JP2545540B2 - Double-sided laminated rubber stopper - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel structure of a rubber stopper for a vial for sealing a container for storing an injectable drug in a pharmaceutical vial preparation.

[Conventional technology]

The quality characteristics required of rubber stoppers for pharmaceutical vial formulations (hereinafter referred to as rubber stoppers for vials) are naturally
It should comply with the 11th Amendment Japanese Pharmacopoeia rubber stopper test for infusion, but it also has gas permeation resistance, non-elution, high cleanliness, chemical resistance, needle stick resistance, self-sealing property, and high sliding property. Many items are required.

In response to such demands, a technique for laminating rubber stoppers for vials has been developed in recent years, and the present inventors have already developed the technology in Japanese Patent Publication No. 57-53184, Japanese Patent Publication No. 61-162145, and Japanese Utility Model Publication No. 61-314.
In No. 41 and No. 62-17545, the airtightness is improved by laminating a fluorine-based resin with excellent chemical resistance to the chemical contact part and making the other parts a rubber elastic body with excellent airtightness. We propose a rubber stopper with good moisture permeability, chemical resistance, and long-term storage stability. These rubber stoppers by the present inventors have an excellent effect that the particulate foreign matter in the vial formulation sealed by using them is remarkably reduced and the long-term stability of the drug is improved and the quality of the drug can be greatly improved. , Currently widely used in the field.

[Problems to be solved by the invention]

By the way, in the conventional rubber stopper for vials, the contact portion with the chemical was laminated with a fluorine-based resin, but the top surface of the rubber stopper main body improves and modifies the basic property of the rubber, namely the adhesiveness. Silicone coating with excellent impulsiveness is applied for the purpose. This was essential for improving the mechanical transportability of the rubber stopper during formulation. Furthermore, in recent years, as part of the cost reduction accompanying the devaluation of drug prices, there is an urgent need to improve productivity, and as a method therefor, speeding up of machines is progressing. Therefore, in terms of the required properties of the rubber plug, it is necessary to improve mechanical transportability, slidability, high operability, etc., and it is necessary to increase the coating amount of the silicone agent which is a sliding agent.

On the other hand, however, the problem is that the trace amount of silicone coated on the top surface migrates to the formulation machine, and also migrates to the rubber stopper foot (the part that goes into the vial) to cause foreign particles. From this point, it is rather desirable to reduce the coating amount of the silicone agent.

Furthermore, when the injection needle is pierced into the rubber stopper of the vial for the purpose of sucking the drug solution when using the injection drug, the rubber piece may drop due to the thickness of the needle, the finishing state, the shape, etc., and so-called needle stick fragment may occur. However, such needle stick property is becoming a problem. In recent years, in particular, the thickness of injection needles has begun to decrease, but this has the effect of improving the injection operability by increasing the inner diameter without changing the needle outer diameter and increasing the flow rate per fixed time. Because. However, by reducing the wall thickness, the incidence of the above-mentioned needle stick fragment increases.

The present invention has been made in view of the current situation as described above,
Provides a laminated rubber stopper for pharmaceutical vials that satisfies conflicting requirements, has high slidability and mechanical transportability, but does not generate fine particles from the coating material and has a low needle stick fragment generation rate even with a thin needle. The purpose is to do.

[Means for solving problems]

The present invention relates to a rubber stopper used for a pharmaceutical vial preparation, wherein the top surface of the rubber stopper is laminated with a fluorine-based resin film and the whole or a part of the foot portion inserted into the vial on the lower surface of the rubber stopper is used. A double-sided laminated rubber stopper laminated with a fluorine-based resin film and a rubber stopper used for a pharmaceutical vial formulation. The top surface of the rubber stopper is laminated with the fluorine-based resin film and inserted into the vial. The present invention relates to a double-sided laminated rubber stopper in which the entire lower surface of the rubber stopper including the foot portion is laminated with a fluorine-based resin film.

The present invention relates to a rubber stopper having a top surface which is on the upper surface of a rubber stopper for a vial and acts as a lid of a container, and a foot portion which is located below the lid and is inserted into the container. A resin resin film is laminated, but the top surface is laminated with a fluorine resin film instead of the conventional silicone coating, which makes it possible to reduce slidability and mechanical transportability and reduce the generation of fine particle foreign matter. .

