WO2014208428A1 - 抗がん剤分解方法および抗がん剤分解装置 - Google Patents
抗がん剤分解方法および抗がん剤分解装置 Download PDFInfo
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- WO2014208428A1 WO2014208428A1 PCT/JP2014/066199 JP2014066199W WO2014208428A1 WO 2014208428 A1 WO2014208428 A1 WO 2014208428A1 JP 2014066199 W JP2014066199 W JP 2014066199W WO 2014208428 A1 WO2014208428 A1 WO 2014208428A1
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- anticancer agent
- decomposition
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- humidity
- ozone
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- A—HUMAN NECESSITIES
- A62—LIFE-SAVING; FIRE-FIGHTING
- A62D—CHEMICAL MEANS FOR EXTINGUISHING FIRES OR FOR COMBATING OR PROTECTING AGAINST HARMFUL CHEMICAL AGENTS; CHEMICAL MATERIALS FOR USE IN BREATHING APPARATUS
- A62D3/00—Processes for making harmful chemical substances harmless or less harmful, by effecting a chemical change in the substances
- A62D3/30—Processes for making harmful chemical substances harmless or less harmful, by effecting a chemical change in the substances by reacting with chemical agents
- A62D3/38—Processes for making harmful chemical substances harmless or less harmful, by effecting a chemical change in the substances by reacting with chemical agents by oxidation; by combustion
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- A—HUMAN NECESSITIES
- A62—LIFE-SAVING; FIRE-FIGHTING
- A62D—CHEMICAL MEANS FOR EXTINGUISHING FIRES OR FOR COMBATING OR PROTECTING AGAINST HARMFUL CHEMICAL AGENTS; CHEMICAL MATERIALS FOR USE IN BREATHING APPARATUS
- A62D2101/00—Harmful chemical substances made harmless, or less harmful, by effecting chemical change
- A62D2101/20—Organic substances
- A62D2101/22—Organic substances containing halogen
-
- A—HUMAN NECESSITIES
- A62—LIFE-SAVING; FIRE-FIGHTING
- A62D—CHEMICAL MEANS FOR EXTINGUISHING FIRES OR FOR COMBATING OR PROTECTING AGAINST HARMFUL CHEMICAL AGENTS; CHEMICAL MATERIALS FOR USE IN BREATHING APPARATUS
- A62D2101/00—Harmful chemical substances made harmless, or less harmful, by effecting chemical change
- A62D2101/20—Organic substances
- A62D2101/26—Organic substances containing nitrogen or phosphorus
-
- A—HUMAN NECESSITIES
- A62—LIFE-SAVING; FIRE-FIGHTING
- A62D—CHEMICAL MEANS FOR EXTINGUISHING FIRES OR FOR COMBATING OR PROTECTING AGAINST HARMFUL CHEMICAL AGENTS; CHEMICAL MATERIALS FOR USE IN BREATHING APPARATUS
- A62D2101/00—Harmful chemical substances made harmless, or less harmful, by effecting chemical change
- A62D2101/20—Organic substances
- A62D2101/28—Organic substances containing oxygen, sulfur, selenium or tellurium, i.e. chalcogen
Definitions
- the present invention relates to a technique for decomposing an anticancer agent scattered at the time of preparation or the like for preventing exposure to medical staff or the like.
- Anti-cancer drugs are widely used in cancer treatment as well as cancer removal surgery and radiation treatment. Anticancer agents are administered to patients orally or by infusion. It is well known that side effects such as hair loss, nausea (nausea), bone marrow suppression, mouth soreness, and rough skin appear in patients receiving anticancer drugs. This is because the anticancer drug not only acts on cancer cells but also destroys normal cells.
- Patent Document 1 discloses leakage of an anticancer agent in an operation of changing the bottle needle of a chemical solution line for each chemical solution bag containing the anticancer agent during infusion (intravenous drug administration). A technique for preventing this is disclosed (Patent Document 1).
- Patent Document 1 With the technique disclosed in Patent Document 1, a certain preventive effect can be expected with respect to leakage of the anticancer agent at the time of infusion preparation.
- an operation of mixing an anticancer agent in a drug solution bag in advance an operation such as dissolution when the anticancer agent is supplied in powder form from a pharmaceutical company, for example, Performed in a safety cabinet.
- a pharmaceutical company for example, Performed in a safety cabinet.
- the technique disclosed in Patent Document 1 has scattered anticancer. It cannot cope with prevention of exposure by chemicals.
- the present invention has been made in view of the above-described problems, and an anticancer agent decomposition method for protecting a medical worker from an anticancer agent scattered outside (safety cabinet, dispensing room, etc.) during dispensing or the like.
- Another object of the present invention is to provide an anticancer agent decomposing apparatus for use in this decomposing method.
- the anticancer agent is decomposed by applying air containing ozone and humidified by a humidifying means.
- the relative humidity of the humidified air containing ozone is preferably 80%.
- air that has been humidified to a relative humidity of 80% or higher by humidification means is allowed to act on these anticancer agents. It is appropriate to disassemble.
- Decomposition of the anticancer agent under humidified conditions is reliable and efficient as follows.
- the degree of decomposition of the anticancer agent accompanying the increase in CT value in the environment humidified by the humidifying means is obtained in advance as a function of the relative humidity and CT value in the decomposition environment.
