臺灣博碩士論文加值系統

摘 要
當病菌引發嚴重骨關節感染，而導致骨組織破壞時，須進行重建手術治療受感染的骨頭，必要時則需置換人工關節，在台灣每年已有超過6,000人，接受關節重建手術，其中以髖關節置換手術最常見，手術之成功與否以及感染的治療，對病患日後之生活品質影響甚鉅。以抗生素混合骨水泥應用於關節重建手術治療感染的給藥方法已行之有年，研究證實此投藥方式具有延長藥效的優點，二階段式的關節重建手術更能有效治療深度的骨感染，感染的治癒率高達82~96%，且含藥骨水泥兼具支持作用；然而，以含藥骨水泥粒的給藥方式迄今並未完整地被評估其抗菌效能及探討藥物釋出機制。
氮烯內醯胺(Aztreonam; AZ)，屬於monobactam抗菌劑，可有效治療由革蘭氏陰性菌(Gram-negative)需氧菌(Aerobes)所引起的各種感染症，投藥後衍生之副作用少而且過敏性低，可作為治療革蘭氏陰性菌引起感染症的首選藥物。本實驗之目的即在於探討氮烯內醯胺自人工骨水泥釋放-體外與體內的釋離情形研究。體外實驗部分係將AZ混入骨水泥製成含藥骨水泥粒，分別製作不同厚度、表面積以及處方之骨水泥粒，比較AZ釋離情形之差異，建立一完整之溶離模式，並評估AZ於骨水泥中的釋出機制。體內實驗部分欲開發一HPLC分析方法，可應用於檢測臨床髖關節置換手術後患者滑囊液中AZ濃度，並討論AZ自髖關節人工骨水泥粒釋出的藥物動力學特性，連結AZ體外的溶離機制與體內釋出的動態，並對於人工骨水泥的給藥模式提供預測以及建議。
以臨床所使用之藥物比例製作含藥實心骨水泥粒，溶離試驗結果顯示，AZ釋出量小於 5 mg，僅佔原骨水泥粒中藥物總量之3.6%，藥物釋出總量少；而不同包覆厚度之含藥骨水泥粒，AZ釋出總量相近，C.V.小於1%，利用統計學上之ANOVA檢定，亦無統計學上差異 (p>0.05)，因此推論AZ僅由表面釋出。不同表面積之含藥骨水泥粒溶離試驗結果顯示，隨著表面積加大，AZ釋出量即增加(R2> 0.9)，更可確定AZ之釋放機制係自骨水泥粒表面釋出。骨水泥之含藥比例增加，AZ的釋出總量呈兩段式線性關係，當含藥比例超過 4.30%，可釋出藥量明顯加大，釋放機制產生改變，對照掃瞄式電子顯微鏡之觀察結果，推論藥物可經骨水泥間孔隙釋出，因而增加釋離量。體外溶離數據之配適結果以Korsmeyer-Peppas model 經過修正後之配適公式配適性最佳，故選用其作為AZ自人工骨水泥中釋出的溶離配適模式，以配適所得之動力學常數以及擴散指數作為判斷藥物釋出情形的指標。將不同厚度的骨水泥粒之溶離結果作曲線配適，得到的擴散指數以及動力學常數相近，顯示厚度不影響藥物釋放；在酸鹼值為5.34及7.4之的溶離媒液中，動力學常數相近，惟AZ於其中之降解速率不同，造成溶離之差異。將骨粒之表面積與動力學常數作圖，可得一線性關係(R2=0.9924)；將含藥比例與溶離速率常數作圖，可得兩段式線性關係。
體內研究方面，檢品中AZ的測定係採用HPLC分析方式，選用逆相層析管柱，配合紫外光偵測，波長設定在310 nm。檢量線濃度範圍介於 0.025 ~ 25 μg/ml 間，線性良好，回內與回間分析之變異係數皆小於7 %，且平均回收率為80.76 %，顯示此分析方法是良好的AZ生物檢品檢測方法。此外，本研究亦探討AZ混合骨水泥所製成之人工關節，植入體內之後AZ的濃度變化，上述HPLC分析方法亦成功應用於檢測關節重建手術後病人之關節滑囊液檢品中AZ之濃度，由分析得知在病患住院期間AZ自髖關節部位的釋出速率常數0.2897±0.0028 (day-1)；而病患出院後至接受第二次手術之間的藥物平均輸移速率常數為0.0370±0.0027(day-1)，與靜脈注射給藥之後輸移速率常數1.60±0.57 (hr-1)相比較，顯示藥物自關節腔到中央室之輸移速率緩慢，不會有快速排除的現象，因此能夠於關節腔中維持高濃度狀態，有利於抗感染治療。又根據病人體內滑囊液中的濃度以及輸移速率常數k21，計算得知在置入手術後於病人體內維持最小抑菌濃度至少44天，占兩次手術間隔時間之42.62%，應可有效治癒感染，顯示此一給藥方式的確具有良好之治療效果。
總結以上體外試驗結果，得知AZ可自骨粒表面釋放，增加含藥骨粒的表面積或者是增加含藥比例皆有助於藥物釋出；於病人滑囊液之分析結果，則證實了含AZ骨水泥裝置應可長期且有效抗感染。但是對於此劑型應該略作改良，以含藥的薄層骨水泥，具有同樣的治療效果，使用加大表面積的植入裝置更可增加藥物之釋出量，既可達到抗菌之效果，並減少藥粉的浪費，最符合經濟效益。

