drug container that contains a drug solution that remains substantially unchanged after sterilization.

In some cases, at least one of the inner and outer surfaces of a synthetic resin container body having a sealable opening in at least one place is formed by the general formula I (where m is an integer of 1 to 5). ) and a silicon compound having the general formula ■ (where n is an integer of 1 to 5, and R1 and R2 are an alkyl or alkoxy group having 1 to 4 carbon atoms, a phenyl group, or a hydroxyl group). However, R1 and R
2 cannot be a hydroxyl group at the same time. ) is reacted with a mixture of silicon compounds to form a continuous film with gas barrier properties. This is accomplished by a drug container.

Further, the present invention provides that the container body made of synthetic resin is made of transparent synthetic resin II.
This is a drug container made by I. Furthermore, the present invention provides a drug container in which the film is a transparent film.

The present invention provides a drug container in which the film has a thickness of 0.01 to 2 μm. Further, the present invention provides that m in the general formula I is an integer of 1 to 5, and n in the general formula
is an integer, and R1 and R2 have 1 to 4 carbon atoms.
It is a drug container that is an alkyl group or a hydroxyl group. Furthermore, the present invention provides that R1 in the general formula (3) has 1 to 1 carbon atoms.
2 is an alkyl group, and R2 is a hydroxyl group. The present invention is a drug container in which the drug is an oxidizing substance. The present invention is also a drug container in which the drug is a liquid. The present invention also provides a drug container, wherein the synthetic resin container body is made of heat-resistant synthetic resin.

Furthermore, the present invention is a drug container, wherein the internal atmosphere is a gas inert to the drug.

(1) Specific structure of the invention Next, the present invention will be explained in detail with reference to the drawings. That is, as shown in FIG. 1, a drug container 1 according to the present invention is composed of a transparent synthetic resin container body 2 having at least one sealable opening 3. A transparent film is formed on at least one of the inner and outer surfaces of the main body 2 by reacting the silicon compounds represented by the general formulas (1) and (2) with the plasma treatment.

For example, as shown in FIG. 2A, the silicon compound is reacted on the entire outer surface of the container body 2 to form a transparent film 2a.
is formed. Moreover, as shown in FIG. 2(B),
The transparent film 2b is formed on the entire inner surface of the container body 2. Furthermore, as shown in FIG. 2(C), the transparent film 2a is formed on the outer surface of the container body 2, and the transparent film 2b is formed on the inner surface thereof. In addition, 2nd (A) ~
2(C), transparent films 2a, 2. The film thickness in b is exaggerated.

The synthetic resin constituting the container body used in the present invention is not particularly limited, but transparent synthetic resin is preferable;
In particular, styrene homopolymers or copolymers, methyl methacrylate homopolymers or copolymers,
Vinyl copolymers, and when heat resistance is required, soft or hard vinyl chloride resins, crosslinked ethylene-vinyl copolymers, polypropylene, polycarbonates, polyesters, and the like are preferred. In addition to polystyrene, styrene polymers include copolymers of styrene and other copolymerizable monomers, and the copolymerizable monomers include at least one of butadiene, methyl methacrylate, maleic anhydride, etc. There is one kind of thing. In addition to polymethyl methacrylate, methyl methacrylate polymers include copolymers of methyl methacrylate and other copolymerizable monomers. Examples of polycarbonates include bisphenol-type carbonates such as 4,4'-isopropylidene diphenol polycarbonate, as well as those described in U.S. Pat. No. 3,305.502.
and other polycarbonates, diethylene glycol bisallyl carbonate, etc., described in "Polycarbonates", co-authored by Christo Farr and Fox, pp. 161-176 (published in 1962). One of the film-forming components is a silicon compound having the general formula (1) (where m is an integer of 1 to 5, preferably 1. to 2).

It is a silicon compound with In the general formula (■), n
is an integer of 1 to 5, preferably 1 to 2.

