WO1998058842A1 - Method for sterilizing packages of medical supplies - Google Patents

Abstract

A sterilization method which comprises the step of enclosing a medical supply together with a deoxidizer in an oxygen-impermeable packaging material to give a package, the step of sterilizing the package by radiation while maintaining the atmosphere in the package in a state with a reduced oxygen concentration, and the step of, after the completion of the radiation sterilization, further reducing the oxygen concentration with the deoxidizer while maintaining the package under the sterile conditions. In this method, the oxygen concentration can be maintained at a low level during the sterilization while sustaining the sterilization efficiency of the radiation sterilization and the oxygen concentration is also maintained at a low level during the subsequent storage, which makes it possible to inhibit the formation of harmful by-products, thus ensuring the provision of highly safe medical supplies.

Description

 Description Sterilization method of medical device package Technical field

 The present invention relates to a method for sterilizing a medical device package and a medical device package sterilized by the method. More specifically, for example, by encapsulating both a medical device and a delayed-acting oxygen scavenger in an oxygen-impermeable material, medical devices that prevent the formation of by-products due to oxidation after radiation sterilization The present invention relates to a method for sterilizing a tool package.

Background art

 At present, radiation sterilization methods such as gamma linear sterilization are widely used as sterilization methods for medical device packages. For example, disposable medical devices such as artificial dialysis machines are sterilized by radiation after being enclosed in packaging materials and delivered to users in that state in order to maintain sterility until just before use.

 When oxygen is present in the packaging material, for example, when the hollow fiber membrane type cell mouth-acetate membrane is used in an artificial dialysis machine, the acetate group constituting the membrane is used. Oxidation produces aldehydes, such as acetoaldehyde and formaldehyde, which may have an adverse effect on patients who are users. In addition, the main material of the dialysis machine is plastic, and the strength may decrease due to the oxidization over time due to oxygen excited during radiation sterilization.

 To solve the problems caused by these oxidations, it is necessary to remove oxygen from the packaging material. However, gamma linear sterilization is a method that can achieve excellent sterilization effects in the presence of oxygen, although it is possible even in the absence of oxygen.

For this reason, in the conventional method, an artificial dialyzer is placed in a gas-permeable sterilization bag, which is sterilized by gamma, and then put into an aluminum packaging material while keeping the sterilization bag while maintaining the sterility. The nozzle is inserted into the aluminum packaging material, the air in the packaging material is evacuated by a vacuum pump, and nitrogen gas is injected. This process is performed twice in order to reduce the amount of oxygen removed. After that, the nozzle is pulled out, sealed, and shipped. In this way, the gas permeable The air in the packaging material is replaced with nitrogen gas to remove oxygen without compromising the sterility of the sterilization bag.

 However, the conventional methods described above clearly have poor workability and low productivity. Also, it is difficult to replace the air inside the dialysis machine, so the efficiency of oxygen removal is not good.

 Considering workability and productivity, it is also conceivable to put the oxygen absorber in the oxygen-impermeable material packaging before sterilization before sterilization. In order to obtain a sufficient sterilization effect, it is necessary to increase the gamma dose by one dose.

 Another method of sterilizing a blood processing apparatus is disclosed in Japanese Patent Publication No. Hei 4-70023 (USP4, 813, 210). In this method, the blood processor is first placed in a gas-permeable bag for sterilization, and then the bag containing the blood processor is placed in an oxygen-impermeable bag together with a deoxidizer and sealed. Yes, oxygen is removed by the oxygen scavenger, preventing the blood processor from deteriorating. According to this gazette, performing gamma linear sterilization in the presence of an oxygen scavenger significantly increases the D value, especially when the blood processing device is a blood processing device using a cellulose acetate hollow fiber membrane. (Column 5, line 5, line 1, column 6, line 1). Therefore, according to this method, it is preferable that the gamma linear sterilization be performed without the presence of an oxygen scavenger.