Abstract
The arthroplasty or revision surgery was used to treat osteomyelitis and infected bone destruction. Every year in Taiwan, more than 6000 patients receipted the implantation surgeries and the hip arthroplasty is mostly performed of all. Using antibiotics-loaded bone cement was against the infection in the arthroplasty. As for the higher hip score and the shorter hospital-stay treatments, the two-stage revision provided good efficacy. Aztreonam (AZ), a monocyclic β-lactam antibiotic, can be used against infections caused by gram-negative and aerobic bacterial. After administration of AZ, there were little adverse effects and low percentage of allergy. Nevertheless, the mechanisms of AZ releasing from bone cement and its clinical anti-bacterial efficacy were not well established. The aim of this study was to realize the mechanisms of AZ releasing from bone cement in vitro and pharmacokinetics of AZ in vivo. Compared the release profiles of AZ from AZ-loaded cement spheres between the coating thickness, surface area and formulation of the spheres. A HPLC method was developed to determine the AZ concentrations in human synovial fluid after the hip arthroplasty. Investigation AZ released from bone cement in vivo and estimated pharmacokinetics of AZ at hip.

With the same formulation in clinical surgeries, the amounts of drug released from AZ-loaded solid cement spheres were only 3.6% of the total amounts of antibiotic incorporated into the cement spheres. After coated with different thickness of the cement spheres, the release-profiles of AZ in vitro were similar. With the extensive surface area of AZ-loaded cement spheres, the total amounts of AZ released from cement spheres increased linearly (r2=0.9692). It demonstrated AZ released from the surface of cement spheres. Adding the coating thickness of AZ-loaded cement spheres did not increase drug released. The spacer should be modified to the thin coating and the extensive area of AZ-loaded cement spacer with the efficiency and economy. Increasing the ratio of the drug in AZ-loaded cement spheres from 3.2 to 4.3 percent, the total release percentage increased linearly (Y = 0.286 X + 2.38, r2 = 0.9432). When the ratio was over 4.3 percent, the total percentage released significantly increased with the ratio of the drug (Y = 1.342 X – 2.30, r2=0.9793). Compared with the SEM results, the more loaded drugs and cracks on the surface of cement spheres, the more amounts of drug were released.

