JPH0142213B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to pharmaceutical containers. 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 store medical solutions, such as infusions such as fat infusions, nutritional supplements containing amino acids, aqueous glucose solutions, physiological saline, etc. There is a medicine container stored there. As such drug containers, glass containers have conventionally been used because the container main body is not gas permeable and has good transparency. However, glass containers have the disadvantage that they are easily damaged during storage, transportation, or use, and are heavy. For this reason, we investigated the use of lightweight and transparent synthetic resin containers, but since synthetic resins are more or less gas permeable, during long-term storage, surrounding atmospheric gases, such as air (oxygen This had the disadvantage that gases) permeated through it, and as a result, the quality of the chemical inside changed. 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 will be oxidized by oxygen contained in the surrounding air that passes through the container and flows in. If a synthetic resin container were to be used, it would be necessary to store the synthetic resin container in a vacuum packaging container. However, storage in a reduced pressure packaging container has the drawback that, since the packaging container is a reduced pressure container, it is extremely expensive and also 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. In addition, as in the past, such plastic containers containing chemical solutions must 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.
Oxygen present in the atmosphere enters the container through the container wall made of plastic material and alters the solution inside. If the internal solution contains components that are easily altered by oxygen, such as high-concentration amino acid infusions containing tryptophan or fat emulsions for infusion, there is a high risk of deterioration. In addition, plastic containers were sometimes damaged under normal high-pressure steam sterilization conditions. OBJECTS OF THE INVENTION It is therefore an object of the present invention to provide a novel drug container. Another object of the present invention is to provide a drug 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. It is in. Still another object of the present invention is to
It is an object of the present invention to provide a drug container which has no fear of breakage 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. These purposes are based on the general formula (However, in the formula, m is an integer of 1 to 5.) and a silicon compound having the general formula (However, in the formula, n is an integer from 1 to 5, and
R ¹ and R ² are an alkyl or alkoxy group having 1 to 4 carbon atoms, a phenyl group, or a hydroxyl group, but R ¹ and R ² are never a hydroxyl group at the same time. ) and a gas barrier synthetic resin container having a plasma-treated continuous coating of a mixture of silicon compounds having the following properties: This is achieved by a drug container characterized by: Further, the present invention is a drug container in which the synthetic resin container body is made of transparent synthetic resin. 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 is an integer of 1 to 5, and n in the general formula is an integer of 1 to 5, and R ¹ and R ² are an alkyl group having 1 to 4 carbon atoms or It is a drug container with a hydroxyl group. Furthermore, the present invention is a drug container in which R ¹ in the general formula is an alkyl group having 1 to 2 carbon atoms, and R ² 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. The present invention is a drug container in which the opening is closed by a plug member. Specific Configuration of the Invention Next, the present invention will be described in detail with reference to the drawings. That is, as shown in FIG. 1, the drug container 1 according to the present invention consists 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 silicon compound by plasma treatment with the silicon compound of the general formula described above.
For example, as shown in FIG. 2A, a transparent film 2a is formed on the entire outer surface of the container body 2 by reacting the silicon compound. Further, as shown in FIG. 2B, the transparent film 2b is formed on the entire inner surface of the container body 2. Further, as shown in FIG. 2C, the transparent film 2a is coated on the outer surface of the container body 2.
However, the transparent film 2b is also formed on its inner surface. In addition, in FIGS. 2A to 2C, the thicknesses of the transparent films 2a and 2b are exaggerated. The synthetic resin constituting the container body used in the present invention is not particularly limited, but transparent synthetic resins are preferred, particularly styrene homopolymers or copolymers, methyl methacrylate homopolymers or copolymers. If heat resistance is required, soft or hard vinyl chloride resin, crosslinked ethylene-vinyl copolymer, polypropylene, polycarbonate, polyester, etc. 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 type. 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 US Pat.
