Ceftriaxone Sodium及Moxifloxacin Hydrochloride與Icodextrin腹膜透析液相容性

Abstract

第一部分 研究背景 腹膜炎為腹膜透析病人常見的併發症之一，可能導致病人需要住院、轉換為血液透析或死亡。Ceftriaxone sodium為廣效的第三代cephalosporin類抗生素，可用於治療革蘭氏陽性菌及陰性菌所造成的感染，對於腹膜透析病人之腹膜炎感染可能為治療選擇。而目前並無ceftriaxone與含icodextrin之腹膜透析液之相容性資料。 研究目的 本研究之目的為分析ceftriaxone sodium與PVC材質包裝之含icodextrin的腹膜透析液儲存於8°C七天，25°C兩天及37°C一天之物理及化學相容性。 研究材料與方法 九包含icodextrin之腹膜透析液（Extraneal®，2L/包）每包各加入1000 mg的ceftriaxone做為實驗組，儲存於8°C、25°C、37°C不同溫度下各3包，並以不加入藥品之9包腹膜透析液做為對照組。藥品配置後於不同時間點進行採樣分析，8°C檢品於0、24、48、168 小時，25°C於0、6、12、24、48小時，而37°C於0、6、9、12、24小時採樣。物理相容性分析部分包括以粒子計數器檢驗溶液中每mL大於10 μm及25 μm之微粒物質，廷得耳試驗以及肉眼觀察是否有沉澱、混濁、變色等情形。化學相容性分析包括pH值分析以及以高效能液相層析儀/紫外線可見光偵測器（HPLC/UV）分析實驗組檢品溶液中ceftriaxone之含量，以溶液中ceftriaxone含量大於起始濃度之90%視為安定。 研究結果 物理相容性分析部分實驗組與對照組檢品在實驗過程中皆通過美國藥典第33版光阻微粒物質測計法之規定，每mL微粒物質>10 μm者不大於25個，且微粒物質>25μm者不高於3個。廷得耳實驗在兩組皆看到有一道光束通過。實驗過程中未觀察到溶液有沉澱、混濁現象，但ceftriaxone加入含icodextrin之腹膜透析液儲存於37°C之檢品，在實驗過程中溶液顏色有逐漸變深情形，其他組溶液顏色無明顯變化。 化學相容性分析部分，實驗組與對照組溶液在分析過程中pH皆介於5.12~5.18之間。於8°C冰箱儲存的ceftriaxone腹膜透析溶液，在7天後濃度仍有起始濃度的94.24% ± 1.07%；在25°C室溫儲存的溶液在24小時後濃度為起始濃度的90.90% ± 1.47%；在37°C保溫箱儲存的溶液在6小時就不安定，濃度僅有起始濃度之88.36% ± 1.01%，12小時後更降到79.78% ± 4.01%。推估降解至90%之時間為4.7小時。 結論 Ceftriaxone與含icodextrin之腹膜透析溶液（Extraneal®）在8°C、25°C有物化相容性，安定性在8°C至少7天，在25°C為24小時。而混合溶液在37°C儲存，於6小時就低於起始濃度的90%，可能限制其腹膜腔給藥的有效性。因此，若含icodextrin之腹膜透析液需被加熱至37°C，ceftriaxone應該在使用前再加入腹膜透析液中。 第二部份 研究背景 腹膜炎為腹膜透析病人常見的併發症之一，可能導致病人需要住院、轉換為血液透析或死亡。Moxifloxacin hydrochloride為fluoroquinolone類抗生素，可用於對抗革蘭氏陽性菌及陰性菌、厭氧菌、非典型病原菌，對於腹膜透析病人之腹膜炎感染可能為治療選擇。然而目前並無moxifloxacin與含icodextrin之腹膜透析液之相容性資料。 研究目的 本研究之目的為分析moxifloxacin hydrochloride與PVC材質包裝之含icodextrin的腹膜透析液儲存於8°C、25°C七天及37°C一天以及含4.25%及1.5% dextrose之腹膜透析液儲存於37°C 一天之物理及化學相容性。 研究材料與方法 九包含icodextrin之腹膜透析液（Extraneal®，2L/包）每包各加入250 mL含400 mg的moxifloxacin靜脈注射液做為實驗組，儲存於8°C、25°C、37°C不同溫度下各3包，並以不加入藥品之9包腹膜透析液做為對照組。另外，準備六包含4.25% destrose及6包含1.5% dextrose之腹膜透析液（Dianeal PD-2®，2L/包），其中3包為實驗組，另外3包為對照組藥品。含icodextrin之腹膜透析液組，藥品配置後於不同時間點進行採樣分析，8°C檢品於0、24、48、168 小時，25°C於0、6、12、24、48、168小時，而37°C於0、6、9、12、24小時採樣。而含4.25% destrose及含1.5% dextrose之腹膜透析液組儲存於37°C並於0、6、12、24小時採樣。物理相容性分析部分包括以粒子計數器檢驗溶液中每mL大於10 μm及25 μm之微粒物質，廷得耳試驗以及肉眼觀察是否有沉澱、混濁、變色等情形。化學相容性分析包括pH值分析以及以高效能液相層析儀/紫外線可見光偵測器（HPLC/UV）分析實驗組檢品溶液中moxifloxacin之含量，以溶液中moxifloxacin含量大於起始濃度之90%視為安定。 