The concentrations of AZ in biological fluid were determined by an accuracy and simple HPLC method consisted of a reversed column with UV detection at 310 nm. The standard curve of plasma samples showed good linearity in the concentration range of 0.025 ~ 25 μg/ml. The coefficients of variance and the relative errors were less than 7%. The average recovery of AZ was 80.76%. The HPLC method had been successfully applied to determine the concentration of AZ in human synovial fluid after the first stage revision hip arthroplasty with an AZ-loaded cement spacer. The average elimination rate constant from hip after surgery was 0.2897±0.0028 (day-1) at hostipial stay. The average distribution rate constant k21 was 0.0107 ± 0.0027 (day-1) until the second revision surgery. Because of low elimination rate at hip, it remained higher concentration of AZ than the MIC90. The durations of AZ concentration above the MIC90 were for months and covered more than 40% of the dosage interval in two-stage therapy (t>MIC90 > 40% dosage interval). AZ-loaded cement prosthesis could maintain AZ concentration above the MIC longer and provide anti-infection effect.

In summary, with extensive surface area and modified formulation, AZ-loaded cement spheres could increase the drug release. The concentration of AZ was more than the MIC of pathogens in vivo. The spacer would provide sufficient local concentration of AZ to maintain the bactericidal action for months.

目 錄
頁次
目錄 Ⅰ
流程目錄 Ⅶ
附表目錄 Ⅷ
附圖目錄 ⅩⅠ
中文摘要 ⅩⅤ
英文摘要 ⅩⅦ
第一章 緒論 1
1. 簡介AZ 1
1. 1. 物理化學性質 2
1. 2. 作用機轉 3
1. 3. 抗菌範圍 3
1. 4. 抗菌活性 5
1. 5. 藥物動力學 6
1. 6. 臨床應用 6
1. 6. 1. 尿道感染(urinary tract infections) 6
1. 6. 2. 下呼吸道感染(lower respiratory tract infections) 7
1. 6. 3. 敗血症(speticaemia)及菌血症(bacteraemia) 7
1. 6. 4. 骨關節感染(bone and joint infections) 7
1. 7. 副作用 8
2. 人工骨水泥 10
2. 1. 加成聚合反應(Addition polymerization) 12
2. 2. 聚甲基丙烯酸甲酯聚合物的應用 12
2. 2. 1. 牙科方面應用 12
2. 2. 2. 骨科方面應用 13
2. 2. 3. 植入劑型 13
2. 3. 含抗生素骨水泥與關節重建手術 13
3. AZ自骨水泥中釋出之溶離機制與數學模式 14
3. 1. Zero-order kinetics 14
3. 2. First-order kinetics 15
3. 3. Hixson-Crowell model 15
3. 4. Weibull model 16
3. 5. Higuchi model 16
3. 6. Baker-Lonsdale model 17
3. 7. Hopfenberg model 17
3. 8. Korsmeyer-Peppas model 18
3. 9. Extended Korsmeyer-Peppas model 19
4. 實驗目的 20

第二章 實驗部分 21
一、實驗材料及儀器 21
1. 實驗試藥 21
2. 儀器 22
3. 試藥製備與試劑的配製 22
3. 1. AZ儲備溶液之配製 22
3. 2. 阿魏酸(Ferulic acid；FA)儲備溶液之配製 23
3. 3. 溶離媒液之製備 23