- a specific set humidity is assumed, and the CT set value is defined as the end point of the decomposition treatment corresponding to the humidity.
- the relative humidity and ozone concentration of humidified air containing ozone are measured.
- the increment of the CT value in a predetermined time of the decomposition process is corrected by using a ratio between the degree of decomposition at the set humidity calculated by applying the function of the relative humidity and the CT value and the degree of decomposition at the measured relative humidity.
- the decomposition treatment of the anticancer agent with ozone ends when the CT value with the increment reaches the CT set value defined as the decomposition end point at the set humidity.
- the anticancer agent decomposing apparatus is received by the storage means, the input means for receiving the relative humidity measured by the hygrometer and the ozone concentration measured by the ozone concentration meter, and the data and the input means stored in the storage means. Arithmetic means for performing arithmetic processing based on the data is included.
- the memory means determines the degree of decomposition of the anticancer agent accompanying the increase in the CT value in the process of decomposing the anticancer agent by the action of the air containing ozone and humidified by the humidifying means, and the relative humidity of the air containing ozone and
- the CT value can be stored as a function. Also.
- the storage means stores the CT set value as the decomposition end point at the set humidity of the decomposition process.
- the calculation means calculates the increment of the CT value at a predetermined time during the decomposition process between the degree of decomposition at the set humidity obtained by applying a function having the relative humidity and the CT value as a variable, and the degree of decomposition at the measured relative humidity. Correct using the ratio.
- the computing means is configured to terminate the anticancer agent decomposition process when the CT value obtained by adding the corrected increment reaches the CT set value.
- “Humidifying means” refers to a device that artificially vaporizes water to increase the humidity of the decomposition environment of the anticancer agent.
- the method for decomposing an anticancer agent for protecting a medical worker from an anticancer agent scattered outside can be provided.
- FIG. 1 is a front view of a test apparatus used for an anticancer agent decomposition test.
- FIG. 2 is a plan view of the test apparatus.
- FIG. 3 is a front view of the operation display unit 22.
- FIG. 4 is a diagram showing ozone concentration, temperature, and humidity during the decomposition test process.
- FIG. 5 is a calibration curve of fluorouracil.
- FIG. 6 is a diagram showing the CT value and the anticancer agent residual rate in the degradation test process of the anticancer agent during humidification.
- FIG. 7 is a graph showing the relationship between the relative humidity at a CT value of 80000 and the decomposition rate of fluorouracil by ozone.
- FIG. 1 is a front view of a test apparatus used for an anticancer agent decomposition test.
- FIG. 2 is a plan view of the test apparatus.
- FIG. 3 is a front view of the operation display unit 22.
- FIG. 4 is a diagram showing ozone concentration, temperature,
- FIG. 8 is a graph showing the relationship between the relative humidity at the CT value of 80000 and the decomposition rate of cytarabine by ozone.
- FIG. 9 is a diagram in which the CT value is proportional to the anticancer agent degradation rate.
- FIG. 10 is a diagram when the increase in the anticancer agent degradation rate decreases as the CT value increases.
- FIG. 11 is a flowchart for reflecting the measured humidity on the end point of the decomposition process.
- FIG. 12 is a diagram showing the concept of the procedure of FIG.
- FIG. 1 is a front view of the test apparatus 11 used for the decomposition test of the anticancer agent
- FIG. 2 is a plan view of the test apparatus 11
- FIG. 3 is a front view of the operation display unit 22.
- the test apparatus 11 includes a container 12, an ozone generator 13, a CT value management apparatus 14, a humidifier 15, and a hygrometer 16.
- the container 12 is a rectangular parallelepiped hollow box, and the upper surface is closed by a removable lid 17.
- the container 12 is made of a transparent vinyl chloride resin so that the inside can be easily observed from the outside.
- the ozone generator 13 is a stationary ozone gas generator known in the art that includes an ozone lamp and a forced circulation fan.
- the CT value management device 14 includes an ozone concentration sensor 21 and an operation display unit 22.
- the ozone concentration sensor 21 detects the ozone concentration in the container 12.
- the CT value management device 14 includes storage means for storing data, input means for taking in the humidity measured by the hygrometer 16 and the ozone concentration measured by the ozone concentration sensor 21, arithmetic means for performing arithmetic processing based on the ozone concentration, etc.
- Output means for sending data to the outside based on the result of the arithmetic processing and for starting and stopping the connected device.
- the operation display unit 22 includes a setting input unit 23, an ozone concentration display unit 24, an elapsed time display unit 25, a CT measurement value display unit 26, and the like.
- the setting input unit 23 includes a CT set value display unit 27, an up button 28, and a down button 29.
- the CT set value display unit 27 displays a CT set value that is an index of the end of the sterilization test.
- the up button 28 and the down button 29 are operated to change the CT set value displayed on the CT set value display unit 27.
- the ozone concentration display unit 24 displays the ozone concentration detected by the ozone concentration sensor 21.
- the elapsed time display unit 25 displays the elapsed time since the start of the decomposition test of the anticancer agent using ozone.
- the CT measurement value display unit 26 displays the CT value at the elapsed time displayed on the elapsed time display unit 25.
- the CT value is an integration of products of ozone gas concentration and minute time in minute time.
- the test apparatus 11 starts the ozone generator 13 in the container 12 and simultaneously starts management of an anticancer agent decomposition test based on the ozone concentration detected by the ozone concentration sensor 21.