Furthermore, Japanese Patent Publication No. 5-509496 discloses a method in which a hollow fiber type blood processor and an oxygen scavenger are both sealed in a container made of a gas impermeable material and irradiated with radiation for sterilization. Have been. Examples of the radiation include gamma rays (Claim 2), and examples of the blood processor include a blood processor using a regenerated cellulose hollow fiber membrane (Claim 5). According to the present invention, oxygen in the container is absorbed by the oxygen scavenger, and is in an oxygen-free state during sterilization (column 4, line 10, line 15). This publication does not mention that the absence of oxygen during sterilization reduces the sterilization effect. Increasing the radiation dose is sometimes undesirable because radiation also affects the material of the dialyzer. Therefore, the present inventors did not require the necessary increase in radiation dose in the invention disclosed in Japanese Patent Publication No. 5-50964, and disclosed the invention in Japanese Patent Publication No. 5-509946. As small as can be obtained with the disclosed invention. They faced the technical challenge of providing a method that could sterilize the dialyzer with no steps.

Disclosure of the invention

 According to the present inventors, it has been observed that the sterilization effect is obtained by the formation of oxygen radicals during gamma ray irradiation, and that oxygen radicals are obtained by influencing and killing bacteria. It was found that the sterilization effect was obtained even at low oxygen levels. That is, there was no substantial change in the sterilization effect if the oxygen concentration was above 0.1%, preferably above 0.2%, more preferably 1% or above.

 On the other hand, oxygen radicals formed during sterilization can affect the material of dialysis machines, especially in the case of dialysis machines made from regenerated cellulose, and may generate aldehydes. On the other hand, the present inventors have also found that performing sterilization under a reduced oxygen concentration can suppress the generation of unwanted by-products while maintaining the sterilization effect. That is, when the reduced oxygen concentration is lower than 4-5%, preferably lower than 2%, and more preferably 1% or lower, excellent production conditions are obtained. Thus, the present inventors have reached the present invention, and the effects of the present invention can be explained by harmful substances such as aldehydes generated by irradiation for sterilization. That is, according to the sterilization in the reduced oxygen atmosphere of the present invention, almost no such harmful products were generated. In addition, radiation sterilization may initiate a reaction that will later produce harmful products under the influence of oxygen.

 The prior art states that this technical challenge in providing medical devices, the sterilization with reduced oxygen concentration, minimizes the formation of harmful products, but maintains the sterilization effect without much power. That is, none deal with the combined issues. Furthermore, the reduced oxygen concentration during long-term storage also minimizes the production of harmful products during long-term storage. Everything is done in an oxygen-impermeable wrapping material without introducing other materials or using double wrapping.

That is, the first object of the present invention is to provide a medical device and an oxygen absorber in an oxygen-impermeable packaging material. A step of performing radiation sterilization on the package while maintaining the atmosphere in the package at a reduced oxygen concentration; maintaining the sterilized state of the package after the radiation sterilization A method of sterilizing a medical device package, further comprising a step of reducing the oxygen concentration with a deoxidizer. Products manufactured in this manner are harmful due to the reduced oxygen atmosphere during sterilization while maintaining the efficiency of sterilization by radiation sterilization, and the reduced oxygen concentration during subsequent storage. It was possible to suppress the generation of by-products, and thus to avoid an increase in irradiation dose.

 Preferably, the reduced oxygen concentration is above 0.1%, preferably above 0.2%, more preferably at or above 1%. Further, the reduced oxygen concentration is below 5%, preferably below 4%, more preferably below 2%, even more preferably 1% or below. Furthermore, the reduced oxygen concentration after sterilization is below 0.1%.

 The method comprises sealing the package under a reduced oxygen concentration atmosphere, and encapsulating the oxygen scavenger in a sealed packaging material having opening means such as breaking means; and Can be carried out by radiation sterilization under a reduced oxygen concentration, then breaking the breaking means and exposing the oxygen absorber to the atmosphere inside the package to further reduce the oxygen concentration. The breaking means may be one that breaks under the influence of radiation sterilization.

 However, a preferred method of the present invention is a method in which the oxygen scavenger is sealed in a sustained-release packaging material, whereby the oxygen concentration of the package can be reduced at a constant rate at a certain rate. The package is illuminated when reduced to the desired value. This method provides very favorable manufacturing conditions and provides an improved method with very limited manufacturing steps. The invention also relates to a product made by the method described above.