Further, as a result of diligent studies by the present inventors on the relationship between the occurrence of the needle stick fragment and the rubber plug, it was found that the higher the surface smoothness of the rubber plug, the lower the occurrence of the fragment. According to the present invention, the needle sticking fragment can be reduced by laminating the top surface with a fluorine resin film having a high degree of lubricity and laminating both surfaces.

If the top surface of the rubber stopper of the present invention is laminated with fluorine resin, a part or all of the foot portion thereof is laminated with fluorine resin, and the sealing portion in contact with the upper edge flange portion of the container remains the rubber element body. Alternatively, all the foot portions and the closed portions, that is, all the rubber lower surfaces may be laminated with fluorine resin.

FIG. 1 is a diagram for explaining a specific example of the rubber stopper of the present invention and its stoppered state. The rubber stopper C has its top surface laminated with a fluorine resin film G ₁ , The foot portion inserted into the upper end opening portion of the filled vial A is laminated with a fluorine resin film G ₂ , but the sealing portion H in contact with the upper edge flange portion B of the mouth portion of the vial A is not laminated and is rubber. The quality part F is left as it is. The rubber stopper C is capped on the vial A, covered with the aluminum casing E, and wound. E'is a winding tightening portion of the aluminum casing E. I is an injection needle.

2 to 4 are a top view, an aa 'sectional view and a bottom view showing an embodiment of the rubber stopper of the present invention suitable for a freeze-dried preparation. C, G ₁ , G ₂ and H mean the same as in the case of FIG. 1, 1 is the top surface, 2 is the foot portion, 3 is the convex portion of the top surface 1 and 4 is the needle stick position on the top surface 1. The recesses 5, 5 are the sealing portions H below the top surface, 6 are the sealing portions H of the foot portion 2, and H remains the rubber element surface. Reference numeral 7 is a cutout portion of the foot portion 2 used for vacuum drying, which is provided at two places. Reference numeral 8 is a deep portion of the notch, and 9 and 10 are convex portions of the foot portion 2, which are portions for keeping the stoppered state.

5 and 6 are a top view and a bb 'sectional view showing an embodiment of the rubber stopper of the present invention suitable for a reduced pressure gas displacement preparation, in which the entire foot portion 2 is laminated (G ₂ ). But
A part 5 of the lower surface of the rubber plug remains the rubber surface.

FIG. 7 to FIG. 9 are a top view, a cc ′ cross-sectional view and a bottom view showing another embodiment of the rubber stopper of the present invention which is suitable for a freeze-dried preparation. In this case, one notch 7 is provided. is there.

10 and 11 are a top view and a d-d 'cross-sectional view showing an embodiment of the rubber stopper of the present invention, which is a modification of the one shown in FIGS. 5 and 6. Fluorine-based resin laminate G ₁ and G _{2 on the} top surface 1 of the stopper and on the bottom surface of the rubber stopper
It is an example that is done.

The rubber stoppers of the types shown in FIGS. 2 to 9 are suitable for a positive pressure preparation having a vial internal pressure higher than the atmospheric pressure, a negative pressure preparation having a vial internal pressure lower than the atmospheric pressure, or a gas displacement preparation. Further, the rubber stopper of the type shown in FIGS. 10 and 11 is suitable for a normal pressure preparation in which the internal pressure of the vial is almost equal to the atmospheric pressure.

In the present invention, as the fluorine-based resin film for laminating the top surface, a part or all of the foot portion or the entire bottom surface, for example, tetrafluoroethylene-ethylene copolymer (ETFE), tetrafluoroethylene-hexafluoropropylene copolymer Polymer (FEP), tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PF
A), chlorotrifluoroethylene-ethylene copolymer (ECTPE), polyvinyl fluoride (PVF), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene (PCTFE), polytetrafluoroethylene (PTF)
E) and the like. The resin for laminating the top surface and the resin for laminating the feet and the entire lower surface may be the same or different.

The thickness of the fluorine-based resin film used for laminating part or all of the top surface or feet is preferably 0.01 to 0.2 mm.If it is less than 0.01 mm, it may be damaged during processing and the product warranty may be insufficient. On the other hand, if it exceeds 0.2 mm, the rigidity is too strong and the self-sealing property and the needle stick property are unsuitable.

In order to obtain a strong adhesive surface between the fluorine-based resin film and the rubber surface, the film surface is pre-treated by a known technique such as corona discharge treatment, plasma discharge treatment, glow discharge treatment, arc discharge treatment, and spatter etching. It is preferable to keep.