- the humidifier 15 is a ceramic container having a heater at the bottom. The humidifier 15 is filled with water (hot water).
- An anticancer agent decomposition test using ozone gas using the test apparatus 11 will be described.
- An anticancer drug preparation sample to be decomposed was obtained by dropping 100 ⁇ L of an anticancer drug solution having a concentration of 1 ⁇ g / mL onto a small piece of aluminum overnight and leaving it to dry at 30 ° C. for 2 days.
- the aluminum foil to which the anticancer agent after drying adheres is referred to as “anticancer agent sample”.
- the anticancer agent used in the degradation test is fluorouracil (trade name 5-FU, manufactured and sold by Kyowa Hakko Kirin Co., Ltd.).
- the anticancer agent decomposition test using ozone was performed by putting the anticancer agent sample in the test apparatus 11 and operating the ozone generator 13 for a certain period of time.
- the humidifier 15 is always operated to increase the humidity, or the humidifier 15 is stopped, and the ozone concentration, humidity, and CT value are recorded, and the amount of the remaining anticancer drug after the degradation test is measured. It was done by doing.
- FIG. 4 is a diagram showing the ozone concentration, temperature, and humidity in the container 12 in the anticancer agent degradation test process when the humidifier 15 is operated.
- the anticancer agent sample after the decomposition test with ozone is vibrated together with 1 mL of MilliQ water (registered trademark, Merck Millipore Corporation) in a container, and the residue adhering to the aluminum foil is dissolved in MilliQ water.
- MilliQ water registered trademark, Merck Millipore Corporation
- the fluorouracil concentration in the aqueous solution was quantitatively analyzed by high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- the degree of decomposition of fluorouracil by ozone was evaluated by preparing a dissolved sample of an anticancer agent sample that was not subjected to a separately prepared decomposition test and comparing it as a blank.
- FIG. 5 is a calibration curve of fluorouracil under the above analysis conditions.
- FIG. 5 shows that the quantitative analysis of fluorouracil by HPLC is sufficiently reliable. From this calibration curve, the remaining amount of fluorouracil after the decomposition test, that is, the amount of fluorouracil decomposed by the decomposition test can be obtained.
- Table 1 shows the results of measuring the (undecomposed) fluorouracil concentration in the dissolved sample after the decomposition test. The five “untreated” fluorouracil concentration measurements in Table 1 are believed to be due to variations in the preparation of the anticancer drug dissolution sample.
- FIG. 6 is a graph showing the CT value of the anticancer agent degradation test process at the time of humidification when the results shown in Table 1 are obtained, and the anticancer agent residual ratio obtained from Table 1.
- the ozone concentration, temperature, and humidity during the decomposition process of the anticancer agent (fluorouracil) at a relative humidity of 80% (hereinafter referred to as “humidity”) at this time are those in FIG.
- the temperature in the process of decomposing the anticancer agent at a humidity of 40% was not significantly different from the change in FIG.
- the decomposition of fluorouracil by ozone gas proceeds in a shorter time in a high humidity environment.
- Table 2 shows test results obtained by examining the degree of decomposition of the fluorouracil described above by changing the relative humidity.
- the anticancer drug sample used for the fluorouracil degradation test was a 5-FU injection 250 Kyowa (250 mg / 5 mL) (manufactured and sold by Kyowa Hakko Kirin Co., Ltd.) equivalent to 100 ⁇ L of the stock solution (fluorouracil 5 mg) in a stainless steel plate (10 cm ⁇ 10 cm). ) And dried by standing at room temperature.
- the decomposition test was performed by putting the stainless steel plate (anticancer agent sample) to which this fluorouracil adheres into the test apparatus 11, and operating the ozone generator 13 under a humidity adjustment until the CT value reached 80000.
- the actual dropping on the stainless steel plate was performed not with the stock solution but with 1 mL of 10-fold diluted stock solution for convenience of volume control.
- the numerical value indicated by “equivalent” is not an actual dripping amount but a numerical value in terms of a stock solution.
- Table 3 shows the test results obtained by examining the degree of degradation of the other anticancer drug cytarabine by changing the relative humidity.
- an anticancer drug sample obtained by dropping a stock solution (1 g / 50 mL) of kiloside N1 g (registered trademark, Nippon Shinyaku Co., Ltd.) equivalent to 10 ⁇ L (cytarabine 0.2 mg) onto a stainless steel plate and drying it.
- the humidity was adjusted, exposure was performed to ozone until the CT value reached 80000 (ppm ⁇ min).
- FIG. 7 and 8 are diagrams in which the relationship between the relative humidity and the decomposition rate of the anticancer agent is obtained from Tables 2 and 3. From FIG. 7, it can be seen that there is a large difference in the decomposition rate of fluorouracil when the relative humidity is 70% and when it is 80%, that is, the decomposition rate increases when the relative humidity is at least 80% or more.
- the decomposition rate of fluorouracil after 24 hours decomposition treatment was 80% relative humidity and 100%, whereas in Table 2, the decomposition rate was 80% relative humidity and CT value 80000. However, some were around 80%. This is considered to be due to the difference in the method of adjusting the anticancer agent sample, the humidity distribution in the container 12, the position of the adjusted sample, and the like. From FIG. 8, cytarabine has a high decomposition rate when it has a relative humidity of 70% compared to fluorouracil (easy to be decomposed), and, like fluorouracil, has a high decomposition rate when the relative humidity is at least 80% or more. I guess that.