 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing an embodiment of the medical device package according to the present invention from above, FIG. 2 is a diagram showing an embodiment of the medical device package according to the present invention from the side, FIG. Sectional view schematically showing one embodiment of the laminate used for the oxygen scavenger packaging material, 5 FIG. 4 is a side view of another embodiment of the medical device package according to the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

 In a preferred embodiment of the present invention, the medical device and the delayed-acting oxygen scavenger packaging material are both enclosed in a packaging material made of an oxygen-impermeable material.

 The above-mentioned delayed-acting oxygen scavenger packaging material is a gas-permeable packaging material in which a relatively small air permeability can be obtained stably, in which the oxygen scavenger is stored, and the medical device packaging for radiation sterilization. The body has an oxygen concentration above 0.1%, preferably above 0.2%, more preferably at or above 1%, and below 5%, preferably below 4%. More preferably, the oxygen concentration is controlled to be less than 2%, more preferably 1% or less, and the oxygen concentration after 2 weeks of radiation sterilization is controlled to be less than 0.1%.

 Radiation sterilization is usually performed within 3 to 7 days after the completion of the production of medical devices. In the above, the oxygen concentration in the packaging material is described assuming that radiation sterilization is performed 5 days after the completion of production. This was adopted as a criterion to indicate the degree of delayed action of the oxygen scavenger package and does not mean that radiation sterilization should be performed 5 days after encapsulation.

 The oxygen concentration can be realized, for example, by controlling the air permeability of the material constituting the packaging material, and various types of resin films made of synthetic polymers or natural polymers, woven fabrics conventionally used in the field of laminates One material having desired air permeability may be selected from nonwoven fabrics and the like, or these materials may be appropriately combined to form a laminate to obtain desired air permeability. Further, if necessary, a ventilation hole may be provided in some or each layer of the laminate to obtain a desired air permeability. The thickness of each layer is appropriately set.

As shown in Fig. 3, the inner layer perforated plastic film 6 (hereinafter referred to as the inner layer film), because of its low breathability and low danger of the oxygen scavenger leaking out of the packaging material. A cross-sectional breathable sheet 7 and an outer layer plastic film 8 (hereinafter, referred to as an outer layer film) are laminated in this order from the inside of the packaging material containing the oxygen scavenger. Ventilate through the exposed section of the air-permeable sheet at the end section of the packaging material, or reduce the porosity of the outer film to the inner film. It is preferable that a laminated body having a structure in which ventilation is further provided by providing a ventilation hole to control the ventilation is used for at least a part of the packaging material.

 When vents are provided in the outer layer film, the porosity (the ratio of the open area to the total area of the outer layer film) is preferably less than 1%. The porosity of the inner layer film is not particularly limited, but is usually 1 to 10%.

 The oxygen scavenger packaging material is used to reduce the oxygen in the various sizes of packaged goods to which it is applied within two weeks after radiation sterilization within a certain period of deoxidation required to obtain good preservability. In order to absorb and remove to less than or equal to%, the oxygen absorber, the size of the packaging material used for packaging the oxygen absorber, and the air permeability must be changed according to the amount of oxygen present in the article package when the oxygen absorber is enclosed.

 The air permeability suitable for the delayed-acting oxygen absorber packaging material used in the medical device package of the present invention is as follows: the moisture permeability of the oxygen absorber packaging material is P (mg / 24 Hrs) as a measure of air permeability; Assuming that the amount of oxygen present in the package at the time of packaging is V (ml), the value K represented by the following relational expression is preferably 10 or less, more preferably 8 or less.

K-P / V ^1/3

 The moisture permeability P of the oxygen scavenger packaging material was determined by filling a sample filled with anhydrous calcium chloride in place of the oxygen scavenger packaging material (oxygen scavenger) at 25 ° C or lower and 75% RH. Determined by storing within a desiccated overnight humidified condition and measuring the weight gain per sample 24 hours later.