研究結果 物理相容性分析部分含icodextrin之腹膜透析液以及含1.5% destrose、4.25% dextrose之腹膜透析液，實驗組與對照組檢品在實驗過程中皆通過美國藥典第33版光阻微粒物質測計法之規定，每mL微粒物質>10 μm者不大於25個，且微粒物質>25μm者不高於3個。廷得耳實驗在含icodextrin之腹膜透析液看到有一道光束通過，但含在1.5% destrose、4.25% dextrose之腹膜透析液則無觀察到此現象。實驗過程皆中未觀察到溶液有沉澱、混濁或顏色變化現象。 化學相容性分析部分，在含icodextrin之腹膜透析液實驗組與對照組溶液在分析過程中pH皆介於5.11~5.17之間。於8°C冰箱儲存的moxifloxacin腹膜透析溶液，在7天後濃度仍有起始濃度的97.54% ± 0.26%；在25°C室溫儲存的溶液在7天後濃度為起始濃度的98.45% ± 0.69%；在37°C保溫箱儲存的溶液在24小時後濃度為起始濃度的99.37% ± 0.50 %。 在含4.25% destrose之腹膜透析液實驗組與對照組溶液在分析過程中pH皆介於5.08~5.13，在37°C保溫箱儲存的溶液在24小時後濃度為起始濃度的99.55% ± 0.56 %。而含1.5% dextrose之腹膜透析液pH介於5.12~5.18，在37°C保溫箱儲存的溶液在24小時後濃度為起始濃度的100.39% ± 0.29 %。顯示moxifloxacin在分析過程中相當安定。 結論 Moxifloxacin與含icodextrin之腹膜透析溶液在8°C、25°C、37°C有物化相容性，安定性在8°C及25°C至少7天，在37°C至少24小時。而moxifloxacin在含4.25%、1.5% dextrose之腹膜透析溶液，於37°C安定性至少24小時。

Part1 ackground Peritonitis remains a leading complication of peritoneal dialysis. It contributes to patient technique failure, hospitalizations, and occasionally, mortality. Ceftriaxone is a third generation cephalosporin antibiotic which has activity against both gram-positive and gram-negative bacteria. It may be used in patients with peritonitis. However, there are no compatibility data of ceftriaxone with dialysis solution containing icodextrin at different temperature. Objective The objective of this study was to evaluate the physical and chemical stability of ceftriaxone sodium in icodextrin peritoneal dialysis (PD) solution (Extraneal®) in PVC containers over 7 days at 8°C, 2 days at 25°C, and 1 day at 37°C. Materials and Methods Nine bags of 2L icodextrin PD solution (Extraneal®) were prepared. To each bag, ceftriaxone 1000 mg was added. Three bags of ceftriaxone– icodextrin solution were stored at 8°C, three at 25°C and three at 37°C. The samples were taken at 0, 24, 48, 168 hours at 8 °C; 0, 6, 12, 24, 48 hours at 25°C; and 0, 6, 9, 12, 24 hours at 37°C. Another 9 bags of icodextrin solution (Extraneal®) were used as control. Physical compatibility tests include Tyndall experiments, visual inspection and measurement of the numbers of insoluble particles per milliliter with diameter equal to or greater than 10 µm and 25 µm by the particle counter.

