201017164 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種品管控制液及其使用方法。特別β 關於一種儲存期限長、穩定性高、檢測精準且製裎簡p， 非酵素型電化學檢測系統的品管控制液及其使用方法便之 【先前技術】 ' 利用電化學法所製成之電極試片τ區分成兩類，酵201017164 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a quality control liquid and a method of using the same. Special β About a long shelf life, high stability, accurate detection and simple p, p-type control solution for non-enzyme type electrochemical detection system and its use method [Prior Art] 'Using electrochemical method The electrode test piece τ is divided into two types, leaven
電極試片及非酵素型電極試片。由於多數酵素電極試片具 有受濕式保存條件限制、製程複雜及控制條件繁瑣等諸多 缺點，導致其製作成本高而無法大量生產。因此，近年 來，電化學檢測系統之研究多朝向非酵素型電極試 展。 . 在血液或其他體液等檢體中之尿酸的檢測，係用以醫學 界診斷與監測不同病況期間之工具之一。目前有多種不= 的方式可用於檢測尿酸含量，常用的檢測方法包括化學法 及酵素法。然而，化學法具有容易被干擾、專一性不佳之 缺點，而酵素法的檢驗費用昂貴，貯存不便，無法普及居 家使用。因此，發展出一種如美國專利第6,258,23〇扪號 所揭露之非酵素型尿酸檢測電極試片。 此外，捐血中心對於血液筛選與捐血者的安全防護均需 藉由血紅素檢測系統來把關，其檢測方法眾多包含化學 法、氣測法、比重法及比色法等，其中目前最常被使用的 檢測方法為硫酸酮比重法及血紅素檢測儀。血紅素檢測儀 又以HemoCue Inc.製造之Hem〇cue最常被使用。Hem〇cue 131728.doc 201017164 為一種利用光學原理的檢測儀，但是其所需之光學元件及 耗材成本較高’因此，美國專利第4,876,2〇5號提供一種血 紅素電化學檢測試片。 而口 管控制液的主要使用目的在於確認電化學 檢測系統之功能是否正常，以及當檢測過程中出現具有疑 慮、的結果，且待確認檢㈣統是否異常時，可以根據品管 控制液所檢測的結果作為判斷依據，以確認該檢測系統是 否正常。 參 一般市售血紅素檢測儀係以動物重組缝作為校正檢測 $之⑽g控制液。然而’含有動物重組血液之品管控制液 需要保存於低溫狀態下，保存條件不易控制且效期不長， 、、 個月各易受到溫度及操作使用不當等影響，使得 品官控制液之品質受到污染，以致於此類血紅素檢測儀基 於⑽管控制液的品質而造成其使用上受到明顯限制。 鑑於上述諸多因素，實有必要提供-種儲存期限長、穩 • 定性高、檢測精準且製程簡便之適用於非酵素型電化學檢 、Χί系統的管控制液，以滿足在檢測系統方面之需求。 【發明内容】 本發明之主要目的在於提供一種用於非酵素型電化學檢 測系統之απ管控制液，可供灰紅素、尿酸或其他不需使用 酵素檢測之待分析物的檢測系統之品質管制用。 本發明之品質控制液係包含一亞鐵氰化物鹼金屬鹽及一 水性媒介，其中該水性媒介係用於溶解該亞鐵氰化物鹼金 屬鹽。 131728.doc 201017164 本發明之另一目的在於提供—種品管控制非酵素型電化 學檢測系統之方法，其包含： ()將本發月之管控制液與該非酵素型電化學檢測系 統上的鐵氰化物接觸； (b)於該測试系統施加固定電遷；及 ⑷量測電流變化並換算成㈣統之檢測讀值。 【實施方式】 ❹、本發明侧於-種非酵素型電化學檢測系統之品管控制 、、其包含s鐵氰化物驗金屬鹽及一可溶解該亞鐵氣化 物鹼金屬鹽之水性媒介。 .本發明中「品管控制」乙詞係指確認㈣素型電化學檢 測系統之功能是否正常，且確認該檢測系統針對受測樣本 所測量的結果數據是否為可信賴值。 適用於本發明之非酵素型電化學檢測系統係此技藝中任 何已知的非酵素型電化學檢測系統，其包括但不限於美 • 國第6,258,230 B1號專利、中華民國第466344號發明專利 及中華民國第0921〇6502號發明專利申請案所揭示用於檢 測血紅素及尿酸之電極試片與其感測器。適用於本發明之 非酵素型電化學檢測系統通常包含一非酵素型電化學試片 及一電化學感測器。 本發明之品管控制液係利用非酵素型電化學試片上之電 子媒介物（例如鐵氰化物（如鐵氰化鉀與亞鐵氰化物鹼金屬 鹽的亞鐵氰離子（ferrocyanide ion)反應後，電子媒介物由氧 化狀態還原成還原狀態，再藉由施加一外加電壓，促使電子媒 131728.doc 201017164 介物由還原狀態逆反應回復為氧化狀態與產生氧化還原反應 之原理，在該反應過程中偵測電子訊號之變化，以測量亞 鐵氰化物鹼金屬鹽之濃度，再辨識該濃度值是否落於一事 先決定之數值範圍内，以判斷該非酵素型電化學檢測系統 是否正常，而可運用於受測樣本的測量。 適用於本發明中之亞鐵氰化物鹼金屬鹽包含但不限於亞 鐵氰化鉀（potassium ferrocyanide)、亞鐵氰化鈉或亞鐵氰 ❹ 化鋰。而適用於本發明中之水性媒介，係為任何可用於溶 解亞鐵氰化物鹼金屬鹽並提供電子傳遞之媒介，其包含但 不限於水或各種緩衝液（如磷酸鹽緩衝液、檸檬酸緩衝液 或檸檬酸鹽緩衝液），較佳為水。 技藝人士可根據不同非酵素型電化學檢測系統來配製含 有不同亞鐵氰化物鹼金屬鹽濃度之品管控制液，例如依據 非酵素型電化學檢測系統正常使用的標準範圍來調配。在 本發明之具體實施態樣中，亞鐵氰化物鹼金屬鹽之含量越 Φ 鬲，該非酵素型電化學檢測系統之檢測讀值會成比例地增 加。 一般而言，品管控制液中之亞鐵氰化物鹼金屬鹽的含量 係與焚測樣本之種類有關。在本發明之較佳實施態樣中， δ非酵素型電化學檢測系統係用於檢測金紅素時，品管控 制液中之亞鐵氰化物鹼金屬鹽的含量為約〇 〇5重量體積百 分比（w/v%)至約0 5 w/v%，較佳為約〇 16 w/v%至約〇 2 w/v% ;當非酵素型電化學檢測系統係用於檢測尿酸時， 品管控制液中之鐵氰化物的含量，為約0.01 w/v%至約0.05 131728.doc 201017164 w/v°/。’ 較佳為約 〇.〇15 w/v%至約 〇 〇3 w/v〇/〇。 本發明之品管控制液可視需要進一步包含此技術領域中 具有通常知識者所熟知但不致對本發明品管控制液產生不 利影響之其他成份，例如黃原膠（xanthan gum)、甘油 (glycerol)或聚乙二醇（p〇lyethylene glyc〇ls; pEG)。 此外，本發明提供品管控制非酵素型電化學檢測系統之 方法，其包含： (a) 將本發明之品管控制液與該非酵素型電化學測系統 上的鐵氰化物接觸； (b) 於該測試系統施加固定電壓；及 (c) 量測電流變化並獲得亞鐵氰化物鹼金屬鹽濃度值。 本發明品管控制非酵素型電化學檢測系統之方法進一步 包含將量測結果值與一事先決定之數值範圍進行比對，若 該量測結果值落於該事先決定之數值範圍，則表示該非酵 素型電化學檢測系統之功能正常，而可運用於受測樣本的 測量；若該量測結果值高於或低於該事先決定之數值範 圍，則表示該非酵素型電化學檢測系統之功能不正常，而 無法運用於受測樣本的測量。技藝人士可根據不同型式之 非酵素型電化學檢測系統及受測樣本之種類，來訂定該事 先決定之數值範圍。 在本發明之較佳實施態樣中，非酵素型電化學檢測系統 可量測之血紅素範圍為約4克/分升至約2〇克/分升，及尿酸 範圍為約3毫克/分升至約20毫克/分升。在本發明之具體實 施態樣中，使用品管控制液所得之血紅素系統檢測結果為 131728.doc •10- 201017164 約12克/分升至約14克/分升或約16克/分升至約19克/分 升；使用品管控制液所得之尿酸系統檢測結果為約5毫克/ 分升至約7毫克/分升或約1〇毫克/分升至約12毫克/分升。 以下實施例係用於對本發明作進一步說明，唯非用以限 制本發明之範圍。