- Table 4 shows the results of decomposition treatment with ozone gas for other anticancer agents other than those described above until the CT value reaches 60000 at a relative humidity of 80%.
- each anticancer agent sample (anticancer agent sample) in Table 4 was prepared as follows. [Cyclophosphamide] Dissolve 100 mg of “Injection Endoxan 500 mg (registered trademark, manufacturer: Shionogi Seiyaku Co., Ltd.)” in 5 mL of purified water to prepare a stock solution, and add 10 ⁇ L of stock solution (cyclophosphamide 0.2 mg) to a stainless steel plate ( 10 cm ⁇ 10 cm) was dropped in the vicinity of the center and dried by standing at room temperature.
- Stainless steel is equivalent to 10 ⁇ L of stock solution (0.1 mg of doxorbin). It was dropped near the center of the plate (10 cm ⁇ 10 cm) and dried by standing at room temperature.
- CT set value a CT value for terminating the decomposing process is set in advance according to the type of anticancer agent, and increases as the decomposing process proceeds.
- the CT set value for determining the end point of the decomposition treatment of the anticancer agent by ozone is set corresponding to the humidity during the treatment.
- safety cabinets and dispensing rooms that require decomposition treatment of scattered anticancer agents with ozone often do not have a humidity control function, and fluctuations in humidity can be avoided simply by operating a humidifier. Absent. That is, in an environment where the constant humidity control is insufficient, there is a time during which the decomposition process proceeds at a humidity different from the humidity H corresponding to the CT set value.
- the decomposition treatment may be terminated with insufficient decomposition of the anticancer agent. Further, when the humidity in the decomposition process is higher than the humidity H corresponding to the CT set value, excessive time is spent on the decomposition process, and the operation of the decomposition apparatus is not efficient and uneconomical.
- FIGS. 9 and 10 are diagrams showing the influence of humidity on the relationship between the decomposition of an anticancer agent and the CT value (hereinafter sometimes referred to as “CT”).
- FIG. 10 is a diagram assuming that the increase in the anticancer agent degradation rate R ( ⁇ R ⁇ ⁇ CT) decreases as the CT value increases.
- the anticancer agent degradation rate R is “concentration of anticancer agent before decomposition treatment (blank) ⁇ concentration of remaining anticancer agent after decomposition” ⁇ concentration of anticancer agent before decomposition treatment in the dissolved sample.
- the anticancer agent degradation rate R accompanying the increase in CT value under each humidity environment is obtained in advance using, for example, the test apparatus 11.
- the relationship between the CT of each humidity and the decomposition rate R can be expressed by a linear expression (1), and the coefficient K can be approximated by an expression (2) in which the humidity H is an independent variable.
- R K x CT (1)
- K f (H) (2)
- f (H) can be calculated by the method of least squares by plotting each humidity and the coefficient K at that humidity on graph paper, semi-logarithmic paper or bilogarithmic paper to determine the correlation.
- the specific form of f (H) may vary depending on the type of anticancer agent.
- FIG. 11 is a flowchart of the procedure for reflecting the measured humidity in the determination of the end point of the anticancer agent decomposition process
- FIG. 12 is a diagram showing the concept of the procedure of FIG. The process described below is performed by the CT value management device 14, for example.
- the decomposition treatment of the anticancer agent with ozone gas is performed for most of the treatment time at a humidity of H1%, and a CT set value corresponding to the humidity of H1% is input to the CT value management device. If the humidity of the space where the anticancer agent decomposition process is performed is H1% and does not change, the decomposition process ends when the actually measured CT value reaches the CT set value.
- the humidity drops from H1% to H2% after elapse of time t1 from the start of the decomposition process (H1> H2).
- the CT value after the elapse of time t1 is CT1.
- Te (sampling interval) in FIG. 11 is a preset sampling interval stored in the CT value management device 14 in advance, and Ts is a preset sampling interval Te elapsed after the sampling timer is reset (S1) by the previous sampling. This is the actual sampling interval immediately after (YES in S3).
- the CT value management device 14 adds ⁇ CTr instead of ⁇ CT to the stored CT value (CT1), and compares the CT value (CT2) after the addition with the CT set value (S5), thereby performing the decomposition process. Is configured to determine whether or not to terminate.
- CT value after addition CT2, Sct in FIG. 11
- Ect CT set value
- ⁇ CT which is the product of the measured ozone concentration and the actual elapsed time
- ⁇ CTr corrected by the measured humidity to the CT value to reflect the actual degradation level of the anticancer drug.
- the end point of the anticancer agent decomposition treatment can be determined.
- the above-described anticancer agent decomposition method has a problem that the decomposition process is terminated in a state where the decomposition of the anticancer agent is insufficient in an anticancer agent decomposition environment humidified by a humidifier that does not have a constant value control function, In addition, the problem that excessive time is spent in the decomposition process can be solved.
- the CT value after the elapse of time t1 is CT1.
- the increment of the CT value after a lapse of a minute time is ⁇ CT
- the increment of the anticancer agent degradation rate R when the humidity expected from FIG. 10 is H1% is Rb
- the anticancer agent degradation when the humidity is H2% Let Rr be the increment of rate R.
