复合MTX硫酸钙人工骨体外释药特性研究
摘要
目的:了解硫酸钙人工骨复合MTX在Tris缓冲生理盐水的体外模拟环境中的释药特性。方法:以硫酸钙人工骨OSTEOSET?为载体,制备载药量20mg,质量百分比为4﹪的药粒。采用浸出法,以Tris缓冲生理盐水作为模拟体液,在37℃,转速50rpn的条件下,收集最初24小时内和后续20天的液体标本,经高效液相色谱分析药物浓度。结果:25粒药粒进入实验,20粒药粒完成全部实验设计。24小时内平均药物浓度初期为10.535mg/L,后期在4～6mg/L之间,累计药物浓度与时间平方根成指数关系。药物释放以4～6﹪的速度,持续稳定释放达18天。早期释药量较高,为10～11﹪。结论:OSTEOSET?硫酸钙人工骨复合MTX药物释放稳定,是良好的药物缓释载体。
Objective: To investigation the character of drug release of calcium sulfate combined with MTX in the circumstance of Tris-buffered natural saline. Methods: The drug particles combined with 20 mg MTX, 4% in weight percentage, were made manually, as the calcium sulfate (OSTEOSET?) for the carrier. The experiment was carried under the condition of 37℃in temperature, rotation rate 50rpn. The mimesis of body fluid was Tris-buffered natural saline. The extraction method was adopted. Samples were collected every 2 hours in the first 24hours and everyday in the next 20 days. The drug concentration of each sample was analyzed through high performance liquid chromatogram. Results: Twenty-five particles were put into the experiment, and twenty were observed throughout the experiment. The average drug concentration of the first two hours was 10.535mg/L, the highest of the first twenty-four hours, and maintains between 4 mg/L and 6mg/L latterly. There was an exponential relation between the accumulative drug concentration and the square root of time. The drug release maintains stably for 18 days, under the rate of 4～6﹪. In the early period, the drug release rate was the highest, from 10 to 11 percent.Conclusion: The drug particles of calcium sulfate (OSTEOSET?) combined with MTX release stably, and the calcium sulfate (OSTEOSET?) was a better carrier of drug implants.
Objective: To investigation the character of drug release of calcium sulfate combined with MTX in the circumstance of Tris-buffered natural saline. Methods: The drug particles combined with 20 mg MTX, 4% in weight percentage, were made manually, as the calcium sulfate (OSTEOSET?) for the carrier. The experiment was carried under the condition of 37℃in temperature, rotation rate 50rpn. The mimesis of body fluid was Tris-buffered natural saline. The extraction method was adopted. Samples were collected every 2 hours in the first 24hours and everyday in the next 20 days. The drug concentration of each sample was analyzed through high performance liquid chromatogram. Results: Twenty-five particles were put into the experiment, and twenty were observed throughout the experiment. The average drug concentration of the first two hours was 10.535mg/L, the highest of the first twenty-four hours, and maintains between 4 mg/L and 6mg/L latterly. There was an exponential relation between the accumulative drug concentration and the square root of time. The drug release maintains stably for 18 days, under the rate of 4～6﹪. In the early period, the drug release rate was the highest, from 10 to 11 percent.Conclusion: The drug particles of calcium sulfate (OSTEOSET?) combined with MTX release stably, and the calcium sulfate (OSTEOSET?) was a better carrier of drug implants.
引文
1. 刘恩菊,项永兵,金凡,等. 上海市区恶性肿瘤发病趋势分析( 1972～1999 年)[J]. 肿瘤.2004;24(1):11～15.
2. 刘子君,李瑞宗,刘茂昌,等. 骨肿瘤及瘤样病变 12404 例病理统计分析[J] .中华骨科杂志.1986;6(3):163～169.
3. Campanacci M, Bacci G, Bertoni F, et al. The treatment of osteosarcoma of the extremities: twenty year's experience at the Istituto Ortopedico Rizzoli[J]. Cancer. 1981;48(7):1569～1581.
4. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols[J]. J Clin Oncol. 2002 ;20(3):776～790.