任何熟悉此項技藝之人士可輕易達成之 修飾及改變均包括於本案說明書揭示内容及所附申請專利 範圍之範圍内。 實施例 ❹ 實施例1:本發明品管控制液之配製 分別配製用於非酵素型電化學血紅素檢測系統及非酵素 型電化學尿酸檢測系統中之兩種具有不同亞鐵氰化鉀濃度 的品管控制液。於血紅素檢測系統中，品管控制液包含約 〇·16重量％之亞鐵氰化鉀，其餘為水時，所得到的電訊號 為約13·2克/分升，而當品管控制液包含約〇2〇重量％之亞 鐵氰化鉀，其餘為水時，所得到的電訊號為約克/分 • 彳。於尿酸檢測系統中，當品管控制液包含約0.03重量％ 之亞鐵氰化鉀時，所得到的電訊號為約丨丨毫克/分升，而 當品管控制液包含約〇.〇15重量％之亞鐵氰化鉀時，所得到 的電訊號為約6·8毫克/分升。 由表1可知，在LEVEL 1 Φ ,丄λ * ^ 1中血紅素檢測系統所使用之 亞鐵氛化卸濃度為尿酸檢測系統所使用者約5.3倍，然而 系統測試結果相差了 12倍。此結果清楚顯示，在本發明品 管控制液中，所使用的亞鐵氛化卸濃度並不特定，需依不 同待分析物之非酵素型電化學檢測系統而定。此外，在相 131728.doc 201017164 同待分析物之檢測系統中，亞鐵氰化鉀之含量越高，檢測 系統之檢測讀值會成比例地增加。 表1 非酵素型電化學檢測系統 亞鐵氰化鉀濃度 系統檢測結果 血紅素檢測系統 Level 1 0.16% 13.2克/分升 Level 2 0.20% 18.2克/分升 尿酸檢測系統 Level 1 0.015% 6.8毫克/分升 Level 2 0.03% 11毫克/分升 φ 據上所述，本發明係使用穩定性較高的亞鐵氰化物鹼金 屬鹽溶液取代習知利用動物重組血液來進行非酵素型電化 學檢測系統之品管控制。本發明之非酵素型電化學檢測系 統之品管控制液具有儲存期限長、穩定性高、檢測精準且 製程簡便等優點，適合用於檢測多種非酵素型電化學檢測 系統是否正常運作。 雖然本發明已以較佳實施例揭露如上，然其並非用以限 定本發明，任何熟習此技藝者，在不脫離本發明之精神與 ® 範圍内，當可做些許之更動與潤飾，因此本發明之保護範 圍當視後附之申請專利範圍所界定者為準。 131728.doc -12-Electrode test piece and non-enzyme type electrode test piece. Since many enzyme electrode test pieces have many disadvantages such as limited storage conditions due to wet storage conditions, complicated process conditions, and cumbersome control conditions, the production cost is high and mass production cannot be performed. Therefore, in recent years, research on electrochemical detection systems has mostly been directed toward non-enzymatic electrode experiments. The detection of uric acid in blood or other body fluids is one of the tools used by the medical community to diagnose and monitor different conditions. There are a variety of methods that can be used to detect uric acid levels. Common methods of detection include chemical methods and enzyme methods. However, the chemical method has the disadvantage of being easily disturbed and having poor specificity, and the enzyme method is expensive to inspect and inconvenient to store and cannot be used at home. Therefore, a non-enzymatic uric acid detecting electrode test piece as disclosed in U.S. Patent No. 6,258,23 has been developed. In addition, the blood donation center needs to check the safety of blood screening and blood donors by the heme detection system. The detection methods include chemical method, gas measurement method, specific gravity method and colorimetric method. The detection methods used were a ketone sulfate specific gravity method and a heme detector. Heme Detector Hem 〇 cue manufactured by HemoCue Inc. is most commonly used. Hem〇cue 131728.doc 201017164 is a detector that utilizes optical principles, but which requires higher optical components and consumables. Thus, U.S. Patent No. 4,876,2,5 provides a heme electrochemical test strip. The main purpose of the oral control solution is to confirm whether the function of the electrochemical detection system is normal, and when there are doubts and results in the detection process, and if the inspection (four) system is abnormal, it can be detected according to the quality control liquid. The result is used as a basis for judging whether the detection system is normal. The general commercially available heme detector is an animal recombination joint as a calibration test (10) g control solution. However, the quality control fluid containing animal recombinant blood needs to be stored in a low temperature state, the storage conditions are not easy to control and the effect period is not long, and each month is susceptible to temperature and improper operation, which makes the quality of the product control liquid. It is