- ⁇ f (H2) ⁇ ⁇ ⁇ Exp ⁇ f (H1) ⁇ CT1 ⁇ When determining the end point of anticancer agent decomposition based on the CT set value set assuming humidity H1%, it contributes to decomposition of anticancer agent in the time zone when decomposition treatment was performed at humidity H2% It is practical to adopt a correction value obtained by multiplying ⁇ CT by “ ⁇ f (H
- the humidity of the decomposition environment fluctuates from the expected value even in the decomposition treatment of anticancer agents, where the correlation between CT value and residual rate (1-anticancer agent decomposition rate R) has the strongest correlation on both logarithmic papers
- ⁇ CT residual rate
- anticancer agents such as gemcitabine hydrochloride (Gemzar: registered trademark), paclitaxel (taxol: registered trademark), docetaxel hydrate (taxotere: registered trademark), etc. Can do.
- each component of the anticancer agent decomposing apparatus used for decomposing the anticancer agent in a humidified environment and the anticancer agent decomposing apparatus, or the overall structure, shape, dimensions, number, material, etc. are the gist of the present invention. Can be changed as appropriate.
- the present invention can be used for decomposing anticancer agents scattered during preparation or the like to prevent exposure of the anticancer agents to medical workers or the like.
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Abstract
Description
これに関して、例えば、特許文献1には、輸液(静脈内への薬剤投与)の際に、抗がん剤を収容する薬液バッグごとに薬液ラインの瓶針を付け替える作業における抗がん剤の漏洩を防止する技術が開示されている(特許文献1)。
しかし、特許文献1に開示された技術においても抗がん剤を事前に薬液バッグに混合する作業、製薬会社から抗がん剤が粉体で供給される場合には溶解等の作業が、例えば安全キャビネット内で行われる。このような、薬液バッグを取り扱う前の作業で飛散した抗がん剤から医療従事者を保護する方策については未だ明確なものがなく、特許文献1に開示された技術では、飛散した抗がん剤等による曝露の防止に対応できない。
加湿された前記オゾンを含む空気の相対湿度は80%が好ましい。
抗ガン剤であるフルオロウラシル、シタラビン、シクロフォスファミド、イホスファミド、ドキソルビシンおよびエトポシドを分解する場合、オゾンを含み加湿手段により相対湿度80%以上に加湿された空気をこれらの抗ガン剤に作用させて分解するのが適切である。
予め、加湿手段により加湿された環境でのCT値の増加に伴う抗がん剤の分解程度を、分解環境における相対湿度およびCT値の関数として求める。
オゾンによる抗がん剤の分解処理では、特定の設定湿度を想定し、その湿度に対応する分解処理の終点としてCT設定値を規定する。抗がん剤の分解処理においては、オゾンを含む加湿された空気の相対湿度およびオゾン濃度を測定する。そして、分解処理の所定時間におけるCT値の増分を、相対湿度およびCT値の関数を適用して算出した設定湿度における分解程度と測定された相対湿度における分解程度との比を用いて補正する。抗がん剤のオゾンによる分解処理は、増分を加えたCT値が、設定湿度における分解終点として規定したCT設定値に達したときに終了させる。
記憶手段は、オゾンを含み加湿手段により加湿された空気を作用させて抗がん剤を分解する過程におけるCT値の増加に伴う抗がん剤の分解程度を、オゾンを含む空気の相対湿度およびCT値を変数とする関数として記憶することができる。また。記憶手段は、分解処理の設定湿度における分解終点としてのCT設定値を記憶する。
「加湿手段」とは、水を人為的に気化させて抗がん剤の分解環境の湿度を高める装置をいう。
試験装置11は、容器12、オゾン発生器13、CT値管理装置14、加湿装置15および湿度計16からなる。
容器12は、直方体の中空の箱であり、上面は取り外し可能な蓋17で閉じられる。