5. Bacci G, Ferrari S, Mercuri M, et al. Predictive factors for local recurrence in osteosarcoma: 540 patients with extremity tumors followed for minimum 2.5 years after neoadjuvant chemotherapy[J]. Acta Orthop Scand. 1998;69(3):230～236.
6. Weeden S, Grimer RJ, Cannon SR, et al. The effect of local recurrence on survival in resected osteosarcoma[J]. Eur J Cancer. 2001;37(1):39～46.
7. Jurgens H, Beron G, Winkler K. Toxicity associated with combination chemotherapy for osteosarcoma: a report of the cooperative osteosarcoma study (COSS 80). J Cancer Res Clin Oncol. 1983;106(Suppl):14～18.
8. Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups[J]. J Clin Oncol. 2005;23(34):8845～8852.
9. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup[J]. Lancet. 1997 ;350(9082):911～917.
10. Fu JC, Moyer DL, Cuevas J, et al. Effects of subcutaneously implanted sustained-release cyclophosphamide capsules on Walker 256 solid rat tumor[J]. J Surg Oncol. 1977;9(3):235～241.
11. Langendorff HU, Jungbluth KH, Dingeldein E, et al. Bone cement containing cytostatic drugs: new aspects in the treatment of malignant bone tumors. I. Experimental studies[J]. Langenbecks Arch Chir. 1987;371(2):123～136.( Article in German, English Abstract)
12. Wang HM, Galasko CS, Crank S, et al. Methotrexate loaded acrylic cement in the management of skeletal metastases. Biomechanical, biological, and systemic effect[J]. Clin Orthop Relat Res. 1995 ;(312):173～86.
13. Mestiri M, Benoit JP, Hernigou P, et al. Cisplatin-loaded poly(methyl methacrylate ) implants: a sustained drug delivery system[J]. J Control Release. 1995; 33(1):107～113
14. Lebugle A, Rodrigues A, Bonnevialle P, et al. Study of implantable calcium phosphate systems for the slow release of methotrexate[J]. Biomaterials. 2002 ;23(16):3517～3522.
15. Kim HS, Park YB, Oh JH, et al. The cytotoxic effect of methotrexate loaded bone cement on osteosarcoma cell lines [J]. Int Orthop. 2001;25(6):343～348.
16. Haggard WO, Kaufman ME, Parr JE, et al. Two-component calcium sulfate composites having different dissolution rates used for the controlled release of medicaments e.g. in implants. Derwent Primary Accession Number:2000-514879 [14]
17. Tahara Y, Ishii Y. Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained releaseof the anticancer drug and bone formation [J]. J Ort hop Sci. 2001;6(6):556～565.
18. 张文明,戴伯川,林建华,等. 磷酸钙骨水泥作为药物缓释载体的研究进展 [J] .福建医科大学学报.2002;36(3):340～342.
19. Wasserlauf S, Warshawsky A, Arad-Yelin R, et al . The release of cytotoxic drugs from acrylic bone cement[J]. Bull Hosp J t Dis. 1993;53(1):68～74.
20. 吴芳,林建华,戴伯川,等. 阿霉素-磷酸盐骨水泥制备及体外释药特性[J]. 福建医科大学学报. 2003;37(3):304～306.
1. 方志伟,施学东,魏广奇,等. 骨软组织恶性肿瘤患者大剂量顺铂、甲氨喋呤化疗的肾损害[J]. 中国肿瘤临床. 1998;25(3):184～186.
2. 蔡樵伯,牛晓辉,张清,等. 肢体原发成骨肉瘤综合治疗的远期结果[J]. 中华外科杂志. 2000;38(5):329～331.
3. Fu JC, Moyer DL, Cuevas J, et al. Effects of subcutaneously implanted sustained-release cyclophosphamide capsules on Walker 256 solid rat tumor[J]. J Surg Oncol. 1977;9(3):235～241.
4. Langendorff HU, J ungbluth KH, Dingeldein E, et al. Bone cement containing cytostatic drugs: new aspects in the treatment of malignant bone tumors.I. Experimental studies[J]. Langenbecks Arch Chir. 1987;371(2):123～136.