Further, R'J5 and R2 are an alkyl or alkoxy group having 1 to 4 carbon atoms, a phenyl group, or a hydroxyl group, but R1 and R2 are never a hydroxyl group at the same time. R
1 and R2 are preferably an alkyl group having 1 to 4 carbon atoms or a hydroxyl group, but both are not hydroxyl groups. In particular, when R1 is an alkyl group having 1 to 2 carbon atoms, R
It is preferable that 2 is a hydroxyl group.

Therefore, the blending ratio of the silicon compound of the general formula (2) to 1 mole of the silicon compound of the general formula (I) is 0.5 to 3 moles, preferably 1 to 2 moles. A mixture of such silicon compounds is methanol, ethanol.

It is used as a solution in an organic solvent such as isopropanol. Its concentration is 3-50% by weight, preferably 5-35% by weight.

The transparent film is formed as follows.

For example, in the case of forming a film on the outer surface of the container body, the opening is sealed and then immersed in the mixed solution of the silicon compound. This immersion time is usually 0.01 to 1
0 minutes, preferably 1 to 5 minutes. In this case, applying ultrasonic waves during dipping will promote the removal of air from the micropores on the surface of the synthetic resin container and the infiltration of solutes into the micropores, thereby improving the gas barrier properties of the resulting film. do.

Note that the application of the mixed solution is not limited to dipping, but can also be performed by spraying or other methods.

The temperature of the immersion treatment is usually 0 to 50°C, preferably 10 to 50°C.
The temperature is 30°C. In addition, when carrying out under the action of ultrasonic waves, the liquid temperature is 0 to 50°C, preferably 10 to 30°C, and 20 to 20°C.
It is carried out at a frequency of 200 KHz, preferably 25-5 KHz, for 0.1-10 minutes, preferably 0.5-5 minutes.

The container body coated with the mixed solution in this way is
3 at a temperature of 50-120°C, preferably 60-70°C.
After being dried for ~30 minutes, preferably 5-15 minutes,
Subjected to plasma treatment.

Plasma treatment of the coating film on the surface of the pronuclear container body to form a transparent film can be carried out, for example, as follows. That is, as shown in FIG. 3, an electrode 14 is provided on a reaction group 13 equipped with a gas inlet 11 and a gas outlet 12, a container body support 15 is provided on the electrode 14, and a container body support 15 is provided on the electrode 14. to support the container body 2 coated with the mixed solution.

For example, the container body support 15 is inserted and supported inside the container body 2 after the seal is removed. Note that a cooling device 16a is brought into contact with the electrode 14, and the cooling device 16a is connected to a temperature regulator 16b to circulate a cooling medium, for example, water. Further, the electrode 14 is connected to a ground 17 . On the other hand, a counter electrode 18 is provided on the opposite side of the electrode 14, and the counter electrode 18 is connected to a high frequency power source 20 via a matching box 19: 3! tied together. An oxygen container 21 and a flow meter 22 are quickly connected to the gas inlet 11 . On the other hand, the gas outlet 12 has
Oil diffusion pump 24 and oil rotary pump 2 via trap 23
A pressure reducing device such as No. 5 is connected.

In FIG. 3, numeral 26 is a pressure sensor, numeral 27 is a vacuum gauge, and numeral 28 is a temperature gauge.

Then, a pressure reducing device such as an oil rotary pump is operated to exhaust the atmospheric gas in the reactor 13 from the gas exhaust port 12, and while maintaining a predetermined degree of pressure reduction, the oxygen gas is passed from the oxygen container 21 through the flow meter 22. While supplying the gas to the reactor 13 through the gas inlet 11, the electrodes are energized to irradiate the coating surface with plasma for treatment.

In this case, so that the coating is uniformly irradiated with plasma,
For example, it is desirable to perform irradiation while rotating the container body.

The pressure inside the reactor during plasma treatment is O, 01~2To
rr preferably 0. There is a range of 1 to 0.5 Torr.

The electrode 14, which is the base, is cooled by a cooling medium circulated in the cooling device 16a, but the humidity inside the reactor is between 0 and 150.
℃, preferably 30 to 70℃.