Further, depending on the rubber composition and the type of fluorine resin film (for example, PVDF, PVF, etc.), a strong adhesive surface can be obtained only by cleaning the film surface or applying a primer treatment. Whichever method is used, it is important that the adhesive force between the rubber surface and the film is 1 to 30 kg / cm.

The compounding of the rubber used as the element body of the rubber stopper of the present invention may be carried out substantially by a conventional technique. That is, copolymer rubber of isoprene and isobutylene (IIR), rubber chlorinated or brominated of IIR (CIIR, BIIR), copolymer rubber of acrylonitrile and butadiene (NBR), further isoprene triple copolymer (NBIR) , Isoprene rubber (IR), butadiene rubber (BR), styrene-butadiene rubber (SBR), ethylene-propylene rubber (EPM), ethylene-propylene-diene rubber (EPDM), chlorosulfonated polystyrene (CS)
M), ethylene-vinyl acetate copolymer (EVA), styrene-isoprene rubber (SIR), thermoplastic elastomer natural rubber, etc. vulcanizing agent, vulcanization accelerator, vulcanization activator, processing aid, filler, A reinforcing agent and the like are blended to maintain the physical properties and heat resistance of the rubber stopper.

The method for producing a rubber stopper laminated on both sides of the present invention is disclosed in
This is an application of the manufacturing method described in JP-A-57-53184 and JP-A-61-162145. A mold having a rubber plug foot recess is overlaid with a fluorine resin film whose surface has been surface-treated and an unvulcanized rubber sheet, and then vulcanized by pressing and heating with the upper mold. It is molded and then cut according to the shape of the foot, and it is reloaded into the lower mold having the depression of the lower surface of the rubber stopper. Unvulcanized rubber with a fluorine-based resin film pasted on top of it is placed, and vulcanization molding is performed by pressurizing and heating with an upper mold that has a rubber plug top surface shape, and the top surface and feet. The rubber plug of the present invention shown in FIGS. 1 to 9 is obtained by laminating all or a part of the above and also having a sealing portion on the rubber surface. In addition, an upper mold having a recess on the top of the rubber stopper is used with a lower mold having a rubber stopper lower portion, and a sheet in which a fluorine film and an unvulcanized rubber sheet are sequentially laminated between the upper and lower molds is loaded, and Vulcanization molding was carried out by a method of pressurizing and heating, and then the top surface and the bottom surface of the rubber plug were laminated by punching along the outer diameter of the rubber plug, respectively, as shown in FIGS. 10 and 11. The rubber stopper of the present invention is obtained.

〔Example〕

Examples 1 to 4 The following rubber compound parts by weight IIR (JSR Butyl 365, trade name, manufactured by Nippon Butyl Co., Ltd.) 100 zinc white 3 stearate clay (Burges Iceberg, trade name,
60) Processing aid (Hiwax # 110P, trade name, manufactured by Mitsui Petrochemical) 1.2 Magnesium oxide (Kyowamag 150, trade name, manufactured by Kyowa Chemical Industry) 5 White carbon (Carplex 1120, trade name, Shionogi) Pharmaceutical product) 10 titanium oxide 3 sulfur yellow 0.7 di-n-butyldithiocarbamate zinc 0.7 diethyldithiocarbamate zinc 0.5 using a double roll, compounded according to the method described in SRIS3603 (1979), and foot parts Are all the same as 1) below
ETFE film is used, and the top surface is 1) ~
The method of laminating at the same time as the rubber stopper molding using the four types of fluorine-based resin films of 4), each of which has a thickness of 75 μm and one-sided sputter etching treatment product, Daikin industrial product, A rubber stopper was produced (Example 1)
~ 4): 1) ETFE film: NEOFLON ETFE (trade name) 2) PTFE film: Polyflon TFE (trade name) 3) PFA film: NEOFLON PFA (trade name) 4) FEP film: NEOFLON FEP (trade name) First The resin film for G ₂ above 1) and unvulcanized compounded rubber are overlaid on the mold, and the mold is placed on it, and the rubber is pressed at a temperature of 150 ± 1 ° C to form a rubber stopper. Simultaneously with vulcanization, laminate the rubber plug element (foot). Next, after cutting to a predetermined size, the unsealed rubber (foot) is placed in the lower mold, the unvulcanized compounded rubber 1 is placed on it, and G ₁ is placed on the upper surface of the rubber ₁ . Resin film of 1) ~
An upper die having a recess forming a rubber plug head (top surface portion) with any one of 4) was placed and pressed at a temperature of 150 ± 1 ° C. to obtain a rubber plug of FIG. This was cut into individual pieces and then washed.