5. Wang HM, Galasko CS, Crank S, et al. Methotrexate loaded acrylic cement in the management of skeletal metastases. Biomechanical, biological, and systemic effect[J]. Clin Orthop Relat Res. 1995;(312):173～186.
6. Mestiri M, Benoit J P, Hernigou P, et al. Cisplatin-loaded poly (methyl methacrylate) implants: a sustained drug delivery system[J]. J Control Release. 1995;33(1):107～113.
7. Hernigou P, Thiery J P, Benoit J, et al. Methotrexate diffusion from acrylic cement. Local chemotherapy for bone tumours[J]. J Bone Joint Surg Br. 1989;71(5):804～811.
8. Wasserlauf S, Warshawsky A, Arad-Yelin R, et al . The release of cytotoxic drugs from acrylic bone cement[J]. Bull Hosp J t Dis. 1993;53(1):68～74.
9. Froschle GW, Mahlitz J, Langendorff HU, et al. Release of daunorubicin frompolymethylmethacrylate for the improvement of the local growth control of bone metastasis animal experiments[J]. Anticancer Res. 1997;17(2A):995～1002.
10. Decker S, Winkelmann W, Nies B, et al . Cytotoxic effect of methotrexate and its solvent on osteosarcoma cells in vitro[J]. J Bone Joint Surg Br. 1999;81(3):545～551.
11. Kirchen ME, Menendez LR, Lee J H, et al. Methotrexate eluted from bone cement: effect on giant cell tumor of bone in vitro[J]. Clin Orthop Relat Res. 1996;(328):294～303.
12. Wang HM, Crank S, Oliver G, et al. The effect of methotrexate-loaded bone cement on local destruction by the VX2 tumour[J]. J Bone Joint Surg Br. 1996;78(1):14～17.
13. Ot suka M, Matsuda Y, Fox JL, et al. A novel skeletal drug-delivery system using self-setting calcium phosphate cement.9 : Effect of t he mixing solution volume on anticancer drug release from homogeneous drug-loaded cement[J]. J Pharm Sci. 1995;84(6):733～736.
14. 吴芳,林建华,戴伯川,等. 阿霉素-磷酸盐骨水泥制备及体外释药特性[J]. 福建医科大学学报. 2003;37(3):304～306.
15. Tahara Y, Ishii Y. Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation[J]. J Ort hop Sci. 2001;6(6):556～565.
16. Lebugle A, Rodrigues A, Bonnevialle P, et al. Study of implantable calcium phosphate systems for the slow release of methotrexate[J]. Biomaterials. 2002;23(16):35173522.
17. Itokazu M, Sugiyama T, Ohno T, et al. Development of porous apatite ceramic for local delivery of chemot herapeutic agents[J]. J Biomed Mater Res.1998;39(4):536～538.
18. Itokazu M, Kumazuwa S, Wade E, et al. Sustained release of adriamycin from implanted hydroxyapatite blocks for the treatment of experimental osteogenic sarcoma in mice[J]. Cancer Lett. 1996;107 (1):11～18.
19. 游洪波,黄瑛,孙淑珍,等. 阿霉素-多孔磷酸三钙陶瓷缓释体的研制及体内释药试验[J]. 广东医学院学报. 1999,17(3):196～198.
20. 徐蔚,曹毅,张纪. 壳聚糖微球释药机制的研究[J]. 昆明医学院学报. 2002;23(1):7～10.
21. 章莹,侯春林,陈爱民. 几丁糖阿霉素缓释药粒的体外实验研究[J]. 解放军医学杂志. 1998;23(1):16～18.
22. 章莹,侯春林,陈爱民. 几丁糖阿霉素缓释药粒治疗骨巨细胞瘤的临床初步观察[J]. 中国修复重建外科杂志. 1998;12(5):280～281.
2. 刘子君,李瑞宗,刘茂昌,等. 骨肿瘤及瘤样病变 12404 例病理统计分析[J] .中华骨科杂志.1986;6(3):163～169.