Further, the high frequency power amount is 0.05 to 2 W/cm2, preferably 0.2 to 1.5 W/cm2. Furthermore, gases containing oxygen atoms include molecular oxygen, ozone, carbon oxide, carbon dioxide, nitrogen oxide, dinitrogen oxide, and mixed gases of these and other gases (e.g., argon, nitrogen helium), etc. However, molecular oxygen (hereinafter referred to as oxygen gas) is preferred, and the oxygen content is preferably 20 to 100 mol%. Plasma irradiation was performed for 0.1 to 60 minutes.
Preferably, irradiation is performed for 0.3 to 5 minutes. Therefore, it is possible to prevent an increase in humidity due to plasma irradiation of the container body, which is a base material, and is therefore suitable.

The thickness of the transparent film formed under such reaction conditions is
It is 0.01-2 μm, preferably 0.03-0.2 μm.

In the method of the present invention, even better results can be obtained if the container body is cleaned before applying the silicon compound mixed solution.

Cleaning can be done with water, acid aqueous solution, alkaline aqueous solution, alcohol,
This is carried out using an aqueous interfacial viscous material solution, but an alkaline aqueous solution is preferred. Examples of alkaline aqueous solutions include sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc.
It is used as an aqueous solution of 1 to 20% by weight, preferably 3 to 10% by weight. The processing time is usually 0°1~30°
minutes, preferably 5 to 10 minutes, and the liquid temperature is 0 to 10 minutes.
The temperature is 150°C, preferably 10-40°C. Furthermore, even better results can be obtained if the cleaning treatment is performed using ultrasonic waves. Ultrasonic treatment is 20-200KH2
, preferably 0.1-10 at a frequency of 25-50KH7
This is carried out for 0.5 to 5 minutes, preferably 0.5 to 5 minutes. It goes without saying that if cleaning treatment is carried out using ultrasonic waves, fairly good results can be obtained even with treatment agents other than aqueous alkaline solutions. Further, the best results can be obtained by performing ultrasonic cleaning using an alkaline aqueous solution.

The drug container 1 obtained in this way contains, for example, fat infusions, other infusions, nutrients containing amino acids, etc., medicinal solutions such as glucose aqueous solution, and physiological saline. The container is sealed with a plug member 4 having a good gas barrier property while enclosing a gas inert to the drug, such as argon, carbon dioxide, or the like.

The drug container 1 containing the drug solution 5 and sealed tightly with the stopper member 4 needs to be sterilized before use, as in the past. Sterilization is generally performed by high-pressure steam sterilization. In the sterilization process, a plurality of the drug containers 1 are placed in an autoclave where the sterilization process is performed, and after evacuating the autoclave to substantially remove oxygen in the autoclave, water vapor is introduced into the autoclave to saturate it. Then an inert gas such as argon, helium or nitrogen.

Preferably, sterilization is performed after nitrogen is introduced and pressurized. The sterilization temperature is generally 100°C to 130°C, preferably 115°C to 126°C.

The sterilization atmosphere pressure is about 10-200% (for example, about 0.3-200% of the saturated water vapor pressure at the sterilization temperature) in absolute pressure.
It is further pressurized by inert gas by 0.8 k (1/cm2). Generally, the pressure during sterilization is about 1.2 to 2. It is Oka/cm2. A suitable sterilization time is 10 to 40 minutes. During sterilization, appropriate inert gas is introduced into the autoclave to ensure a predetermined pressure.

Next, the present invention will be explained in more detail by giving examples.

. Example 1 Container made of polyethylene terephthalate! degree 2.5%
It was immersed in Na2CO+ solution for 5 minutes (ultrasonic treatment was performed), then immersed in the above-mentioned silicon compound concentration 12% by weight isopropanol solution at 20°C for 1 minute B, and then pulled up at a pulling speed of 160 m/min. . Then, it was dried at 70°C for 30 minutes.

Next, the synthetic resin tube was inserted into the low-temperature plasma reactor (Fig. 3, 13), and degassed (0.05 TOrr).
Then, charge oxygen gas and heat it to about 0°31'-0r.
Plasma output power 100W under r pressure.