For comparison, the above rubber composition was used and the foot was laminated as in Example 1) above, and the top surface was left as a rubber element body (Comparative Example 1) and the following 5) by the conventional method. ~ 7) was subjected to surface treatment or lamination by the method of 7) to produce a rubber plug having the same shape as that of the example shown in Fig. 6 (Comparative Examples 2 to 4).

5) Silicone A method: Silicone emulsion with water
Dilute 30 times and brush twice.

6) Silicone B method: A isopropyl alcohol solution containing 1.2% by weight of silicone oil is brushed twice.

7) PP (polypropylene film): Mitsui Polypro (trade name, manufactured by Mitsui Petrochemical Co., Ltd., thickness of 75 μm) For the products of the present invention (Examples 1 to 4) and comparative products (Comparative Examples 1 to 4) obtained above, The following test was conducted. The test results are summarized in the table.

I. Legal test i) Eluted substance test: According to the 11th revised Japanese Pharmacopoeia “Rubber stopper test method for infusion”, properties, foaming, pH, zinc, potassium permanganate reducing substance, evaporation residue, ultraviolet absorption spectrum The item was tested.

ii) Fragment test: In accordance with BS (Pretension Standard) 3263 (1960) and Fragmentation test, fragments (fragments) generated during needle insertion with a rubber stopper.
Count the number of dropouts (rubber pieces / 100 times).

II. Physical property test (voluntary test) i) Measurement of friction coefficient of the top surface of rubber stopper (tilt method): The surface of a flat and well-polished stainless steel plate is wiped with a solvent to dry it sufficiently, and the top of the rubber stopper is placed on top of it. Place it face down. Tilt the stainless steel plate at an angular velocity of 0.3 ° / sec, read the sliding start angle of the rubber plug, and calculate the friction coefficient (μ) using the following formula.

Coulomb's law Friction coefficient (μ) = tan θ ii) Measurement of silicone adhesion (μg): sample rubber stopper 10
100 ml of chloroform was added to each piece and shaken to extract S
The i amount is measured by an atomic absorption spectrophotometric method, and is calculated as a dimethylpolysiloxane amount μg from a calibration curve.

iii) Fine particle test: Add 100 ml of dust-free water (fine particles of 2μ or more are 10 or less in 10 ml) to 10 rubber stoppers for 20
After shaking gently for 30 minutes, leave it for 30 minutes to use it as the test solution. Use an automatic particle counter to measure the number of particles of 2 μm or larger in 10 ml of test solution.

iv) Water absorption test: Five rubber stoppers were placed in a 100 ml beaker, dried at 65 ° ± 1 ° C for 24 hours, allowed to cool in a P ₂ O ₅ desiccator for 15 minutes, and weighed exactly as A. . Next, sterilize in a water-immersed autoclave at 121 ° ± 1 ° C for 30 minutes, then add P ₂ O.
After cooling in ₅ desiccator 15 minutes, and B by precisely weighed its weight again.

V) Heat resistance test (deterioration confirmation test): During autoclave,
After drying 5 sample rubber stoppers sterilized at 121 ° C for 1 hour at 150 ° C for 3 hours, observe the surface change with a magnifying glass 10 times and press the top of the rubber stopper strongly against the aluminum foil. The degree of adhesion is determined.

The test results of Table 1 are summarized as follows.

Dissolution test In Comparative Example 1, the top surface not covered with a rubber surface and having no coating passed all the standards of the Pharmacopoeia, except that the evaporation residue was 3.6 g and failed. In particular, the products of Examples 1 to 4 of the present invention were able to satisfy all the values.

Fragment number Very few of Examples 1-4, Comparative Examples 2 and 3
The silicone-treated product of Comparative Example 1 was next to this, but the uncoated product of Comparative Example 1 and the PP laminate of Comparative Example 4 had many fragments.

The friction coefficient of the top surface of the rubber stopper. Examples 1 to 4 of the product of the present invention in which fluorine-based resins ETFE, PTFE, PFA, and FEP are laminated on the top surface, and Comparative Example 4 in which PP is laminated, the top surface is a rubber element body. It was found that compared with Comparative Example 1 of Comparative Example 1 and Comparative Examples 2 and 3 treated with silicone oil, the frictional resistance to stainless steel was greatly reduced, it was very slippery, and the mechanical transportability was excellent.