so contaminated that such hemoglobin detectors are significantly limited in their use based on the quality of the (10) tube control fluid. In view of the above factors, it is necessary to provide a tube control solution suitable for non-enzyme type electrochemical detection and Χί system with long storage period, high stability, high accuracy, accurate detection and simple process to meet the requirements of the detection system. . SUMMARY OF THE INVENTION The main object of the present invention is to provide an απ tube control solution for a non-enzymatic electrochemical detection system, which can be used for the quality of the detection system of the analyte to be analyzed by using gray pigment, uric acid or other enzymes without using an enzyme. Control. The quality control liquid of the present invention comprises an alkali metal ferrocyanide salt and an aqueous medium for dissolving the ferrous cyanide alkali metal salt. 131728.doc 201017164 Another object of the present invention is to provide a method for controlling a non-enzymatic electrochemical detection system, comprising: () a tube control liquid of the present month and the non-enzyme type electrochemical detection system Ferricyanide contact; (b) applying a fixed electromigration to the test system; and (4) measuring the current change and converting it into a (four) test reading. [Embodiment] The present invention relates to the quality control of a non-enzymatic electrochemical detection system, which comprises a metal salt of s-ferricyanide and an aqueous medium capable of dissolving the alkali metal salt of the ferrous gas. In the present invention, the term "quality control" refers to confirming whether the function of the (four) type electrochemical detection system is normal, and confirming whether the result data measured by the detection system for the sample to be tested is a reliable value. A non-enzymatic electrochemical detection system suitable for use in the present invention is any known non-enzymatic electrochemical detection system of the art, including but not limited to U.S. Patent No. 6,258,230 B1, and Republic of China No. 466344 An electrode test piece for detecting heme and uric acid and a sensor thereof are disclosed in the Patent Application No. 0921〇6502 of the Republic of China. The non-enzymatic electrochemical detection system suitable for use in the present invention generally comprises a non-enzymatic electrochemical test piece and an electrochemical sensor. The quality control liquid of the present invention utilizes an electron carrier on a non-enzyme type electrochemical test piece (for example, ferricyanide (such as potassium ferricyanide and ferrocyanide ion of ferrocyanide alkali metal salt) The electron mediator is reduced from the oxidized state to the reduced state, and then an applied voltage is applied to promote the reverse reaction of the electron media from the reduced state to the oxidized state and the principle of generating a redox reaction during the reaction. Detecting changes in the electronic signal to measure the concentration of the ferrous cyanide alkali metal salt, and then identifying whether the concentration value falls within a predetermined range of values to determine whether the non-enzymatic electrochemical detection system is normal, and can be used Measurement of the sample to be tested. The alkali metal ferrocyanide salt suitable for use in the present invention includes, but is not limited to, potassium ferrocyanide, sodium ferrocyanide