JPS60139253A - Pasturization of medical tool or material thereof - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for sterilizing medical devices or materials thereof.

Sterilization methods for medical devices include gas sterilization (mainly ethylene oxide), radiation attenuation, heat sterilization, and chemical sterilization (mainly formalin and glutaraldehyde).

Gas sterilization is one of the most common methods for sterilizing medical tools, but it requires dry conditions due to the problem of gas remaining in the product and the constraints on its application. It is said that if ethylene oxide remains, it may cause an allergic reaction in the human body, and repeated use on the same patient may increase eosinophils in the blood, which is undesirable.

Radiation sterilization has become relatively popular in recent years, but it is not only expensive for equipment and processing, but also has restrictions on the materials to which it can be applied. Furthermore, even if the material is said to be applicable, it may not be applicable because it is susceptible to deterioration due to the influence of small amounts of coexisting additives. In general, there are still many unknowns about the effects of radiation irradiation on product characteristics, and investigating product characteristics requires considerable effort and time, and the case of medical devices is no exception.

On the other hand, although heat sterilization is relatively widely used as a method of sterilizing medical devices, the application range is severely restricted because the material deteriorates due to the application of high heat.

Furthermore, even when heat-resistant plastic materials are used, trace amounts of stabilizers, plasticizers, and other substances may be extracted into the solution, leading to safety concerns.

Sufficient consideration must always be given to toxicity.

As mentioned above, there are several methods for sterilizing medical devices, each of which has its advantages and disadvantages, and is used depending on the characteristics of the object to be sterilized, the ease of use of the medical device, the workability of sterilization, etc. Considering economic efficiency, it is often necessary to sterilize the solution without heating it. Conventionally, sterilization methods have been carried out using chemicals such as formalin and glycaldehyde in the form of solutions. However, these drugs are not only highly toxic, but also relatively stable substances, and their removability by washing is poor, making it difficult to remove them even if the object is treated with a large amount of washing liquid before use. Therefore, the present inventors have conducted intensive research on a new sterilization method using a propylene oxide solution.As a result, the sterilization effect can be reliably guaranteed, the amount of residual chemicals is extremely small, and it is relatively easy to use by washing before use. They found that it could be removed, and after further study, they completed the present invention.

That is, the present invention is characterized in that a medical device or its material is brought into contact with a 0.3 to 10% by volume aqueous solution of propylene oxide which may contain up to 35% by volume of ethanol/L/l or isopropano-μ. The medical devices targeted by the sterilization method of the present invention are for diagnosis of human or animal diseases,
An instrument intended for therapeutic or prophylactic use or for influencing the structure or function of the human or animal body. In particular, it is preferably applied to circulatory system medical supplies and related products, biological function assisting devices, and the like. Examples of the former include artificial heart valves, artificial blood vessels, and materials for blood vessel repair, while examples of the latter include artificial heart-lung machines, heart base manufacturers, blood circuits (e.g., for artificial kidneys, artificial heart-lung machines, etc.), and blood purification. Devices and equipment (e.g., hemofilters, adsorption blood purifiers, model plasma separators, model plasma component separators, recirculating irrigation systems, etc.), artificial kidney devices and dialyzers, ascites filtration concentrators, auxiliary circulation Examples include devices.

Furthermore, raw materials for the above-mentioned medical devices are also included in the scope of sterilization.

In the sterilization method of the present invention, 0.3% of propylene oxide
~10% by volume aqueous solution is used, preferably 0.3-7% by volume. Regarding the propylene oxide aqueous solution in this concentration range having a sterilizing effect, Bacillus auts-tilia N, which is an indicator bacterium for sterilizing effect,
This is clear from the results of Experimental Example 1, which will be described later, in which a survival curve was calculated using CT C1007B spores. If the concentration of propylene oxide is lowered to as low as 0.3% by volume, the sterilization effect will be weak and a long period of time will be required for sterilization, or the sterilization effect will become #1 in medical care. It has little or no collective value as a method for sterilizing tools or their materials. On the other hand, if the concentration exceeds 10% by volume, the sterilization effect will be strong, but the residual amount of propylene oxide or its decomposition products (propylene glyco-IV) will increase, and furthermore, the quality of medical devices or their materials may deteriorate. Well, it's not really practical.

