JPH07184978A - Rubber plug of container for medical treatment - Google Patents

Abstract

PURPOSE:To form a rubber plug of silicone rubber as base rubber and to make this rubber plug usable as a rubber plug of a plastic container for infusion. CONSTITUTION:The rubber plug of a desired shape is molded by using the silicone rubber. The rubber plug made of the silicone rubber is good in resealability, eluate, coring and needle prick resistance. However, pull-out of the rubber plug arises. The molded rubber plug is, thereupon, subjected to a surface treatment. A strong acid soln. or strong alkali soln. is used for the treatment. A sulfuric acid, nitric acid and hydrochloric acid are suitable for the strong acid and a sodium hydroxide and potassium hydroxide are suitable for the strong alkali. The rubber plug is immersed into the soln. thereof and is taken out after 5 to 60 minutes. The rubber plug is washed with water and dried. The surface of the rubber plug having a slippery feel is then changed to a dry feel. As a result, the pull-out of the rubber plug made of the silicone rubber does not arise any more.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical container, and more particularly to a rubber stopper of a container containing a liquid medicine for infusion.

[0002]

2. Description of the Related Art A pharmaceutical container containing a liquid medicine is provided with a rubber stopper so that a needle can be inserted. Among the medical containers, infusion containers are rigorously required to have many properties for their rubber stoppers. The required properties will be described below centering on the rubber stopper of the infusion container.

I) Resealability The rubber stopper of the infusion container sometimes sticks a plastic needle in addition to the stainless needle. The plastic needle is thick and not easily cut. The infusion container should be hung upside down. If the plastic needle is pulled out of the rubber stopper and the part is not closed properly, liquid leakage will occur. This is said to have poor resealability of the rubber stopper. Resealability is related to the impact resilience of rubber. Rubber with high impact resilience has good resealability.

Ii) Eluted substance The chemical liquid in the infusion container should not be eluted from the rubber stopper. It's hard to find out what's eluting. Therefore, the Japanese Pharmacopoeia and the method of testing rubber plugs for infusions are the standard. The rubber stopper of the infusion container must pass this test.

Iii) Coring When the needle is pierced into the rubber stopper, the needle sometimes breaks the rubber into small pieces. This is called coring. The pieces of rubber that are torn off enter the liquid medicine and become foreign matter. The rubber stopper is required not to cause coring.

Iv) Needle stick resistance The rubber stopper of the infusion container sticks a plastic needle. Since the plastic needle is thick, it has a large resistance when piercing. It is better to stab the needle with as little force as possible. Needle stick resistance is related to the frictional resistance of rubber. Rubber with low frictional resistance has low needlestick resistance.

V) Rubber stopper removal In a container for infusion, the needle once pierced the rubber stopper may be pulled out. Since a thick plastic needle has a large resistance when it is pulled out, the rubber stopper may come out of the container together with the needle. Since the infusion container is hung upside down, if the rubber stopper comes off, all the drug solution will come out. The rubber stopper omission relates to the friction resistance of the rubber stopper material. Rubber with low friction resistance is easy to pull out.

Next, the rubber stopper of the existing infusion container will be described. The base rubber of the rubber stopper depends on the material of the container.
That is, it is properly used depending on whether it is a glass container or a plastic container.

The glass container uses butyl rubber as a base rubber. Butyl rubber has good eluate and relatively high friction resistance. For this reason, the butyl rubber rubber plug has good properties ii) elution and v) rubber plug omission. But i
ii) Coring, iv) Needle puncture resistance is not sufficient. Also, i) the resealability is very poor. The glass container has a hard mouth. Therefore, I made a slightly larger rubber stopper, pushed it into the container, and crimped it with an aluminum cap. Thus, the rubber stopper made of butyl rubber compensates for the poor resealability by the force from the outside.

A plastic container has a soft mouth. If you push in a large rubber stopper, the mouth of the container will widen. Butyl rubber cannot be used, as no external force is applied to it, unlike glass containers. Instead, isoprene rubber or butadiene rubber, which has high impact resilience and good resealability, is used as the base rubber. However, this rubber stopper also
iv) Needle stick resistance is large. Also, ii) the eluate is poor. In order to pass the rubber plug test method for infusion, it is necessary to process the rubber plug after molding. Even if treated, it may not pass the item of potassium permanganate consuming substance in the rubber stopper test method for infusion. This improvement is strongly desired.

In some rubber stoppers using isoprene rubber or butadiene rubber as a base rubber, a film having a good elution is provided between the rubber stopper and the chemical liquid for the purpose of improving the elution. There is also a Teflon film attached to a rubber stopper. In this way, elution from the rubber stopper into the drug solution is improved. However, from 1992, the rubber stopper test method for infusion will be applied to rubber stoppers using films. Therefore, the eluate of the rubber stopper itself must be improved. The method using a film also has a problem of high cost.