オゾン発生器13は、オゾンランプおよび強制循環ファンを内蔵する据え置き型の、公知のオゾンガスの発生装置である。
CT値管理装置14は、オゾン濃度センサ21および操作表示部22からなる。オゾン濃度センサ21は、容器12内のオゾン濃度を検出する。CT値管理装置14は、データ等を記憶する記憶手段、湿度計16が計測した湿度およびオゾン濃度センサ21が計測したオゾン濃度を取り入れる入力手段、オゾン濃度等に基づいて演算処理を行う演算手段、演算処理の結果に基づいて外部にデータを送出し、また接続された機器の起動、停止等を行う出力手段を有する。
設定入力部23は、CT設定値表示部27、アップボタン28およびダウンボタン29で形成される。CT設定値表示部27は、滅菌試験終了の指標であるCT設定値を表示する。アップボタン28およびダウンボタン29は、CT設定値表示部27に表示されるCT設定値の変更のために操作される。
経過時間表示部25は、オゾンによる抗がん剤の分解試験が開始されてからの経過時間を表示する。CT測定値表示部26は、経過時間表示部25に表示される経過時間におけるCT値を表示する。CT値とは、微小時間におけるオゾンガス濃度と微小時間時間との積の積算である。
加湿装置15は、底にヒーターが設けられたセラミックス製の容器である。加湿装置15には、水(熱水)が入れられる。
分解対象である抗がん剤の調整試料は、濃度1μg/mLの抗がん剤溶液100μLをアルミ泊の小片上に滴下し、これを30℃で2日間放置して乾燥して得た。以後、乾燥後の抗がん剤が付着するアルミ箔を「抗がん剤試料」という。
分解試験に使用した抗がん剤は、フルオロウラシル(商品名5-FU、協和発酵キリン株式会社製造販売)である。
図4は加湿装置15を稼働させたときの抗がん剤分解試験過程における容器12内のオゾン濃度、温度および湿度を示す図である。
HPLCによる分析条件は以下の通りである。
ポンプ:ジーエルサイエンス株式会社L-2130(流速1mL/min)
オートサンプラー:システム・インスツルメント株式会社Model09(注入量100μL)
検出器:株式会社島津製作所 SPD-6AV(波長254nm)
カラム:株式会社資生堂 CAPCELL PAK C18(登録商標)
TYPE MG
SIZE 4.6mmID×150mm
A-Dコンバーター:ダックス技研株式会社 15BXP-E2(gain×1,1000ms)
移動相:50mmol/L、リン酸バッファ(pH5.0):メタノール=85:15
表1は分解試験後の溶解試料における(未分解の)フルオロウラシル濃度を測定した結果である。表1における「非処理」の5つのフルオロウラシル濃度測定値は、抗がん剤の溶解試料の調製におけるバラツキによると考えられる。
表2は前述したフルオロウラシルについて、相対湿度を変えて分解の程度を調べた試験結果である。
フルオロウラシルの分解試験に用いた抗がん剤試料は、5-FU注250協和(250mg/5mL)(協和発酵キリン株式会社製造販売)の原液100μL相当分(フルオロウラシル5mg)をステンレスプレート(10cm×10cm)に滴下して、室温放置により乾燥して得た。分解試験は、このフルオロウラシルが付着するステンレスプレート(抗がん剤試料)を試験装置11内に入れ、湿度調整下でオゾン発生器13をCT値が80000になるまで稼働させて行った。
試験は、キロサイドN1g(登録商標、日本新薬株式会社製造販売)の原液(1g/50mL)10μL相当分(シタラビン0.2mg)をステンレスプレートに滴下し乾燥して得た抗がん剤試料を、湿度が調整された試験装置11内でCT値が80000(ppm×min)になるまでオゾンに暴露させて行った。
また、表3におけるシタラビンについての分解処理後および非処理における残存量の測定は、前述したフルオロウラシルの測定と同じHPLC(検出器、カラム等)を用いて行った。移動相は、0.01mol/Lリン酸2水素カリウム:アセトニトリルが95:5である。
図7から、フルオロウラシルは、相対湿度が70%の場合と80%の場合とでは、その分解率に大きな差があること、つまり相対湿度が少なくとも80%以上で分解率が増加することがわかる。
図8から、シタラビンは、フルオロウラシルと比較して相対湿度が70%の場合に分解率が大きく(分解しやすく)、フルオロウラシルと同様に、相対湿度が少なくとも80%以上であれば高い分解率となることが推測される。
表4は、上述した以外の他の抗がん剤について、相対湿度80%でCT値が60000になるまでオゾンガスにより分解処理を行った結果である。
〔シクロフォスファミド〕
精製水5mLに「注射エンドキサン500mg(登録商標、製造販売元:塩野義製薬株式会社)」を100mg溶解して原液を調整し、原液10μL相当分(シクロフォスファミド0.2mg)をステンレスプレート(10cm×10cm)の中央付近に滴下し、室温放置により乾燥させた。
〔イホスファミド〕
精製水25mLに「注射用イホマイド1g(登録商標、製造販売元:塩野義製薬株式会社)」を溶解して原液を調整し、原液10μL相当分(イホスファミド0.4mg)をステンレスプレート(10cm×10cm)の中央付近に滴下し、室温放置により乾燥させた。
〔ドキソルビシン〕
精製水1mLに「アドリアシン注用10(登録商標、製造販売元:協和発酵キリン株式会社)」を溶解して原液(10mg/mL)を調整し、原液10μL相当分(ドキソルビン0.1mg)をステンレスプレート(10cm×10cm)の中央付近に滴下し、室温放置により乾燥させた。
〔エトポシド〕
「ラステット注100mg/5mL(登録商標、製造販売元 日本化薬株式会社)」を原液とし、原液10μL相当分(エトポシド0.2mg)をステンレスプレート(10cm×10cm)の中央付近に滴下し、室温放置により乾燥させた。
表4から、シクロフォスファミド、イホスファミド、ドキソルビシンおよびエトポシドのいずれも、CT値60000における分解の程度に差があるものの、相対湿度80%の雰囲気下でオゾンガスによる分解が進行する。