or lithium ferrocyanide. The aqueous medium in the present invention is any medium which can be used for dissolving the alkali metal salt of ferrocyanide and providing electron transfer, including but not limited to Or various buffers (such as phosphate buffer, citrate buffer or citrate buffer), preferably water. The skilled person can formulate alkali metal containing different ferrocyanides according to different non-enzyme type electrochemical detection systems. The quality control solution of the salt concentration is formulated, for example, according to the standard range of normal use of the non-enzyme type electrochemical detection system. In the specific embodiment of the present invention, the content of the ferrous metal cyanide alkali metal salt is Φ 鬲, the non-enzyme The detection reading of the electrochemical detection system will increase proportionally. In general, the content of the ferrous cyanide alkali metal salt in the quality control liquid is related to the type of the incinerated sample. In the aspect, when the δ non-enzyme type electrochemical detection system is used for detecting rutheid, the content of the ferrocyanide alkali metal salt in the quality control liquid is about 5% by weight (w/v%) to about 0 5 w/v%, preferably about w16 w/v% to about w2 w/v%; when the non-enzyme type electrochemical detection system is used for detecting uric acid, the ferricyanide in the quality control liquid Content of about 0.01 w/v% to Approximately 0.05 131728.doc 201017164 w/v°/.' preferably from about 〇.〇15 w/v% to about w3 w/v〇/〇. The quality control fluid of the present invention may further comprise this technology as needed. Other ingredients in the art that are well known to those of ordinary skill but do not adversely affect the quality control fluids of the present invention, such as xanthan gum, glycerol or polyethylene glycol (p〇lyethylene glyc〇ls; pEG) In addition, the present invention provides a method for controlling a non-enzymatic electrochemical detection system of a quality control comprising: (a) contacting a quality control liquid of the present invention with ferricyanide on the non-enzymatic electrochemical measuring system; b) applying a fixed voltage to the test system; and (c) measuring the current change and obtaining a ferrocyanide alkali metal salt concentration value. The method for controlling a non-enzymatic electrochemical detection system of the present invention further comprises comparing the measured result value with a predetermined range of values, and if the measured result value falls within the predetermined range of values, indicating the non- The function of the enzyme type electrochemical detection system is normal, and can be applied to the measurement of the sample to be tested; if the value of the measurement result is higher or lower than the predetermined range of values, it means that the function of the non-enzymatic electrochemical detection system is not Normal, not applicable to measurements of the sample under test. The skilled person can determine the range of values to be determined based on the type of non-enzyme type electrochemical detection system and the type of sample to be tested. In a preferred embodiment of the invention, the non-enzymatic electrochemical detection system can measure hemoglobin ranging from about 4 grams per deciliter to about 2 g/dL, and the uric acid range is about 3 mg/min. Rose to about 20 mg / dl. In a specific embodiment of the present invention, the hemoglobin