3. Campanacci M, Bacci G, Bertoni F, et al. The treatment of osteosarcoma of the extremities: twenty year's experience at the Istituto Ortopedico Rizzoli[J]. Cancer. 1981;48(7):1569～1581.
4. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols[J]. J Clin Oncol. 2002 ;20(3):776～790.
5. Bacci G, Ferrari S, Mercuri M, et al. Predictive factors for local recurrence in osteosarcoma: 540 patients with extremity tumors followed for minimum 2.5 years after neoadjuvant chemotherapy[J]. Acta Orthop Scand. 1998;69(3):230～236.
6. Weeden S, Grimer RJ, Cannon SR, et al. The effect of local recurrence on survival in resected osteosarcoma[J]. Eur J Cancer. 2001;37(1):39～46.
7. Jurgens H, Beron G, Winkler K. Toxicity associated with combination chemotherapy for osteosarcoma: a report of the cooperative osteosarcoma study (COSS 80). J Cancer Res Clin Oncol. 1983;106(Suppl):14～18.
8. Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups[J]. J Clin Oncol. 2005;23(34):8845～8852.
9. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup[J]. Lancet. 1997 ;350(9082):911～917.
10. Fu JC, Moyer DL, Cuevas J, et al. Effects of subcutaneously implanted sustained-release cyclophosphamide capsules on Walker 256 solid rat tumor[J]. J Surg Oncol. 1977;9(3):235～241.
11. Langendorff HU, Jungbluth KH, Dingeldein E, et al. Bone cement containing cytostatic drugs: new aspects in the treatment of malignant bone tumors. I. Experimental studies[J]. Langenbecks Arch Chir. 1987;371(2):123～136.( Article in German, English Abstract)
12. Wang HM, Galasko CS, Crank S, et al. Methotrexate loaded acrylic cement in the management of skeletal metastases. Biomechanical, biological, and systemic effect[J]. Clin Orthop Relat Res. 1995 ;(312):173～86.
13. Mestiri M, Benoit JP, Hernigou P, et al. Cisplatin-loaded poly(methyl methacrylate ) implants: a sustained drug delivery system[J]. J Control Release. 1995; 33(1):107～113
14. Lebugle A, Rodrigues A, Bonnevialle P, et al. Study of implantable calcium phosphate systems for the slow release of methotrexate[J]. Biomaterials. 2002 ;23(16):3517～3522.
15. Kim HS, Park YB, Oh JH, et al. The cytotoxic effect of methotrexate loaded bone cement on osteosarcoma cell lines [J]. Int Orthop. 2001;25(6):343～348.
16. Haggard WO, Kaufman ME, Parr JE, et al. Two-component calcium sulfate composites having different dissolution rates used for the controlled release of medicaments e.g. in implants. Derwent Primary Accession Number:2000-514879 [14]
17. Tahara Y, Ishii Y. Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained releaseof the anticancer drug and bone formation [J]. J Ort hop Sci. 2001;6(6):556～565.
18. 张文明,戴伯川,林建华,等. 磷酸钙骨水泥作为药物缓释载体的研究进展 [J] .福建医科大学学报.2002;36(3):340～342.
19. Wasserlauf S, Warshawsky A, Arad-Yelin R, et al . The release of cytotoxic drugs from acrylic bone cement[J]. Bull Hosp J t Dis. 1993;53(1):68～74.
20. 吴芳,林建华,戴伯川,等. 阿霉素-磷酸盐骨水泥制备及体外释药特性[J]. 福建医科大学学报. 2003;37(3):304～306.
1. 方志伟,施学东,魏广奇,等. 骨软组织恶性肿瘤患者大剂量顺铂、甲氨喋呤化疗的肾损害[J]. 中国肿瘤临床. 1998;25(3):184～186.
2. 蔡樵伯,牛晓辉,张清,等. 肢体原发成骨肉瘤综合治疗的远期结果[J]. 中华外科杂志. 2000;38(5):329～331.
3. Fu JC, Moyer DL, Cuevas J, et al. Effects of subcutaneously implanted sustained-release cyclophosphamide capsules on Walker 256 solid rat tumor[J]. J Surg Oncol. 1977;9(3):235～241.