Materials for the inner layer film and the outer layer film include polymers of olefins such as ethylene, propylene, butene, pentene, and hexene, vinyl chloride, vinylidene chloride, vinyl acetate, vinyl alcohol, acrylate, and methacrylate. And polymers of vinyl compounds such as acrylonitrile and styrene, polymers of diolefins such as butadiene and isoprene and copolymers thereof, polyamides and polyesters. Of these, polyester, polyamide, and polyolefin are preferred for the outer layer film, and polymers of polyolefin or vinyl compound having a lower melting point than the outer layer film are preferred for the inner layer film so that bag making by heat welding is easy. . Polyester is more preferably used for the outer layer film, and polyethylene is more preferably used for the inner layer film. The cross-sectional breathable sheet is a laminate-like sheet that has air permeability in the plane direction at least inside the thickness thereof, and is preferably made of paper or nonwoven fabric, and is printed on the inner surface or outer surface of the outer layer film. A layer may be provided, and a reinforcing layer or the like may be provided at an arbitrary position.

 The laminate shall be folded or laminated with the perforated plastic film inside, sealed with an oxygen scavenger, and sealed to form a three-sided or four-sided sealed bag. In addition, a deoxygenating agent may be sealed in the laminated body, and a non-breathable plastic film may be stacked and sealed to form a four-side seal bag.

 The sealing may be performed using an adhesive, but it is preferable to heat seal the plastic film as a sealant.

 As the oxygen scavenger, those mainly containing iron powder, which can use various compounds conventionally used in this field, are preferable. Further, an auxiliary such as a water donor impregnated with water on a porous carrier, activated carbon, or silica may be appropriately selected and added to the oxygen scavenger.

 As the packaging material of the oxygen-impermeable material, any material conventionally used in the field of laminates, for example, a metal foil, a metal deposition film, a metal oxide deposition film, a glass deposition film, a vinylidene chloride synthetic resin, Those containing at least one layer of a vinylidene acetate-based synthetic resin, an acrylonitrile-based synthetic resin, or the like can be used. In terms of ease and efficiency of use, for example, the outer layer is made of nylon, the intermediate layer is a laminate of EVOH (ethylene vinyl acetate polymer, saponified), the inner layer is a laminate of polyethylene, the outer layer is nylon, and the intermediate layer is A laminate of polyvinyl alcohol, an inner layer of polyethylene; an outer layer of polyester, an intermediate layer of aluminum foil, and an inner layer of polyethylene are preferred.

 Although the medical device is not particularly limited, considering the effects of the present invention, an artificial dialyzer which has conventionally been considered unsuitable for radiation sterilization, particularly a regenerated cellulose membrane of a hollow fiber membrane type, particularly a cellulose acetate membrane Suitable for use are artificial dialysers that use dialysis and medical devices that are susceptible to adverse effects such as deterioration due to oxygen.

Radiation sterilization is used as a sterilization method. Among them, gamma ray sterilization is preferable from the viewpoint of cost. Example

 Hereinafter, the medical device package of the present invention will be described with reference to preferred embodiments shown in the accompanying drawings. 1 and 2 are views showing one embodiment of the medical device package according to the present invention at different angles. As shown in FIGS. 1 and 2, the main body of the medical device 1 is sealed together with the oxygen-absorbing material 2 in an oxygen-impermeable material.

 First, an oxygen-impermeable laminate sheet (Pairflex FA29I trade name, manufactured by Kureha Chemical Co., Ltd.) used on the bottom side 5 of the packaging material is drawn out of the roll, heated by a heater, and air-heated. And pressed into a mold to form a concave shape with a medical device enclosure as shown in FIG.

 Next, the oxygen scavenger packaging material 2 (Ageless Z—300 PK gas, moisture permeability of the package 3 O mg / 24 Hr, trade name, product of Mitsubishi Gas Chemical Co., Ltd., manufactured by Mitsubishi Gas Chemical Co., Ltd.) is automatically loaded by the automatic feeding machine. Put in the center of part 5. Next, the medical device is placed on top of it, and the oxygen-impermeable laminate sheet (Boblon, trade name, product of Kureha Chemical Co., Ltd.) used for the packaging material top 3 is pulled out of the roll and the packaging material bottom It is overlapped with the part 5, and the periphery is sealed and sealed by heat sealing (the amount of oxygen at the time of sealing is about 120 ml).

 Aldehyde formation

 Using a cellulose acetate hollow fiber membrane-type artificial dialyzer as a medical device, and after irradiating 25 KGy of gamma rays, the effect of this example on the degree of aldehyde generation in the artificial dialyzer A comparison was made between the case where the oxygen scavenger package was sealed, the case where the package was not sealed, and the case where the conventional nitrogen gas replacement treatment was performed.