Amount of Silicone Adhesion on Rubber Plug Surface No silicone adhesion was observed in Examples 1 to 4 and Comparative Example 4 of the top surface fluorine resin laminate. In Comparative Examples 2 and 3 treated with silicone emulsion or oil, naturally, a large amount of silicone was detected.

Fine Particle Test While the number of fine particles in Examples 1 to 4 was extremely small, a huge number of fine particles were recognized in Comparative Examples 2 and 3 treated with silicone. A large number of fine particles were also found in Comparative Example 4 of the PP laminate.

Water Absorption Test The water absorption rates of the rubber stoppers of the present invention of Examples 1 to 4 are shown in Comparative Examples 1
It was a very low value of 1/10 to 1/120 of that of No. 4.

Heat resistance test According to the observation of the top surface, no change was observed in Examples 1 to 4, but in Comparative Examples 1 to 3, tackiness was observed and the PP film surface in Comparative Example 4 was changed. It turned out that it was thermally deteriorated.

Comprehensive Evaluation From the above test results, all of Examples 1 to 4 of the product of the present invention can be used as a rubber stopper of a pharmaceutical vial formulation (marked with ⊚), and those of Comparative Example 1 and Comparative Example 2 cannot be used (× mark)
Therefore, although those of Comparative Examples 3 and 4 can be used, it was found that there are some problems in heat resistance, the number of fine particles, the number of fragments, etc. (marked by Δ).

〔The invention's effect〕

From the above description and the results of Examples 1 to 4 and Comparative Examples 1 to 4, the difference in effect between the product of the present invention, the conventional product, and the comparative product is clear. That is, the both laminated rubber stoppers of the present invention are rubber stoppers with very little eluate, can prevent generation of fine particles derived from silicone because a silicone coat is unnecessary, and water absorption of the rubber stopper during cleaning and sterilization is almost eliminated. No, it is possible to improve the efficiency such as shortening the time of rubber stopper processing, has excellent mechanical properties at high speed, increases surface lubricity, can prevent fragments at the time of injection needles and needle sticks, and has no mechanical contamination due to transfer of silicone Also, it has the effect that it is not sticky, and stable production is possible without picking it into the freeze dryer top plate.

Therefore, by using the rubber stopper of the present invention, the formulation speed can be increased and a large reduction effect of the formulation cost can be expected, while many conventional products have been generated due to silicone. Since the amount of fine particles is remarkably reduced, a high-quality preparation can be obtained, and in addition, fragmentation due to needle stick during use of the preparation can be prevented.

As described above, the double-sided laminated rubber stopper of the present invention exhibits excellent properties at any time of formulation, storage, and use, and thus greatly contributes to a high-quality pharmaceutical vial formulation.

[Brief description of drawings]

FIG. 1 is a sectional view for explaining a state in which the double-sided laminated rubber stopper of the present invention is capped and wound with an aluminum cab. 2, 3, and 4 are top views showing an embodiment of the rubber stopper of the present invention suitable for use in a freeze-dried preparation, a-
It is an a'sectional view and a bottom view. 5 and 6 are a top view and a bb 'sectional view showing an embodiment of the rubber stopper of the present invention suitable for use in a reduced pressure gas displacement preparation. FIGS. 7, 8 and 9 are top views showing another embodiment of the rubber stopper of the present invention suitable for use in a freeze-dried preparation, c-
It is c'sectional view and a bottom view. 10 and 11 are a top view and d- showing an embodiment of the rubber stopper of the present invention in which the top and bottom surfaces are all laminated.
It is a bottom view of d '.

Claims (2)

(57) [Claims] 1. A rubber stopper for use in a pharmaceutical vial formulation, wherein the top surface of the rubber stopper is laminated with a fluorine-based resin film, and all or one of the legs inserted into the vial on the lower surface of the rubber stopper. A double-sided laminated rubber stopper whose part is laminated with a fluorine-based resin film. 2. A rubber stopper used for a vial preparation for pharmaceuticals, wherein the top surface of the rubber stopper is laminated with a fluorine-based resin film, and the entire lower surface of the rubber stopper including a foot portion to be inserted into the vial. A double-sided laminated rubber stopper laminated with a fluorine-based resin film.