system using the quality control fluid is 131728.doc •10-201017164 about 12 g/dl to about 14 g/dl or about 16 g/dl. Up to about 19 g/dl; the uric acid system test using the quality control solution is from about 5 mg/dl to about 7 mg/dl or about 1 mg/dl to about 12 mg/dl. The following examples are intended to be illustrative of the invention and are not intended to limit the scope of the invention. Modifications and variations that may be readily made by those skilled in the art are included within the scope of the disclosure of the present disclosure and the scope of the appended claims. EXAMPLES Example 1: Preparation of the quality control liquid of the present invention is separately formulated for use in a non-enzymatic electrochemical hemoglobin detection system and a non-enzymatic electrochemical uric acid detection system having two different concentrations of potassium ferrocyanide Quality control fluid. In the hemoglobin detection system, the quality control liquid contains about 16% by weight of potassium ferrocyanide, and when the rest is water, the obtained electric signal is about 13.2 g/dl, and when the quality control is The liquid contains about 2% by weight of potassium ferrocyanide. When the rest is water, the obtained electric signal is York/min • 彳. In the uric acid detection system, when the quality control liquid contains about 0.03% by weight of potassium ferrocyanide, the obtained electric signal is about 丨丨mg/dl, and when the quality control liquid contains about 〇.〇15 When the weight% of potassium ferrocyanide is obtained, the obtained electric signal is about 6.8 mg/dl. It can be seen from Table 1 that in the LEVEL 1 Φ , 丄λ * ^ 1 , the ferrous solution detection system used by the heme detection system is about 5.3 times that of the user of the uric acid detection system, but the system test results are 12 times different. This result clearly shows that the concentration of ferrous iron to be used in the control solution of the present invention is not specific and depends on the non-enzyme type electrochemical detection system of the analyte to be analyzed. In addition, in the detection system of the analytes, the higher the content of potassium ferrocyanide, the higher the detection reading of the detection system. Table 1 Non-enzymatic electrochemical detection system potassium ferrocyanide concentration system test results Heme detection system Level 1 0.16% 13.2 g / deciliter Level 2 0.20% 18.2 g / deciliter uric acid detection system Level 1 0.015% 6.8 mg / Divided Level 2 0.03% 11 mg / deciliter φ According to the above, the present invention uses a highly stable ferrocyanide alkali metal salt solution to replace the conventional use of animal recombinant blood for non-enzyme type electrochemical detection system. Quality control. The quality control system of the non-enzyme type electrochemical detection system of the invention has the advantages of long storage period, high stability, accurate detection and simple process, and is suitable for detecting whether a plurality of non-enzyme type electrochemical detection systems are operating normally. Although the present invention has been described above by way of a preferred embodiment, it is not intended to limit the invention, and it is to be understood that those skilled in the art can make some modifications and refinements without departing from the spirit and scope of the invention. The scope of the invention is defined by the scope of the appended claims. 131728.doc -12-