オゾンは、その滅菌処理において残存菌数がCT値の増加と共に減少することが知られている(例えばURL:http://www.fujielectric.co.jp/about/company/jihou_2004/pdf/77-03/14.pdf#search='%E3%82%AA%E3%82%BE%E3%83%B3+%E7%B5%8C%E6%99%82CT'、富士時報Vol.77 No.3 2004、オゾン利用による下水処理・排水処理)。オゾンによる滅菌処理等では、CT値を監視し、CT値が予め設定した数値に達したとき処理を終了させるのが一般的である。以下に説明する抗がん剤分解方法においても、抗がん剤の種類に応じて予め分解処理を終了させるCT値(「CT設定値」という)を設定しておき、分解処理の進行とともに増加するCT値がCT設定値に達したとき分解処理を終了させる。
ところで、飛散した抗がん剤のオゾンによる分解処理が必要な安全キャビネット、調剤室等には、湿度制御機能を備えない場合が多く、加湿器等を稼働させるのみでは、湿度の変動が避けられない。つまり、湿度の定値制御が不十分な環境では、CT設定値に対応する湿度Hと異なる湿度で分解処理が進行する時間がある。そのような時間帯では、湿度の低い時間が続くと抗がん剤の分解が不十分なまま分解処理が終了されるおそれがある。また、分解処理における湿度がCT設定値に対応する湿度Hより高くなる場合には、過剰な時間が分解処理に費やされ、分解装置の稼働が効率的でなく、また不経済でもある。
図9および図10は湿度が抗がん剤の分解とCT値(以下「CT」と記すことがある)との関係に与える影響を示す図である。
表1から、湿度が40%以上80%以下において、CT値とフルオロウラシル分解率R(以下「分解率R」ということがある)との関係は、湿度をパラメータとすると図9または図10で表される。図9および図10における二点鎖線は図6からの推定によるものである。
図9において、各湿度のCTと分解率Rとの関係は一次式(1)で表現でき、その係数Kは湿度Hを独立変数とする式(2)に近似できる。
R=K×CT ・・・・・・・ (1)
K=f(H) ・・・・・・・ (2)
f(H)は、各湿度とその湿度における係数Kとを方眼紙、片対数紙または両対数紙にプロットして相関を見極め、最小自乗法により算出することができる。f(H)の具体的な形態は、抗がん剤の種類により異なることがある。
R=f(H)×CT ・・・・・・・ (3)
図11は計測湿度を抗がん剤分解処理の終点判断に反映させる手順のフローチャート、図12は図11の手順の概念を示す図である。
以下に説明する処理は、例えばCT値管理装置14により行われる。
分解処理開始から時間t1経過後に湿度がH1%からH2%に低下した場合(H1>H2)を考える。時間t1経過後のCT値はCT1である。時間t1から微小時間Δt(Ts)経過したとき(S3でYES)、この間のCT値の増分ΔCTは、計測された平均オゾン濃度Coから、ΔCT=Co×Δtとして求められる(S4)。
さて、(3)式から、湿度がH1%のとき、CT値がΔCT増加する間の抗がん剤の分解率ΔRbは、
ΔRb=f(H1)×ΔCT ・・・・・・ (4)
である。
ΔRr=f(H2)×ΔCT ・・・・・・ (5)
である。
(4),(5)式から次の関係が導かれる。
ΔRr÷ΔRb=f(H2)÷f(H1) ・・・ (6)
ここで、f(H2)÷f(H1)は、図11における補正係数F(S4)である。
ΔRr={f(H2)÷f(H1)}×ΔRb ・・ (7)
仮に湿度H1%で抗がん剤の分解処理が行われたと仮定すると、分解率をΔRr増加させるためのCT値の増分ΔCTrは、次のようにして求められる。
ΔRr=f(H1)×ΔCTr ・・・・・・ (8)
ΔCTr=ΔRr÷f(H1) ・・・・・・ (9)
CT値管理装置14が、湿度H1%に対応するCT設定値で抗がん剤の分解の終了を判断するように設定されたとき、湿度H2%で分解処理された間の実際の抗がん剤の分解の程度(ΔRr)に見合うCT値の増分ΔCTrは、(4),(9)式から、
ΔCTr=ΔCT×{f(H2)÷f(H1)}・・ (10)
である。
加算後のCT値(CT2、図11においてはSct)がCT設定値(Ect)よりも大きいとき(S5でYES)、CT値管理装置14は、例えばオゾン発生器13の動作を停止させる。
上述した抗がん剤分解方法は、定値制御機能を有しない加湿器により加湿される抗がん剤分解環境において、抗がん剤の分解が不十分な状態で分解処理が終了される問題、および過剰な時間が分解処理に費やされる問題を解消することができる。
図10において、CT値と抗がん剤の残存率とが直線関係にある場合、(11)式が成立する。
ln(1-R)=-f(H)×CT ・・・・・・ (11)
変形すると、
R=1-Exp{-f(H)×CT} ・・・・・・ (12)
f(H)は、湿度ごとには定数であり、特定の範囲の湿度で成立する、湿度Hを独立変数とする関数である。
ΔR=f(H)×Exp{-f(H)×CT}×ΔCT ・・(13)である。
ΔRb=f(H1)×Exp{-f(H1)×CT1}×ΔCT
・・・・・・ (14)
ΔRr=f(H2)×Exp{-f(H2)×CT1}×ΔCT
・・・・・・ (15)
湿度がH2%に低下した後に微小時間経過したのであるから、実際には抗がん剤分解率Rの増分はΔRrである。湿度H1%環境下では、増分ΔRrを得るCT値の増分ΔCTrは、(14)式のΔRbをΔRrに、ΔCTをΔCTrに置き換えて、
ΔRr=f(H1)×Exp{-f(H1)×CT1}×ΔCTr
・・・・・・(16)
(15),(16)式から、
ΔCTr={f(H2)÷f(H1)}×G×ΔCT ・・・ (17)
ここで、
G=Exp{-f(H2)×CT1}÷Exp{-f(H1)×CT1}