Chemical compatibility tests include measurement of pH value by pH meter, and ceftriaxne concentration by high performance liquid chromatography with ultraviolet detector. A greater than 10% decrease from its initial concentration was considered as clinically significant loss of potency. Results All samples passed the criteria of light obscuration particle count test in the 33rd edition of USP. The average number of particles did not exceed 25 per mL with diameter≧10 µm and did not exceed 3 per mL with diameter≧25 µm. The path of a beam of light was observed in all samples by Tyndall experiments. No precipitation and cloudiness were observed at any time. However, the color of ceftriaxone– icodextrin solution samples change from light yellow to dark amber at 37°C. The range of pH value was 5.12~5.18 for all samples. At 8°C, 94.24% ± 1.07% of the initial concentration was retained after 7 days. At 25°C, 90.90% ± 1.47% of the initial concentration was retained after 24 hours. At 37°C, 88.36% ± 1.01 % of the initial concentration was retained after 6 hours and 79,78% ± 4.01 % of potency was retained after 12 hours. T0.90 is estimated to be 4.7 hours. Conclusions Ceftriaxone is compatible with icodextrin PD solution (Extraneal®) for at least 7 days at 8°C and 24 hours at 25°C.Because it loses more than 10% of the potency after 6 hours at 37°C, and we can not assure its stability during IP administration. If icodextrin PD solution bags shall be warmed to body temperature, ceftriaxone should be added just prior to a PD exchange. Part 2 Background Peritonitis remains a leading complication of peritoneal dialysis. It contributes to patient technique failure, hospitalizations, and occasionally, mortality. Moxifloxacin hydrochloride is a fluoroquinolone antibiotic which has activity against gram-positive, gram-negative bacteria and some mycobacteria. It may be used in patients with peritonitis. However, there are no compatibility data of moxifloxacin with dialysis solutions containing icodextrin at different temperature. Objective The objective of this study was to evaluate the physical and chemical stability of moxifloxacin hydrochloride in icodextrin peritoneal dialysis (PD) solution (Extraneal®) in PVC containers over 7 days at 8°C, 25°C, and 1 day at 37°C and in 4.25 % dextrose, 1.5% dextrose peritoneal dialysis (PD) solution (Dianeal PD-2®) in PVC containers over 1 day at 37°C. Materials and Methods Nine bags of 2 L icodextrin PD solution (Extraneal®) were prepared. To each bag moxifloxacin infusion solution (400 mg/250 mL) was added. Three bags of moxifloxacin– icodextrin solution were stored at 8°C, three at 25°C and three at 37°C. The samples were taken at 0, 24, 48, 168 hours at 8°C; 0, 6, 12, 24, 48,168 hours at 25°C; and 0, 6, 9, 12, 24 hours at 37°C. Another 9 bags of icodextrin solution (Extraneal®) were used as control. Three bags of 2 L 4.25 % dextrose and three bags of 2 L 1.5% dextrose PD solution (Dianeal PD-2®) were prepared. Three bags of moxifloxacin–dextrose solution were stored at 37°C. The samples were taken at 0, 6, 12, 24 hours at 37°C. Another three bags of 4.25 % dextrose and three bags of 1.5% dextrose PD solution were used as control. Physical compatibility tests include Tyndall experiments, and visual inspection and measurement of the numbers of insoluble particles per milliliter with diameter equal to or greater than 10 µm and 25 µm by the particle counter. Chemical compatibility tests include measurement of pH value by pH meter, and moxifloxacin concentration by high performance liquid chromatography with ultraviolet detector. A mean concentration of the samples above 90% of the initial concentration was considered stable. Results All samples passed the criteria of light obscuration particle count test in the 33rd edition of USP. The average number of particles did not exceed 25 per mL with diameter≧10 µm and did not exceed 3 per mL with diameter≧25 µm. The path of a beam of light was observed in all samples of icodextrin PD solution by Tyndall experiments, but was not observed in all samples of dextrose PD solution. No precipitation, cloudiness or color change were observed at any time. The mean moxifloxacin concentration in icodextrin PD solution was retained 97.74% ± 0.26% of the initial concentration after 7 days at 8°C. At 25°C, 98.45% ± 0.69% of the initial concentration was retained after 7 days. At 37°C, 99.37% ± 0.50 % of the initial concentration was retained after 24 hours. The range of pH value was 5.11~5.17 for all samples. The mean moxifloxacin concentration in 4.25 % dextrose PD solution was retained 99.55% ± 0.56% of the initial concentration after 24 hours at 37°C. The range of pH value was 5.08~5.13. The mean moxifloxacin concentration in 1.5 % dextrose PD solution was retained 100.39% ± 0.29% of the initial concentration after 24 hours at 37°C. The range of pH value was 5.12~5.18. Conclusions Moxifloxacin is compatible with icodextrin PD solution for 7 days at 8°C, 25°C, and 24 hours at 37°C and compatible with dextrose PD solution for 24 hours at 37°C.