Plasma treatment was performed for 2 minutes using parallel plate electrodes (50 mm x 50 m).
A transparent film with a thickness of 0.1 μm was deposited on one side of the container. This container was aseptically filled with 10% glucose, further aseptically filled with nitrogen gas, and the opening was sealed with a rubber stopper, followed by high-pressure steam sterilization. The same treatment as above was carried out using a film made of the above material (membrane width 12 um, area 500 m2) for measuring the oxygen and carbon dioxide permeability of this coated container. The gas permeability of this coated film was measured using a gas permeation measuring device manufactured by Reese Co., Ltd., and it was 50.
．． 6m, +2/m2 ・day -atm and h204
ml,/m 2 ·day-atm.

Hereinafter, all the gas permeability tests in the Examples were conducted in the same manner using separate films. Although this drug solution container was stored for a long period of time, no deterioration of the drug solution was observed.

Example 2 In the same method as in Example 1, a mixed solution with a concentration of 5% by weight was sonicated for 5 minutes at 70°C for 3 minutes.
After drying for a minute, plasma treatment was immediately performed under the same conditions, and a permeable film with a thickness of 0.04 μm was formed. This container was filled with a 12% amino acid aqueous solution and nitrogen gas as in Example 1. Similar counts for oxygen and carbon dioxide permeability were 78 and 313, respectively.

Although this drug solution container was stored for a long period of time, no deterioration of the drug solution was observed.

Comparative Example 1 Similar counts of oxygen and carbon dioxide gas permeability of the untreated polyethylene terephthalate used in Example 1 were 231 and 939, respectively. In addition, deterioration of glucose was observed during storage.

Comparative Example 2 In the method of Example 1, the film was immersed in a 32% by weight mixed solution for 5 minutes without ultrasonic treatment and plasma treatment, and then dried at 60°C for 180 minutes, resulting in a film thickness of 0.1
A transparent film of 4 μm was formed. Similar caraton numbers for oxygen and carbon dioxide permeability are 213 and 85, respectively.
It was 4.

Also, deterioration of amino acids was observed during storage.

Example 3-12 Same as Example 1, film thickness 12 μm (Example 8 to
12, a polyethylene terephthalate container with a film thickness of 11.5 μm (film for gas permeability:
The area was 5 Q cm2. ) was subjected to ultrasonic cleaning using a treatment agent shown in Table 1, and then subjected to a drying treatment. Next, a mixed solution of silicon compounds similar to that in Example 1 was used at the concentration shown in Table 1, and the samples were immersed in the mixed solution for 5 minutes, during which time ultrasonication was performed at a frequency of 45K to 1z. Afterwards, it was dried at 70°C for 5 minutes. Next, plasma treatment was performed in the presence of 100% oxygen at the output numbers and times shown in Table 1, and the results shown in Table 1 were obtained. As a result, in the cleaning process, neutral detergent treatment,
It was found that %Na2CO3 treatment, alkali treatment, and methanol treatment had better properties in this order. This indicates that the plasma-generated film is affected by the surface condition of container cleaning method section 1. Although this container was filled with the same chemical solution and gas as in Example 2 and stored, the chemical solution deteriorated. was not recognized.

(The following is a blank space) Example 13 As shown in FIG. 1, a synthetic resin container having a wall thickness of 1 mm and having one end closed and the other end open was made of polycarbonate. This tubular container was placed in a 5% sodium carbonate aqueous solution for 40 minutes.
After ultrasonication at KH2 frequency for 5 minutes, drying was carried out at 60°C and humidity for 5 minutes.

Then, it was immersed for 5 minutes in a mixed solution of the same silicon compound as in Example 1 with a concentration of 32% by weight, subjected to ultrasonic treatment at a frequency of 45 KHz, and then dried at a temperature of 70° C. for 5 minutes.