No. 3305502 and other polycarbonates described in "Polycarbonates" by Christopher and Foxx, pp. 161-176 (published in 1962),
Examples include diethylene glycol bisallyl carbonate. One of the film-forming components is the general formula (However, in the formula, m is 1 to 5, preferably 1 to 2
is an integer. ) is a silicon compound. It is a silicon compound with In the general formula, n is an integer of 1 to 5, preferably 1 to 2. Further, R ¹ and R ² are an alkyl or alkoxy group having 1 to 4 carbon atoms, a phenyl group, or a hydroxyl group, but R ¹ and R ² are never a hydroxyl group at the same time. R ¹ and R ² are preferably an alkyl group having 1 to 4 carbon atoms or a hydroxyl group, but both are not hydroxyl groups, and in particular R ¹ is an alkyl group having 1 to 2 carbon atoms, and R ² is preferably a hydroxyl group. Therefore, the blending ratio of the silicon compound of the general formula to 1 mole of the silicon compound of the general formula is 0.5 to 3
mol, preferably 1-2. Mixtures of such silicon compounds include 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, when 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 10 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
The temperature is 10-30℃. In addition, when conducting under the action of ultrasonic waves, the liquid temperature is 0 to 50°C, preferably 10 to 30°C, and the frequency is 20 to 200KHz, preferably 25 to 5KHz, for 0.1 to 10 minutes, preferably 0.5 to 5. It takes place for a minute. The container body coated with the mixed solution in this manner is dried at a temperature of 50 to 120°C, preferably 60 to 70°C, for 3 to 30 minutes, preferably 5 to 15 minutes, and then subjected to plasma treatment. Ru. The coating film on the surface of the container body can be plasma-treated to form a transparent film, for example, in the following manner. 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. 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 such as water. Further, the electrode 14 is connected to a ground 17 . On the other hand, electrode 1
A counter electrode 18 is provided on the opposite side of 4, and the counter electrode 18 is connected to a high frequency power source 20 via a matching box 19. An oxygen container 21 and a flow meter 22 are connected to the gas inlet 11 . On the other hand, gas outlet 1
2, an oil diffusion pump 24 via a trap 23;
A pressure reducing device such as an oil rotary pump 25 is connected. In FIG. 3, the reference numeral 26 is a pressure sensor, the reference numeral 27 is a vacuum gauge, and the reference numeral 2 is a pressure sensor.
8 is a thermometer. 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, it is desirable to perform the irradiation, for example, while rotating the container body so that the coated surface is uniformly irradiated with the plasma. The pressure inside the reactor during plasma treatment is 0.01~
2 Torr, preferably 0.1 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 temperature inside the reactor is between 0 and
The temperature is 150°C, preferably 30-70°C. In addition, the high frequency power amount is 0.05~2W/ ^cm2 , preferably 0.2~2W/cm2.
It is 1.5W/ ^cm2 . Furthermore, gases containing oxygen atoms include molecular oxygen, ozone, carbon monoxide,
Carbon dioxide, nitrogen monoxide, dinitrogen monoxide and these and other gases (e.g. argon, nitrogen helium)
There are mixed gases with
20 to 100 mol% is preferred. Plasma irradiation is 0.1
Irradiate for ~60 minutes, preferably 0.3-5 minutes. Therefore, it is possible to prevent the temperature of the container body, which is the base material, from increasing due to plasma irradiation, which is preferable. The thickness of the transparent film formed under such reaction conditions is 0.01 to 2 μm, preferably 0.03 to 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. Washing is carried out using water, an aqueous acid solution, an aqueous alkali solution, alcohol, an aqueous surfactant solution, etc., and an aqueous alkaline solution is preferred. 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 0.1 to 20% by weight, preferably 3 to 10% by weight. Its processing time is usually 0.1
-30 minutes, preferably 5-10 minutes, and the liquid temperature is 0-150°C, preferably 10-40°C. Furthermore, even better results can be obtained if the cleaning treatment is performed using ultrasonic waves. Ultrasonication is carried out at a frequency of 20 to 200 KHz, preferably 25 to 50 KHz, for 0.1 to 10 minutes, preferably 0.5 to 5 minutes. It goes without saying that if the cleaning treatment is carried out using ultrasonic waves, very 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 a glucose aqueous solution, and warm saline water. 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, the air is evacuated to substantially remove oxygen in the autoclave, and then 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. Sterilization temperatures are generally between 100°C and 130°C, preferably between 115°C and 126°C. In addition, the sterilization atmosphere pressure is about 10 to 200% of the saturated water vapor pressure at the sterilization temperature (for example, about 0.3 to 0.8
Kg/cm ² ) is additionally pressurized with inert gas. Generally, the pressure during sterilization is approximately gauge pressure.
It is 1.2-2.0Kg/ ^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 Polyethylene terephthalate container with a concentration of 2.5
% Na ₂ CO ₃ solution for 5 minutes (with ultrasonication), the above silicon compound concentration was 12% by weight.
After being immersed in an isopropanol solution at 20°C for 1 minute, it was pulled up at a pulling rate of 16 cm/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), degassed (0.05 Torr), and then oxygen gas was charged and the plasma output power was 100 W, 2 at a pressure of about 0.33 Torr. Plasma treatment was performed for minutes using parallel plate electrodes (50 mm x 50 m flat plates were used) at a distance of about 50 mm, and 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. To measure the oxygen and carbon dioxide permeability of this coated container, a film made of the above-mentioned material (thickness: 12 μm, area: 50 cm ² ) was used to perform the same treatment as described above. The gas permeability of this coated film was measured using a gas permeation measuring device manufactured by Ritsushi Co., Ltd. and was found to be 50.6 ml/m ² . day・atm and 204ml/ ^m2・
It was day ATM. Hereinafter, all the gas permeability tests in the Examples were conducted in the same manner using separate films. This drug solution container was stored for a long period of time, but no deterioration of the drug solution was observed. Example 2 In a method similar to Example 1, a concentration of 5% by weight
When the mixed solution was ultrasonically treated for 5 minutes, dried at 70°C for 3 minutes, and immediately subjected to plasma treatment under the same conditions, a transparent 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 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, 5% was added to a 32% by weight mixed solution without ultrasonic treatment and plasma treatment.