 The oxygen concentration in the packaging material of the oxygen-impermeable material of the medical device package of this example was 1% at the time of radiation sterilization, and 0.1% or less two weeks after the sterilization.

 Method

 First, each of the above three test samples is primed and washed with 150 ml of distilled water only on the blood side. Thereafter, 500 ml of distilled water at 37 ° C is circulated at 6:00 at a flow rate of 400 ml / min only on the blood side. This extract is used as a specimen.

The measurement is performed by reversed-phase high-performance liquid chromatography using acetoaldehyde and formaldehyde as hydrazone derivatives, a column packed with octyl groups in the stationary phase, and acetonitrile / water as the mobile phase. procedure

 1) Mix 4. ml of the sample with 2.0 ml of the hydrazine reagent (0.2 g of 2,4-dinitropheninolehydrazine dissolved in 2M-HC1 to 500 ml).

2) Pour the mixed solution into the pre-treatment cartridge Sep-Pak C18 and let it pass through the cartridge.

 3) Wash with distilled water (2 x 5m1), elute with 1.6m1 of acetonitrile c

4) Measure the eluate by liquid chromatography.

Liquid chromatography-Measurement conditions:

 Mobile phase—acetonitrile / water

 Flow velocity 1.7 m 1 / m i n

 Power ram temperature 1-25. C

 Wavelength-340 nm

 Injection volume-1 0 ^ 1

 Concentration adjustment — 0 min, acetonitrile 35%

 6min, acetonitrile 80%

 7 min, acetonitrile 35%

 Table 1 shows the results.

上記の比較試験の結果から、 本実施例によれば、 遅効性の脱酸素剤包材を使用 することによって、 アルデヒド類の生成を低減させることができることが明らか である。 (Table 1 p pm)

From the results of the above comparative tests, it is clear that according to the present example, the production of aldehydes can be reduced by using a delayed-acting oxygen scavenger packaging material.

According to the present embodiment, by using a packaging material made of an oxygen-impermeable material, There is almost no need to consider the ingress of oxygen. Also, the oxygen present in the packaging material at the time of sealing is absorbed by the enclosed slow-acting oxygen absorber packaging material at the same time, and the interior of the packaging material is almost completely oxygen-free until the packaging material is opened immediately before use. Can be kept.

 As a result, it is possible to prevent the formation of by-products due to oxidation in the medical device package, for example, the formation of aldehydes due to oxidation in an artificial dialysis machine using a hollow fiber membrane-type cellulose acetate membrane. Therefore, the possibility of adversely affecting the patient who is the user can be reduced, and a safer product can be provided. In addition, it is possible to prevent the strength of the plastic material from decreasing over time.

In addition, when ordinary oxygen scavenger packaging is used, deoxidation is completed before performing gamma linear sterilization, and the sterilization effect may be affected. Since oxygen is reliably left at the time of irradiation by using a neutral oxygen-absorbing material packaging material, the production of medical devices can be transferred to the sterilization process with a margin. Moreover, this series of operations is greatly simplified, and the productivity is expected to increase dramatically. Table 2 summarizes the differences in the effects of the three methods: no oxygen scavenger, nitrogen gas replacement, and oxygen scavenger use. The conventional oxygen absorber is a gas permeable packaging material containing the oxygen absorber.

Table 2

 FIG. 4 is a view showing another embodiment of the medical device package according to the present invention. The oxygen scavenger packaging material 2 ′ has a breaking pin 9 as an opening means. The outer film is impervious to oxygen and breaks the breaking pin 9 until the interior of the oxygen absorber 2 ′ is exposed to the oxygen atmosphere inside the package consisting of the package top 3 and package bottom 5. The oxygen cannot enter the oxygen scavenger 2 '.

Industrial applicability

 ADVANTAGE OF THE INVENTION According to this invention, the by-product from a medical device by time-dependent oxidation, for example, the production | generation of aldehydes was suppressed in the hollow fiber membrane type artificial dialyzer of a cellulose acetate, The safe medical device package. Is supplied.