Furthermore, plasma treatment was performed for 15 minutes in the presence of 100% oxygen gas at a power output of 200 W to obtain a transparent 0.14 μm
A synthetic resin container having a coating on the outside was obtained. The inside of this container was filled with an amino acid (containing tryptophan) infusion with a concentration of 12% prepared by a conventional method, and then filled with nitrogen gas, and the open end was sealed with a rubber stopper while the entire container was under reduced pressure. Furthermore, the container was sterilized in an autoclave. The container was left as it was at room temperature and atmospheric pressure for 3 months, but the chemical solution inside did not change in quality.

(0) Specific Effects of the Invention As described above, the present invention provides a synthetic resin container body having a sealable opening in at least one location, on the inner surface or at least one of the surfaces, the general formula I A drug, #J, is stored in a synthetic resin container made by reacting a mixture of a silicon compound having the formula (1) and a silicon compound having the general formula (2) to form a continuous film with gas barrier properties, and the opening is closed. Since this is a drug container that isolates the internal atmosphere from the external atmosphere, its gas permeability, especially the oxygen permeability coefficient, is extremely low.This prevents gas permeation from outside the drug container into the container and from inside the container to the outside of the container. Gas permeation is virtually eliminated. Therefore, when used as a container for storing drugs that are easily oxidized, such as fat infusions or amino acid-containing nutritional supplements, the permeation of gas, especially oxygen, from the container into the container is virtually eliminated, resulting in a long-term There will be no deterioration of the drug. Furthermore, when an electrolyte such as glucose or physiological saline is stored, there is virtually no gas permeability from the inside of the container to the container, so even if the water in the electrolyte evaporates,
The water vapor does not permeate out of the container, so a predetermined level can be maintained for a long period of time. Furthermore, even during high-pressure steam sterilization, the drug container according to the present invention has extremely low gas permeability, and therefore can contain the drug substantially unchanged even after sterilization. Moreover, since the drug container according to the present invention is made of synthetic resin, there is no fear of damage even if it is subjected to impact during transportation, storage, or use.

[Brief explanation of drawings]

FIG. 1 is a sectional view showing an example of a drug container according to the method of the present invention, FIGS. 2(A) to 2(C) are partially enlarged sectional views of the drug container shown in FIG. 1, and FIG. 3 is a sectional view showing an example of the drug container used in the present invention. 1 is a schematic cross-sectional view showing an example of a plasma processing apparatus. 1... Drug container, 2... Container body, 2a, 2b.
...transparent film, 3...opening, 4...plug member,
5...Drug. Figure 1 Figure 20

Claims (10)

[Claims] (1) General formula! (However, in the formula, m is an integer of 1 to 5.) and the general formula
and R2 is an alkyl or alkoxy group having 1 to 4 carbon atoms, a phenyl group or a hydroxyl group, but R1 and R2 are never a hydroxyl group at the same time. ) A drug is stored in a synthetic resin container formed by reacting a mixture of silicon compounds having a gas barrier property to form a continuous film with gas barrier properties,
A drug container that closes the opening to shut off the internal atmosphere and external atmosphere. °゛′□ (2) The drug container according to claim 1, wherein the front synthetic resin container body is made of transparent synthetic resin. (3) The drug container according to claim 2, wherein the coating is a transparent coating. (4) The drug container according to any one of claims 1 to 3, wherein the coating has a thickness of 0.02 to 2 μm. (5) m in general formula) is an integer of 1 to 5, and n in general formula (2) is an integer of 1 to 5, and R1 and R2 are an alkyl group or a hydroxyl group having 1 to 4 carbon atoms. A drug container according to claim 1. (6) The drug container according to claim 5, wherein R1 in the general formula (2) is an alkyl group having 1 to 2 carbon atoms, and R2 is a hydroxyl group. (7) A drug container according to any one of claims 1 to 6, wherein the drug is an oxidizing substance. (8) The drug container according to claim 7, wherein the drug is a liquid. (9) The drug container according to claim 1 or 2, wherein the synthetic resin container body is made of heat-resistant synthetic resin. (10) The drug container according to claim 1, wherein the internal atmosphere is a gas inert to the drug.