After being immersed for a minute, it was dried at 60° C. for 180 minutes, and a transparent film with a thickness of 0.14 μm was formed. Similar counts for oxygen and carbon dioxide permeability were 213 and 854, respectively. Also, deterioration of amino acids was observed during storage. Examples 3 to 12 As in Example 1, containers made of polyethylene terephthalate with a film thickness of 12 μm (however, in Examples 8 to 12, the film thickness was 11.5 μm) (gas permeability was determined using a film with an area of 50 cm ^{2 )} . ) 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 those in Example 1 was used at the concentration shown in Table 1, and the solution was immersed in the mixed solution for 5 minutes, during which time it was subjected to ultrasonication at a frequency of 45 KHz, and then heated to 70°C. Drying was carried out 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, 5%
It was found that the gas barrier properties were better in the order of Na ₂ CO ₃ treatment, alkali treatment, and methanol treatment. It has been found that the plasma-generated film is affected by the container cleaning method, that is, the surface condition. This container was filled with the same chemical solution and gas as in Example 2 and stored, but no deterioration of the chemical solution was observed.

[Table] Example 13 As shown in FIG. 1, a synthetic resin container with a wall thickness of 1 mm and having one end closed and the other end open was made of polycarbonate. This tubular container was subjected to ultrasonic treatment in a 5% aqueous sodium carbonate solution at a frequency of 40 KHz for 5 minutes, and then dried at a temperature of 60° C. 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 ultrasonication at a frequency of 45 KHz, and then dried at a temperature of 70° C. for 5 minutes. In addition, plasma treatment was performed for 15 minutes in the presence of 100% oxygen gas at a power output of 200W to create a transparent
A synthetic resin container having a 0.14 μm coating on the outer surface was obtained. Inside this container, the concentration 12
% of amino acid (containing tryptophan) infusion, and nitrogen gas was further filled, and the open end was sealed with a rubber stopper while the whole was under reduced pressure. Furthermore, the container was sterilized using 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. Specific Effects of the Invention As described above, the present invention provides a silicon compound having a general formula on the inner surface of a synthetic resin container body having at least one sealable opening or on at least one of the surfaces. It has a gas barrier synthetic resin container having a continuous plasma-treated coating of a mixture of silicon compounds having the general formula, and a drug stored in the container, and the opening is closed to separate the internal atmosphere from the external atmosphere. Since there are drug containers characterized by being blocked, gas permeability, especially oxygen permeability coefficient, is extremely low, and therefore gas permeation from outside the drug container to the inside of the container as well as gas permeation from the inside to the outside of the container is extremely low. will virtually disappear. 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 outside the container into the container is virtually eliminated, and as a result, it can last for a long time. Over a period of time, drug deterioration disappears. In addition, when storing electrolytes such as glucose or physiological saline, there is virtually no gas permeability from the inside of the container to the outside of the container, so even if the water in the electrolyte evaporates, the water vapor will permeate to the outside of the container. Therefore, a predetermined concentration 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. 2A to 2C are partially enlarged sectional views of the drug container shown in FIG. 1, and FIG. 3 is a diagram of a plasma processing apparatus used in the present invention. It is a schematic sectional view showing an example. 1... Drug container, 2... Container body, 2a, 2b
...Transparent film, 3...Opening, 4...Plug member, 5
...Drugs.

Claims (1)

[Claims] 1. On at least one of the inner and outer surfaces of a synthetic resin container body having an opening in at least one location, a general formula is provided. (However, in the formula, m is an integer of 1 to 5.) and a silicon compound having the general formula (However, in the formula, n is an integer from 1 to 5, and R ¹ and R ² are an alkyl or alkoxy group having 1 to 4 carbon atoms, a phenyl group, or a hydroxyl group, but R ¹ and R ² are a gas-barrier synthetic resin container having a plasma-treated continuous coating of a mixture of silicon compounds having hydroxyl groups), and a drug housed in the container;
A drug container characterized in that the opening is closed to shut off an internal atmosphere and an external atmosphere. 2. The drug container according to claim 1, wherein the 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 the general formula is an integer of 1 to 5,
and n in the general formula is an integer of 1 to 5,
The drug container according to claim 1, wherein R ¹ and R ² are an alkyl group or a hydroxyl group having 1 to 4 carbon atoms. 6. The drug container according to claim 5, wherein R ¹ in the general formula is an alkyl group having 1 to 2 carbon atoms, and R ² is a hydroxyl group. 7 Claim 1 in which the drug is an oxidizing substance
The drug container according to any one of Items 6 to 6. 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. 11. The drug container according to any one of claims 1 to 10, wherein the opening is closed by a plug member.