二、體外試驗實驗方法 24
1.體外實驗之HPLC分析條件 24
2. 標準檢量線之製作 24
3. 安定性試驗 26
3. 1. 緩衝溶液之製備 26
3. 2. 緩衝溶液中之安定性試驗 26
3. 3. 溶離媒液中之安定性試驗 28
3. 4. 試驗溶液中之安定性試驗 28
3. 5. AZ粉末之熱安定性試驗 28
3. 6. AZ粉末貯存安定性試驗 28
4. AZ 之含量測定 28
5. 聚甲基丙烯酸甲酯人工骨水泥(Osteobond® Copolymer Bone Cement )性質分析 29
5. 1. 聚甲基丙烯酸甲酯粉末之粗細度分析(Powder fineness of Poly
(methyl methacrylate-co-styrene) copolymer powder) 29
5. 2. 甲基丙烯酸甲酯液體之密度分析(Density of Methyl methacrylate liquid) 29
6. 骨水泥與AZ之示差掃描熱分析(Differential scanning calorimetry；DSC) 30
7. 空白及含藥骨水泥粒之製備 30
7. 1. 不同包覆厚度的含藥骨水泥粒的製作 31
7. 2. 不同直徑含藥骨水泥粒的製作 31
7. 3. 不同處方比例的含藥骨水泥粒的製作 31
7. 4. 骨水泥粒之製作步驟 33
8. 含藥骨水泥粒之物性測定 33
8. 1. 重量差異試驗(Weight variation test) 33
8. 2. 圓度分析(Roundness analysis) 33
8. 3. 掃瞄式電子顯微鏡攝影分析(Scanning Electron Micrograph；SEM) 34
9. 溶離試驗(Dissolution test) 35
9. 1. 溶離數據處理 35

三. 體內試驗實驗方法 39
1. 體內試驗之HPLC分析條件 39
2. 臨床檢品之取得 41
2. 1. 臨床檢品之處理 41
3. 標準檢量線之製作 43
4. 分析方法之確效試驗 43
4. 1. 回內分析(within-run assay)之精確性(precision)與準確性(accuracy) 43
4. 2. 回間分析(between-run assay)之精確性與準確性 43
4. 3. 回收率試驗(Recovery test) 43
5. 體內藥物釋出之數據處理 44

第三章 結果與討論 45
一. 體外試驗之結果與討論 45
1. 體外實驗HPLC分析方法之結果與討論 45
2. 自動注射器(autoinjector)體積定量之精確性 45
3. 標準溶液檢量線之結果 47
3. 1. 酸鹼值7.4溶離媒液下AZ的標準檢量線 47
3. 2. 酸鹼值5.34溶離媒液下AZ的標準檢量線 47
4. 安定性試驗之結果與討論 50
4. 1. 緩衝溶液中AZ的安定性 50
4. 2. 試驗溶液中AZ之安定性 50
4. 3. 溶離媒液中AZ的安定性 50
4. 4. 不同溫度下Azactam®注射乾粉之熱安定性 51
4. 5. 經高溫加熱之後Azactam®注射乾粉的貯存安定性 51
5. AZ之含量測定 57
6. Osteobond® Copolymer Bone Cement性質分析 58
6. 1. 聚甲基丙烯酸甲酯粉末之粗細度分析 58
6. 2. 甲基丙烯酸甲酯液體之密度分析 59
7. 骨水泥與AZ之示差掃描熱分析(Differential scanning calorimetry；DSC) 59
7. 1. AZ USP標準品之示差掃瞄熱分析 60
7. 2. Azactam®注射乾粉之示差掃瞄熱分析 60
7. 3. PMMA粉末之示差掃瞄熱分析 60
7. 4. MMA液體之示差掃瞄熱分析 60
7. 5. 空白骨水泥粒之示差掃瞄熱分析 60
7. 6. 含藥骨水泥粒之示差掃瞄熱分析 60
8. 含藥骨水泥粒之物性測定之結果 65
8. 1. 重量差異試驗(Weight variation test)結果 65
8. 2.圓度分析(Roundness analysis)結果 66
8. 3. 電子顯微鏡(Scanning Electron Micrograph)掃瞄結果 66
8. 3. 1. AZ USP標準品之掃瞄式電子顯微圖 66
8. 3. 2. Azactam®注射乾粉之掃瞄式電子顯微圖 66
8. 3. 3. PMMA粉末之掃瞄式電子顯微圖 67
8. 3. 4. 空白骨水泥粒於溶離試驗前後之掃瞄式電子顯微圖 67
8. 3. 5. 含AZ骨水泥粒 (處方 1)於溶離試驗前後之掃瞄式電子顯微圖 67
8. 3. 6. 含AZ骨水泥粒 (處方 2)於溶離試驗前後之掃瞄式電子顯微圖 67
8. 3. 7. 含AZ骨水泥粒 (處方 3)於溶離試驗前後之掃瞄式電子顯微圖 68
8. 3. 8. 含AZ骨水泥粒 (處方 4)於溶離試驗前後之掃瞄式電子顯微圖 68
8. 3. 9. 含AZ骨水泥粒 (處方 5)於溶離試驗前後之掃瞄式電子顯微圖 68
9. 溶離試驗結果及討論 78
9. 1. AZ於酸鹼值5.34及7.4溶離媒液之溶離試驗結果 78
9. 2. 厚度影響含藥骨水泥粒AZ的溶離試驗結果 80
9. 2. 1. 不同包覆厚度的含藥骨水泥粒於酸鹼值5.34溶離媒液之溶離試驗結果 80
9. 2. 2. 不同包覆厚度的含藥骨水泥粒於酸鹼值7.4溶離媒液之溶離試驗結果 80
9. 3. 不同表面積的含藥骨水泥粒之溶離試驗結果 85
9. 4. 不同處方之含藥骨水泥粒之溶離試驗結果 90
10. 溶離結果之配適 95
10. 1. 包覆厚度影響含藥骨水泥粒中AZ溶離試驗的配適結果 95
10. 1. 1. 酸鹼值7.4溶離媒液中溶離的配適結果 95
10. 1. 2. 酸鹼值5.34溶離媒液中溶離的配適結果 102
10. 2. 表面積影響含藥骨水泥粒中AZ溶離試驗的配適結果 108
10. 3. 處方比例影響含藥骨水泥粒中AZ溶離試驗的配適結果 117