0.3~b of propylene oxide;
It may be contained up to 5% by volume. The combination of ethanol/L' or isopropano is advantageous when keeping medical devices or their materials sterile for long periods of time. That is, as shown in Experimental Example 2 below, propylene oxide gradually decomposes in an aqueous solution to produce propylene glyco-μ. Therefore, if it is necessary to maintain medical devices or their materials in a sterile state for a long period of time, and if there is a risk of secondary contamination by microorganisms after the decomposition of propylene oxide, coexisting ethanol Proliferation can be suppressed by Furthermore, ethanol
/l/l or isopropano-μ has the effect of retarding the decomposition of propylene oxide, and is also useful when maintaining sterilization for a long period of time.

The concentration of ethanol or isopropanol is 35% by volume.
The specific concentration is appropriately selected in consideration of the type of medical device or its material, storage period, etc. If the concentration exceeds 35% by volume, the sterilization effect of propylene oxide may be weakened, or denaturation may occur in the case of medical devices that utilize living organisms or proteins, which is undesirable.

The propylene oxide aqueous solution may contain various substances as appropriate, depending on the type and material of the medical device or its material, as long as the sterilization effect is not lost. Examples of such substances include those commonly used for stably preserving medical devices or materials using living organisms or proteins. For example, based on physiological saline, various buffer solutions, propylene oxide and, if necessary, ethanol/L' or isopronoμ
You may use it by dissolving it.

The propylene oxide aqueous solution can be brought into contact with the medical device or its material by a conventional method using a drug solution. For example, methods include immersing the object to be sterilized in the propylene oxide aqueous solution specified in the present invention, spraying the object uniformly with the aqueous solution, and washing the object with the aqueous solution.These operations can be performed independently. Alternatively, it may be carried out in combination and repeated two or more times as necessary. Moreover, when it is desired to sterilize the inside of a medical device having a hollow part, such as a plasma separator, the target can be achieved. Contact is usually carried out at a temperature range of 0°C to about 4 liters. The contact time required for sterilization varies depending on the concentration of propylene oxide, but it is usually better to contact for 3 hours or more. The propylene oxide aqueous solution can be removed by keeping the medical device or its material in contact with it for a period of time until it is used, and then removing the propylene oxide aqueous solution before use.After removing this aqueous solution, add physiological saline, Wash with glucose solution (5%) to remove remaining propylene oxide or its decomposition product (propylene glycol).

Compared to gas sterilization using ethylene oxide, which has been conventionally used to sterilize medical devices, the sterilization method of the present invention requires extremely simple equipment, requires less maintenance costs for the sterilization process, and is easy to use. It has the advantage of being small. Furthermore, unlike methods that use formalin or glycaldehyde, propylene oxide is safe in that it decomposes over time after sterilization, leaving only a small amount of residue, and even if it remains, it can be used before using the medical device. It can be relatively easily removed along with its decomposed products by washing.

Further, according to the method of the present invention, even medical devices that utilize living organisms, proteins, enzymes, etc. can be sterilized without causing any quality problems such as decomposition or denaturation.

The present invention will be explained in more detail below by giving experimental examples and examples. In the following description, unless otherwise specified, % indicates volume %.

Experimental Example I Bacillus 5ubtilis N C'I'
C10073 spores were grown in the following spore formation medium 1) (pH 7).
, 0) Using a plate, culture at 37 tE for 7 days, scrape out the bacterial cells, suspend them in a sufficient amount of sterile distilled water, and incubate for 7 days.
The mixture was left to stand for 1 day, centrifuged again, and dehydrated with sterile distilled water. After repeating this operation 4x9, 1o10 spores/l mushroom
Suspend in sterile distilled water and heat at 8oC for 20 minutes,
It was immediately cooled in ice water. This suspension was mixed with 10 spores/
The solution was diluted with sterile distilled water to give .txt and used in the following experiment.