In recent years, the number of infusion containers made of plastic has become larger than that of glass. Therefore, there is a demand for a rubber stopper that can be used for a plastic container. From these problems, rubber stoppers using silicone rubber as a base rubber have been studied. Silicone rubber has high impact resilience,
Since the frictional resistance is small, this rubber stopper has i) resealability,
ii) eluate, iii) coring, iv) needle stick resistance,
Is satisfied. Particularly, ii) eluate and iv) needle stick resistance are very excellent. However, v) there is a problem with the rubber plug coming off. If this rubber stopper is applied to a plastic container with a soft mouth, the rubber stopper will come out of the container when the needle is pulled out. This is because the friction coefficient of silicone rubber is very small. iv) The excellent needle stick resistance is due to the small friction coefficient. The present inventor has tackled this problem and invented an improved rubber stopper. (Patent Application No. 2-236629, Patent Application No. 2-419260
No.) These are very good rubber stoppers for infusion containers. However, these were also not sufficient with respect to iv) needle stick resistance.

[0013]

SUMMARY OF THE INVENTION The present inventor has found that a rubber stopper made of silicone rubber has the following properties v) among the properties required for the rubber stopper.
We paid attention to the fact that all the items other than the rubber plug removal were satisfied. Therefore, the inventors have invented a rubber plug which uses silicone rubber as a base rubber and which has improved v) rubber plug removal without changing other properties. As described above, the rubber stopper of the infusion container is required to have a high level of property.
Therefore, it can be said that a rubber stopper that can be used for an infusion container can also be used as a rubber stopper for all other pharmaceutical containers.

[0014]

The rubber stopper of the pharmaceutical container of the present invention is manufactured as follows. Make a rubber stopper using silicone rubber as the base rubber. Surface treatment of the molded rubber stopper with a strong acid solution or a strong alkali solution. This will be described in detail below.

A rubber stopper is made using silicon rubber as a base rubber. The rubber stopper of the present invention can have almost any type of silicone rubber as a base rubber. The hardness of the rubber stopper of the plastic container for infusion is 40
A type near the degree (JISA) is suitable. Table 1 exemplifies the composition suitable for the rubber stopper of the present invention and the crosslinking conditions. A rubber plug having a desired shape is molded under the set composition and crosslinking conditions.

[0016]

[Table 1]

The molded rubber stopper is surface-treated with a strong acid solution or a strong alkali solution. Surface-treat the rubber stopper molded in. A strong acid solution or a strong alkali solution is used for the treatment. It is preferable to use sulfuric acid, nitric acid, or hydrochloric acid as the strong acid solution. Appropriate concentrations are about 24 to 10 normal for sulfuric acid, 13 to 10 normal for nitric acid, and 12 to 10 normal for hydrochloric acid. It is preferable to use sodium hydroxide or potassium hydroxide as the strong alkaline solution. Both are aqueous solutions having a concentration of 15 to 12 N.

The surface of the rubber stopper is treated with the prepared solution. Any method may be used as long as the molded rubber stopper can be surface-treated with a strong acid solution or a strong alkali solution,
It is safe to immerse the rubber stopper in the solution. Immerse the rubber stopper molded in step 1 into any of the solutions described above.
When a strong acid solution is used, it is left at room temperature for 5 to 40 minutes, and when a strong alkaline solution is used, it is left at room temperature for 30 to 60 minutes.
Then, the rubber stopper is thoroughly washed with water and dried.

[0019]

The rubber stopper of the present invention is formed into a desired shape by using silicon rubber as a base rubber. If there is a molding die that has been used until then, that die may be used. The molded rubber stopper is immersed in a strong acid solution or a strong alkaline solution, and after a certain period of time, the rubber stopper is taken out and washed with water. Then, the surface condition of the rubber plug changes. The untreated rubber plug has a nulled surface condition as if it was coated with a lubricant. When this is surface-treated as described above, the surface condition of the rubber plug is dry and smooth. This is because the silicone molecules on the surface of the rubber stopper were attacked by the strong acid solution or the strong alkaline solution. That is, in the silicone molecule, the bond of the main chain is broken by the strong acid solution or the strong alkaline solution. Long time,
If the rubber stopper is left in a strong acid solution or a strong alkaline solution, the rubber stopper will be torn by hand. Therefore, in the present invention, the immersion time is set to 5 to 60 minutes. During this time, the main chain of the silicone molecule on the surface of the rubber stopper is cut. Under the surface treatment conditions of the present invention, the thickness of the molecule whose main chain is cleaved is
It is about 0.5 to 10 μm from the surface.