二. 體內試驗之結果與討論 128
1. 體內實驗HPLC分析方法之結果與討論 128
1.1. 分析方法之結果 128
1.2. 分析方法比較 128
2. 分析方法之標準檢量線的結果 129
3. 分析方法之確效的結果 129
4. 分析方法回收率的結果 130
5. 骨科手術之檢品取得 136
6. 滑囊液檢品分析結果 136
7. AZ於髖關節之藥動學模式 138
8. 髖部AZ的抗菌藥效評估 144
9. 體外與體內試驗之相關性 145

第四章 結論 146
第五章 參考文獻 148

流程目錄
Scheme 1. HPLC analytical condition for AZ dissolution samples 25
Scheme 2. HPLC analytical condition for AZ in biological fluid samples 40
Scheme 3. Sample preparation for AZ 42
Scheme 4. Pharmacokinetics model of AZ from bone cement prosthesis 140





















附表目錄
Table 1. The minimum inhibitory concentration (MIC90) of antibiotics 5
Table 2. Adverse reactions of AZ after administration 9
Table 3. Components of Osteobond® Copolymer Bone Cement (Zimmer®, USA) 11
Table 4. Buffers system for stability test (ionic strength μ=0.1) 27
Table 5. Sample and weight for D.S.C. assay 30
Table 6. Coating thickness、diameter and formulation of AZ-loaded cement spheres 32
Table 7. Formulation of AZ-loaded cement spheres 33
Table 8. Samples for S.E.M. examination 34
Table 9. Precision of the injection volume of autoinjector 47
Table10. Precision and accuracy of standard curve of AZ in pH 7.4 buffer solution 48
Table 11. Precision and accuracy of standard curve AZ in pH 5.34 buffer solution 49
Table 12. Remaining of AZ in various pH buffer solutions 53
Table 13. Stability of AZ in pH 5.34 and pH 7.4 buffer solutions at 37℃ 55
Table 14. Stability of Azactam® injection powder under heat 57
Table 15. AZ content in Azactam® injection powder 58
Table 16. Powder fineness of PMMA powder 59
Table 17. Density of MMA liquid 59
Table 18.
Weight of AZ-loaded cement spheres with different diameter and
coating thickness 65
Table 19. Weight of AZ-loaded cement spheres with different formulation 65
Table 20. Roundness analysis of AZ-loaded cement spheres 66
Table 21.
Total amount of AZ release from AZ-loaded cement spheres with different
coating thickness in pH 5.34 buffer solution 83
Table 22. Total amount of AZ release from AZ-loaded cement spheres with different
coating thickness in pH 7.4 buffer solution 83