4. Langendorff HU, J ungbluth KH, Dingeldein E, et al. Bone cement containing cytostatic drugs: new aspects in the treatment of malignant bone tumors.I. Experimental studies[J]. Langenbecks Arch Chir. 1987;371(2):123～136.
5. Wang HM, Galasko CS, Crank S, et al. Methotrexate loaded acrylic cement in the management of skeletal metastases. Biomechanical, biological, and systemic effect[J]. Clin Orthop Relat Res. 1995;(312):173～186.
6. Mestiri M, Benoit J P, Hernigou P, et al. Cisplatin-loaded poly (methyl methacrylate) implants: a sustained drug delivery system[J]. J Control Release. 1995;33(1):107～113.
7. Hernigou P, Thiery J P, Benoit J, et al. Methotrexate diffusion from acrylic cement. Local chemotherapy for bone tumours[J]. J Bone Joint Surg Br. 1989;71(5):804～811.
8. Wasserlauf S, Warshawsky A, Arad-Yelin R, et al . The release of cytotoxic drugs from acrylic bone cement[J]. Bull Hosp J t Dis. 1993;53(1):68～74.
9. Froschle GW, Mahlitz J, Langendorff HU, et al. Release of daunorubicin frompolymethylmethacrylate for the improvement of the local growth control of bone metastasis animal experiments[J]. Anticancer Res. 1997;17(2A):995～1002.
10. Decker S, Winkelmann W, Nies B, et al . Cytotoxic effect of methotrexate and its solvent on osteosarcoma cells in vitro[J]. J Bone Joint Surg Br. 1999;81(3):545～551.
11. Kirchen ME, Menendez LR, Lee J H, et al. Methotrexate eluted from bone cement: effect on giant cell tumor of bone in vitro[J]. Clin Orthop Relat Res. 1996;(328):294～303.
12. Wang HM, Crank S, Oliver G, et al. The effect of methotrexate-loaded bone cement on local destruction by the VX2 tumour[J]. J Bone Joint Surg Br. 1996;78(1):14～17.
13. Ot suka M, Matsuda Y, Fox JL, et al. A novel skeletal drug-delivery system using self-setting calcium phosphate cement.9 : Effect of t he mixing solution volume on anticancer drug release from homogeneous drug-loaded cement[J]. J Pharm Sci. 1995;84(6):733～736.
14. 吴芳,林建华,戴伯川,等. 阿霉素-磷酸盐骨水泥制备及体外释药特性[J]. 福建医科大学学报. 2003;37(3):304～306.
15. Tahara Y, Ishii Y. Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation[J]. J Ort hop Sci. 2001;6(6):556～565.
16. Lebugle A, Rodrigues A, Bonnevialle P, et al. Study of implantable calcium phosphate systems for the slow release of methotrexate[J]. Biomaterials. 2002;23(16):35173522.
17. Itokazu M, Sugiyama T, Ohno T, et al. Development of porous apatite ceramic for local delivery of chemot herapeutic agents[J]. J Biomed Mater Res.1998;39(4):536～538.
18. Itokazu M, Kumazuwa S, Wade E, et al. Sustained release of adriamycin from implanted hydroxyapatite blocks for the treatment of experimental osteogenic sarcoma in mice[J]. Cancer Lett. 1996;107 (1):11～18.
19. 游洪波,黄瑛,孙淑珍,等. 阿霉素-多孔磷酸三钙陶瓷缓释体的研制及体内释药试验[J]. 广东医学院学报. 1999,17(3):196～198.
20. 徐蔚,曹毅,张纪. 壳聚糖微球释药机制的研究[J]. 昆明医学院学报. 2002;23(1):7～10.
21. 章莹,侯春林,陈爱民. 几丁糖阿霉素缓释药粒的体外实验研究[J]. 解放军医学杂志. 1998;23(1):16～18.
22. 章莹,侯春林,陈爱民. 几丁糖阿霉素缓释药粒治疗骨巨细胞瘤的临床初步观察[J]. 中国修复重建外科杂志. 1998;12(5):280～281.