Since the rubber stopper is thoroughly washed with water after the immersion, the inside of the rubber stopper is not affected at all. Among the properties required for the rubber stopper of the pharmaceutical container, i) resealability ii) elution property iii) coring iv) needle stick resistance depends on the internal properties of the rubber stopper. In the present invention, the surface of the rubber stopper is treated to change only the surface layer, so that these properties are at the same level as the untreated rubber stopper. When the rubber plug is surface-treated, it loses the smoothness peculiar to silicone on the surface and has a high friction coefficient. Therefore, the rubber stopper after the surface treatment does not cause v) the rubber stopper coming off.

[0021]

【Example】

Example A) Example of treatment with a strong acid solution Under the conditions shown in Table 1, a rubber plug of a soft bag for infusion is molded. The rubber stopper is dipped in 18N sulfuric acid and left at room temperature for 20 minutes. Then, it is thoroughly washed with water and dried. The surface of the untreated rubber stopper feels slimy to the touch, but after the treatment, it becomes a dry and dry surface.

Example B) Example of Treatment with Strong Alkaline Solution A soft stopper rubber plug for infusion is molded under the conditions shown in Table 1.
This rubber stopper is dipped in a 14N sodium hydroxide aqueous solution and left at room temperature. After about 40 minutes, it is taken out, washed with water and dried. As with Example A), this rubber stopper had a smooth surface after treatment.

(Experiment) Using the rubber stoppers of Examples A and B described above, an experiment was conducted on the eluate and the rubber stopper removal. As a control, a rubber stopper of Example A which was not surface-treated and a rubber stopper currently used for a soft bag for infusion (base rubber is isoprene rubber) were used. Next, the test method will be described. The elution property is Δ according to the Japanese Pharmacopoeia and the rubber stopper test method for infusion.
Two items were tested: pH and potassium permanganate reducing substances. For the rubber stopper removal, an actually used plastic container assembled with a sample was used. The mating force of this rubber stopper was tested by strograph.

The results are shown in Table 2. Although the eluate had no problem in ΔpH in any of the samples, it caused a difference in the potassium permanganate reducing substance depending on the sample. That is, the samples of silicone rubber, Example A, Example B, and Example A without surface treatment all had small values, but the current rubber plugs of isoprene rubber exceeded the standard value. The rubber stopper is
It can be seen that the value of the rubber plug of Example A, which is not surface-treated, is half that of the current rubber plug, and it is easy to pull out. However, the values of the surface-treated rubber stoppers of Examples A and B are equal to or higher than those of the current rubber stoppers, and it can be said that these rubber stoppers do not cause the rubber stopper to come off.

[0025]

[Table 2]

Using the above-mentioned four samples, resealing, coring, and needle puncture resistance were also easily tested. The result was resealability, and coring was at the same level as the current rubber stopper (made of isoprene rubber). The needlestick resistance was far superior to the current rubber stopper, and it was a rubber stopper that the needle can pierce with a small force. This is due to the low friction coefficient peculiar to silicone rubber. The rubber stopper of the present invention can be manufactured by a simple method of surface-treating a rubber stopper molded using a conventional mold.

[0027]

[Effect] The rubber stopper of the pharmaceutical container of the present invention uses silicone rubber as a base rubber. Silicone rubber is one of the properties required for a rubber stopper of an infusion container, i) resealability, i
A base rubber capable of producing a rubber stopper excellent in i) eluate, iii) coring, and iv) needle stick resistance. The rubber stopper of the present invention is also superior in terms of these properties to the rubber stopper using other rubber as a base rubber.

However, since the silicone rubber has a small friction coefficient, v) the rubber plug was pulled out. This problem was solved by surface-treating the rubber stopper. As can be seen from the above experimental results, the force required to pull out the rubber stopper of the present invention is about twice that of the untreated rubber stopper, which is the same level as the current rubber stopper (made of isoprene rubber). . That is, the rubber stopper of the present invention is a rubber stopper excellent in all the properties required for the rubber stopper of the infusion container. Therefore, it can be sufficiently used as a rubber stopper of a pharmaceutical container. Furthermore, the rubber stopper of the present invention eliminates stickiness on the surface. It is easy to handle because the rubber stopper does not become sticky in the process of assembling the rubber stopper in the pharmaceutical container. That is, the workability of the assembly process can be improved.

Claims (1)

[Claims] 1. A rubber stopper for a pharmaceutical container, characterized in that a rubber stopper is molded using silicone rubber as a main base rubber, and the molded rubber stopper is surface-treated with a strong acid solution or a strong alkaline solution.