・・・・・・(18)
湿度H1%を想定して設定したCT設定値に基づいて抗がん剤分解の終点を判断する場合に、湿度H2%で分解処理が行われた時間帯では、抗がん剤の分解に寄与するCT値の増分は、実際に計測されたΔCTではなく、ΔCTに「{f(H2)÷f(H1)}×G」を掛け合わせた補正値を採用するのが現実的である。直前のCT値(CT1)に加算するΔCTをΔCTrに補正することにより、抗がん剤分解環境の湿度が変動しても、抗がん剤分解処理の所望する終点をより正確に判断することができる。
1-R=CT-f(H) ・・・・・・ (20)
f(H)は、両対数紙における各湿度のCT値に対する抗がん剤の残存率(1-抗がん剤分解率R)の変化(傾き)を、湿度の関数として求めたものである。
(20)式から、CT値の微小増分ΔCTにおける分解率の増加ΔRは、
ΔR=f(H)×CT-f(H)-1×ΔCT ・・・・・・ (21)
ΔCTr=G×ΔCT ・・・・・ (22)
G={f(H2)÷f(H1)}×CTf(H1)-f(H2) ・・・ (23)
その他、加湿環境下で抗がん剤の分解に用いる抗がん剤分解装置、および抗がん剤分解装置の各構成または全体の構造、形状、寸法、個数、材質などは、本発明の趣旨に沿って適宜変更することができる。
15 加湿手段(加湿器)
Co オゾン濃度
Ect CT設定値
H,H1,H2 相対湿度
Claims (5)
- オゾンを含み加湿手段により加湿された空気を作用させて抗がん剤を分解する
ことを特徴とする抗がん剤分解方法。 - 加湿された前記オゾンを含む空気の相対湿度が80%である
請求項1に記載の抗がん剤分解方法。 - 抗がん剤であるフルオロウラシル、シタラビン、シクロフォスファミド、イホスファミド、ドキソルビシンおよびエトポシドを分解する抗がん剤分解方法であって、
オゾンを含み加湿手段により相対湿度80%以上に加湿された空気を前記抗がん剤に作用させて分解する
ことを特徴とする抗がん剤分解方法。 - 予め、加湿手段により加湿された環境でのCT値の増加に伴う抗がん剤のオゾンによる分解程度を分解環境における相対湿度および前記CT値の関数として求め、
前記加湿手段による特定の設定湿度を想定して行う前記抗がん剤の分解処理において前記オゾンを含む加湿された空気の相対湿度およびオゾン濃度を測定し、
所定時間における前記CT値の増分を、前記関数を適用して求めた前記設定湿度における前記分解程度と測定された前記相対湿度における前記分解程度との比を用いて補正し、
前記抗がん剤の前記オゾンによる分解処理を、前記CT値が、前記設定湿度における分解終点として規定したCT設定値に達したときに終了させる
ことを特徴とする抗がん剤分解方法。 - オゾンを含み加湿手段により加湿された空気を作用させて抗がん剤を分解する過程におけるCT値の増加に伴う前記抗がん剤の分解程度を、前記オゾンを含む空気の相対湿度および前記CT値を変数とする関数として記憶することができる記憶手段と、
湿度計が計測した相対湿度およびオゾン濃度計が計測したオゾン濃度を受け入れる入力手段と、
前記記憶手段に記憶されたデータおよび前記入力手段が受け入れたデータに基づいて演算処理を行う演算手段と、を有し、
前記演算手段は、
所定時間における前記CT値の増分を、前記関数を適用して求めた前記設定湿度における前記分解程度と測定された前記相対湿度における前記分解程度との比を用いて補正し、
前記抗がん剤の分解処理を、前記CT値が、予め前記設定湿度における分解終点として前記記憶装置に記憶されたCT設定値に達したときに終了させるように構成された
ことを特徴とする抗がん剤分解装置。
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JP7076109B2 (ja) | 2017-10-13 | 2022-05-27 | 株式会社タムラテコ | 有害物処理方法およびオゾン発生装置 |
WO2021230192A1 (ja) * | 2020-05-11 | 2021-11-18 | ウシオ電機株式会社 | 抗がん剤の分解方法 |
JPWO2021230192A1 (ja) * | 2020-05-11 | 2021-11-18 | ||
JP7397416B2 (ja) | 2020-05-11 | 2023-12-13 | ウシオ電機株式会社 | 抗がん剤の分解方法 |
Also Published As
Publication number | Publication date |
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IL242869B (en) | 2019-05-30 |
US10675495B2 (en) | 2020-06-09 |
US10004932B2 (en) | 2018-06-26 |
JPWO2014208428A1 (ja) | 2017-02-23 |
US20160121152A1 (en) | 2016-05-05 |
US20180200554A1 (en) | 2018-07-19 |
EP3015137A1 (en) | 2016-05-04 |
KR20160022288A (ko) | 2016-02-29 |
KR102183801B1 (ko) | 2020-11-27 |
CN105246554A (zh) | 2016-01-13 |
EP3015137B1 (en) | 2022-10-26 |
CN105246554B (zh) | 2019-07-26 |
EP3015137A4 (en) | 2017-01-18 |
JP6301329B2 (ja) | 2018-03-28 |
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