Claims

The scope of the claims 1. A step of storing a medical device and a deoxidizer in an oxygen-impermeable packaging material to form a package; performing radiation sterilization on the package while maintaining the atmosphere in the package with a reduced oxygen concentration. A method of sterilizing a medical device package, comprising: a step of reducing the oxygen concentration with a deoxidizing agent while maintaining the sterilized state of the package after radiation sterilization.  2. The method according to claim 1, wherein the reduced oxygen concentration in the step of performing radiation sterilization is above 0.1%, preferably above 0.2%, more preferably 1% or above.  3. The method according to claim 2, wherein the reduced oxygen concentration in the step of performing radiation sterilization is below 5%, preferably below 4%, more preferably below 2%, more preferably below 1%. The described method.  4. The package according to claim 1, 2, or 3, wherein a reduced oxygen concentration is obtained by sealing the package in a reduced oxygen concentration atmosphere, and the package is radiation-sterilized substantially immediately after sealing. Method.  5. The oxygen absorber is enclosed in a sealed packaging material having an opening means, and the opening means is operated after radiation sterilization to expose the oxygen absorber to the atmosphere inside the package. the method of.  6. The method of claim 5, wherein the opening means is a breaking means, and wherein the actuating the opening means comprises breaking the breaking means.  7. The method according to claim 6, wherein the opening means is operated by radiation sterilization.  8. The oxygen-absorbing agent is a delayed-acting oxygen absorber packaged in a sustained-release packaging material, and after the oxygen concentration has been reduced to the reduced oxygen concentration by the delayed-acting oxygen absorber. 4. The method according to claim 1, 2 or 3, wherein radiation sterilization is performed.  9. The method according to claim 18, wherein the medical device comprises a regenerated cellulose material.  10. The method according to claim 9, wherein the medical device is a dialyzer.  11. A product obtained by the method according to any one of claims 110. 12. Stored in oxygen-impermeable packaging with oxygen absorbers to reduce oxygen concentration And radiation sterilized, sterile medical device packaging.  13. The sterilized medical device package according to claim 12, wherein the oxygen scavenger is enclosed in a packaging material provided with an opening means.  14. The sterilized medical device package according to claim 13, wherein the opening means is a breaking means.  15. The sterilized medical device package according to claim 13, wherein the opening means is made of a material that can be broken by radiation sterilization.  16. The sterilized medical device package according to claim 12, wherein the oxygen scavenger is a delayed-acting oxygen scavenger packaging material enclosed in a sustained-release packaging material.  17. The delayed-acting oxygen absorber packaging material contains an oxygen absorber in a gas-permeable packaging material. The oxygen concentration of the medical device package during radiation sterilization should be higher than 0.1%. Preferably above 0.2%, more preferably 1% or above, and below 5%, preferably below 4%, more preferably below 2%, even more preferably 1% or above. 17. The sterilized medical device package according to claim 16, wherein the oxygen concentration after two weeks of radiation sterilization is controlled to be lower than 0.1%.  18. Slow effect '[A part or all of the raw oxygen scavenger packaging material consists of a laminated body laminated in this order from the inside containing the oxygen scavenger to the perforated plastic film / cross section breathable sheet plastic film. A packaging material having a cross-section of the laminate on at least one of the ends of the packaging material, wherein the ventilation control of the packaging material controls the ventilation from the cross-section of the cross-sectional ventilation sheet exposed at the packaging material end. In addition to the force performed in the above, or the ventilation from the cross section, the ventilation is controlled by providing ventilation holes having a pore ratio smaller than the pore ratio of the perforated plastic film in the plastic film on the surface of the laminate. The sterilized medical device package according to claim 16, wherein the package is performed.  19. The sterilized medical device package according to claim 17, wherein radiation sterilization is performed between 3 days and 7 days after the sealing of the medical device package.  20. When the moisture permeability of the delayed-acting oxygen scavenger packaging material is P (mg / 24H rs) and the oxygen content in the package when the medical device package is sealed is V (ml), the following formula is used. The sterilized medical device package according to claim 19, wherein the ventilation of the delayed-acting oxygen absorber packaging material is controlled so that the value to be obtained is 10 or less. K = P / V ^{I 3} 21. The sterilized medical device package according to any one of claims 12 to 20, wherein the medical device contains a regenerated cellulose material.  22. The sterilized medical device package according to claim 21, wherein the medical device is a dialyzer.