1) Composition of spore-forming medium (pH 7,0) Meat extract 6g Peptone 10 9 MnSO4・nH2Oo, I Q CaC: 12 (1,1'i Agar 15 Q Distilled water added to total volume 100 moss on the other hand, sterilized distilled water, ethanol , propylene oxide and 107 spores/yl of Bacillus previously prepared.
s 5ubtilia N CT CI Q Q 73
using a spore suspension with a spore concentration of 106 spores/
- Prepare the above aqueous solutions containing 0, 3.1.5 and 10% propylene oxide, 15% ethanol aqueous solution and 35% ethanol-μ aqueous solution, seal them tightly and leave them at 20C to count viable bacteria every day. were measured and a survival curve was drawn.

To measure the number of viable bacteria, use the stock solution or the stock solution with the following kaal
Pepton
e-Yeast extract glucose a
gar 3) The cells were cultured on a flat plate at 37°C for 1 to 3 days, and the number of viable bacteria was measured.

The relationship between the number of viable bacteria and the number of days passed was analyzed using the least squares method and summarized.

2) Add 2HPO47f KH2P04 3 1F (Nii4)2so4 1 1F NaC111F ygso4・7H200,19 Tween 80 0.01 f distilled water to the composition of Baaal medium (pH 7,0) to give a total amount of 1000 g/3) Pepto ne-Yeast extraot
Composition of glucose agar Poly peptone 1 (1) Yeast extract 2g NaC12 Glucose 5g Agar 15g Add distilled water and total t 1000 ml As a result, the survival curve is (t is the number of days, K is a constant determined by the type of solution and temperature). From this survival curve, Table 1 shows the relationship between the number of viable bacteria decreased and the number of days required. This is Notooshi.

Table 1 Sterilization effect of propylene oxide aqueous solution (
Note 1) In the table, PO stands for propylene oxide.

(Note 2) Data indicates the number of days required to reduce the number of viable bacteria of initiator μ to 1/10 to 1/10'.

As is clear from the results in Table 1, various aqueous solutions of propylene oxide showed remarkable sterilization effects.

Results similar to those in Table 1 were obtained when the number of viable bacteria was measured with objects to be sterilized, such as cord veins, porcine heart valves, globulin immobilized carriers, and plasma separators, in contact with each solution in Table 1. was gotten. Furthermore, when isopropanol was used instead of ethanol, similar results were obtained when ethanol was used.

As a result, for example, if the sterility guarantee rate is 10-' (for example, when each target object contains one viable bacterium, one viable bacterium is found in only one out of one million target objects, and the others are It has been found that it can be used to sterilize medical tools and materials that are implanted into the body of a patient that have come into contact with blood, which is said to be necessary.

Experimental example 2 1% using propylene oxide, distilled water, and ethanol
An aqueous solution containing propylene oxide and a 35% ethanol-μ aqueous solution were each prepared. 2 m of these solutions
A sample was prepared by filling a colorless transparent ampoule and sealing it. These samples were left in a constant temperature room at 20°C and 3 (1°4), and samples were sampled at initial and chronological intervals, and propylene oxide was measured using a gas chromatograph (measurement conditions, detector: F').

Cuff: 5% PEG-HT on Unipor
t HP (60/80) 3mmφx2m, Column temperature: 50" (, Inlet temperature: 150) Detector temperature:
150°C, carrier gas 2M2 (approximately 40 ml/
min), measuring device: Hitachi model 163 gas chromatograph, sample solution preparation: sample in ethanol-μ while cooling on ice.
diluted 10 times and injected 3 μl) to quantify the amount of propylene oxide. The relationship between propylene oxide residual rate and aging was analyzed using the least squares method and summarized.

As a result, propylene oxide has the following formula (where X is t
It was found that the concentration of propylene oxide after days (t is the number of days) is a constant determined by the temperature and type of solution.

Table 2 shows the decomposition status of propylene oxide.523
．． This is Notooshi.

Table 2 Decomposition days for propylene oxide (Note) The data shows that the initial propylene oxide is 1/10 to 1/1/2
It shows the number of days required to decompose into 106 parts.

As is clear from the above results, in order to reduce the residual amount of propylene oxide, it is necessary to lower the initial yvB degree of propylene oxide, increase the contact time,
What is necessary is to lower the temperature by 1 degree or raise the temperature.