Table 23.
Total amount of AZ release from AZ-loaded cement spheres with
different diameter in pH 7.4 buffer solution 85

Table 24.
Total amount of AZ release per mm2 from AZ-loaded cement spheres
with different diameter in pH 7.4 buffer solution 89

Table 25.
Total amount of AZ release from AZ-loaded solid cement spheres
with different formulation in pH 7.4 buffer solution 90

Table 26.
The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different coating thickness in pH 7.4 buffer solution
(Diameter=17 mm, Formula 3) 97

Table 27.
The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different coating thickness in pH 7.4 buffer solution
(Diameter=20 mm, Formula 3) 98

Table 28.
The Korsmeyer-Peppas kinetic constant of different coating thickness cement
spheres in pH 7.4 buffer solution (Diameter=17mm) 99

Table 29. The Korsmeyer-Peppas kinetic constant of different coating thickness cement
spheres in pH 7.4 buffer solution (Diameter=20 mm) 99
Table 30.
The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different coating thickness in pH 5.34 buffer solution
(Diameter=17 mm, Formula 3) 103

Table 31.
The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different coating thickness in pH 5.34 buffer solution
(Diameter=17 mm, Formula 3) 104

Table 32.
The Korsmeyer-Peppas kinetic constant of different coating thickness cement
spheres in pH 5.34 buffer solution (Diameter=17 mm) 105

Table 33.
The Korsmeyer-Peppas kinetic constant of different coating thickness cement
spheres in pH 5.34 buffer solution (Diameter=20 mm) 105

Table 34.
The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different diameter in pH 7.4 buffer solution
(Coating sphere thickness 0.5 mm, Formula 3) 109

Table 35.
The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different diameter in pH 7.4 buffer solution
(Solid sphere, Formula 3) 110

Table 36. The Korsmeyer-Peppas kinetic constant of different diameter cement spheres
in pH 7.4 buffer solution (Coating sphere thickness 0.5 mm, Formula 3) 111

Table 37.
The Korsmeyer-Peppas kinetic constant of different diameter cement spheres
in pH 7.4 buffer solution (Solid sphere, Formula 3) 111
Table 38. The Korsmeyer-Peppas kinetic constant of different diameter cement spheres
in pH 7.4 buffer solution 111
Table 39. The WRSS and AIC of fitting results of AZ-loaded cement spheres
with different formulation in pH 7.4 buffer solution 118

Table 40. The Korsmeyer-Peppas kinetic constant of different formulations
cement spheres in pH 7.4 buffer solution
(Solid sphere, Diameter= 17 mm, Formula 3) 119

Table 41. Summary of HPLC analysis of AZ in biological samples 132
Table 42. Within-run precision and accuracy of AZ in plasma 134
Table 43. Between-run precision and accuracy of AZ in plasma 134
Table 44. Recovery of AZ 135
Table 45. Concentration and elimination rate constant of AZ in synovial
fluid at hospital stay after first stage revision hip arthroplasty
with an AZ-loaded cement spacer 139
Table 46. Concentration and rate constant of AZ in synovial fluid before the
secondary stage revision hip arthroplasty with an AZ-loaded cement spacer 143
Table 47. The duration of the AZ concentration above the MICs in synovial fluid 145

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