The decomposition of propylene oxide was investigated when each solution in Table 2 was brought into contact with objects to be sterilized, such as sterilization vessels, pig heart valves, globulin carriers, and plasma separators. Indicated.

In Table 2, similar results were obtained when isopropanol was used in place of ethanol.

Example 1 A mandrill was passed through a human-derived cord vein, and 50 parts of the pH was adjusted to 7.5 to 8.5 using a 1% (weight/volume) sodium reconstituted acid solution per 1 part of the weight of the cord vein. 0.5% (
(weight/volume) and stored in a glutaraldehyde solution for 4 to 7 days to sufficiently harden the cord vein.

Next, without performing aseptic procedures, the sample was thoroughly washed with physiological saline to remove glutaraldehyde, and then placed in physiological saline containing 1% propylene oxide and stored at room temperature for two weeks to sterilize it. After that, I handled the ice crystals carelessly and passed the Japanese Pharmacopoeia's sterility test, which found no viable bacteria.

On the other hand, viable bacteria were observed in those treated in the same manner without using propylene oxide.

Example 2 Anti-immunoglobulin G (anti-1gG) 100# was added to IM phosphorus potassium buffer (containing 0.1% sodium azide) 8
Dissolved in ml. This solution was transferred to Eupergit C beads (Rahm Pharm), which is a carrier in a flask.
29 (manufactured by Company A) and carefully stirred. The flask was tightly stoppered and left at room temperature (21-25°C) for 50 hours. Next, the contents were filtered using a glass filter, and distilled water
0 dew l each time twice, then 50 wt each time of 1 l JNa
1M with 1% propylene oxide 5 times in c1 solution
Each was washed twice in potassium phosphate buffer. The washed items were immersed in the above propylene oxide aqueous solution and stored for two weeks. After that, we handled the ice crystals aseptically and tested them using the sterile testing method that is the approval standard for dialysis-type artificial kidney devices.
No viable bacteria were observed.

Example 3 A bundle of polypropylene hollow fibers for blood separation was cut at both ends with a cutter, and while supporting and fixing with adhesive, a plasma volume of 1 ig IR1 (effective surface area 0.5
m2) was filled with an aqueous solution containing 5% propylene oxide and 35% isopropanol and stored at room temperature for 4 days to sterilize. Thereafter, the filled solution was discarded, the tube was washed with 0.3% propylene oxide physiological saline, the same solution was newly filled, and one portion was stored at room temperature for one day. Next, the ice crystals were treated aseptically and a sterility test was performed in accordance with the approval standards for dialysis-type artificial kidney devices, but no viable bacteria were found.

Example 4 A plasma separator (effective surface Ja02m2) in which polypropylene hollow fibers for plasma separation were bundled, both ends were cut with a cutter, supported and fixed with adhesive, and housed in a transparent outer cylinder (effective surface: Ja02m2)
7% propylene oxide and 35% isopropano
It was filled with an aqueous solution containing 〃 and stored at room temperature for 4 days. Thereafter, the filled solution was discarded and washed with 5% ethanol physiological saline under aseptic operation, and the same solution was filled into a new container and stored. Next, we handled the crystal aseptically and conducted a sterility test in accordance with the approval standards for dialysis-type artificial kidney devices, but no bacteria were detected.

Example 5 Pig-derived aortic valve was prepared at 1% (weight/
volume) pH 7,5-8.5 using sodium carbonate solution
The aortic valve was then stored in 100 parts of 0.5% (weight/volume) glutaraldehyde solution for 3 to 6 days to fully harden the aortic valve. Thereafter, the sample was thoroughly washed with physiological saline to remove mutaldehyde without performing aseptic procedures, and processed using pulp nutent (poly, propylene product), Dacron mesh (Dacron cloth), etc. This is 1
% propylene oxide and 15% ethanol and stored at room temperature for 15 days to sterilize. Handling the crystal aseptically and conducting a diurnal sterility test was not accepted. On the other hand, viable bacteria were observed in those treated in the same manner without using propylene oxide.

Claims (1)

[Claims] 0.3 to 1 of propylene oxide which may contain up to 3s61% of ethanol-μ or isopropano-μ
A sterilization method characterized by bringing a medical device or its material into contact with a 0% by volume aqueous solution