芳基丙酸类非甾体抗炎药的透皮机理和氟比洛芬贴剂的研究
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摘要
芳基丙酸类非载体抗炎药，具有良好的解热、镇痛和抗炎作用，临床广泛用于治疗关节炎、类风湿关节炎和慢性疼痛，但此类药口服对胃肠道刺激较大限制了其应用。透皮制剂可以提高局部的药物浓度，避免对胃肠道的副作用，同时具有控缓释效果，所以成为此类药物制剂研究的一个重点。
本文在分别建立氟比洛芬、酮洛芬、布洛芬、罗索洛芬和萘普生反相高效液相色谱测定方法的基础上，考察了其透皮特性与油水分配系数的关系。从正丁醇到正辛醇随着溶剂极性减小，酮洛芬和氟比洛芬的累计透过量和释药速率增加，提示两者的透皮制剂可能更适合用非极性基质。通过氟比洛芬贴剂和巴布剂的体外透皮行为的比较，验证了此推断。
本文以氟比洛芬作为模型药物，通过正交实验考察各组分对透皮释放速率和物理粘性的影响，并确定了优选处方。在此基础上，逐个考察并选择处方的最佳含药量、抗氧剂和透皮促进剂。最终确定以聚异丁烯为主要组分，含8.1%氮酮的氟比洛芬贴剂，含药0.5 mg.cm-2，体外透皮呈零级释放，24 h累计渗透达78.52%±16.87%。考察了贴剂中促进剂的相互作用。用差示扫描量热分析（DSC）研究处方组分的分散状态，发现氮酮可以使药物微晶体消失，形成固溶胶的高分散状态。
本文首次将驻极体引入贴剂的制备。贴剂的无水基质可以保证驻极体的静电场的稳定，而作为背衬层的驻极体提供的负静电场对氟比洛芬的透皮吸收有极显著促进作用（促进倍数1.61±0.33 ，P=0.0053）。
氟比洛芬贴剂含量采用液液提取后UV法测定，桨碟释放液用UV法直接测定。用加速实验法考察了贴剂在40℃，相对湿度75%环境中放置三个月的稳定性，结果表明制剂含药量和释放度均保持稳定。
以酮洛芬为内标用HPLC法测定氟比洛芬在家兔体内的血药浓度，采用酵母和内毒素诱导家兔的发热模型，同时考察了家兔给予氟比洛芬贴剂和口服混悬剂的血药浓度和体温升高抑制率（E%），结果表明氟比洛芬贴剂降温作用持久平缓，血药浓度和体温升高抑制率具有相关性。通过氟比洛芬贴剂残药量测定，得家兔24h药物吸收百分量为58.20%±6.66%。氟比洛芬口服混悬剂和贴剂的最大血药浓度分别为168.72±23.76 μg.mL-1 和7.11±2.57 μg.mL-1，平均滞留时间（MRT）分别为3.19 h±0.99 h和11.87 h±0.79 h，平均相对生物利用度为48.12%。
Aryl propionic acid derivatives in non-steroidal drugs (flurbiprofen, ketoprofen, ibuprofen, loxoprofen, naproxen, etc.) have anti-inflamatory, antifebrile and analgesic actions which have been using in arthritis, rheumatoid arthritis and chronic pains. However, many patients suffer from gastro-intestinal disturbance when these drugs are administered orally, which limits the application of them. When the active ingredients are delivered transdermally, the topical concentration of them in joint location can increase; gastro intestinal disturbance may be avoided; furthermore, the active ingredients are continuously released at a constant rate. Therefore, much attention has been given to the transdermal delivery system (TDS) of these drugs.
The high performance liquid chromatographic (HPLC) method using a reversed-phase column was adopted for determination of flurbiprofen (FP), ketoprofen (KP), ibuprofen (IP), loxoprofen (LP) and naproxen (NP). The relation between the permeation of these drugs through excised rat skin and oil-water partition coefficient was investigated. The cumulative penetrating amount and steady state flux of KP and FP increased when the polarity of alcoholic solvents decreased from n-butyl alcohol to n-octyl alcohol, which indicated that KP and FP in nonpolar polymers can maximize their thermodynamic activity and further increase the skin permeability. It was tested by the comparison of the drug release behavior through excised nude mouse skin between the transdermal delivery system of FP (FP-TDS) with polyisobutylene and FP-patch with hydrophilic matrix.
Orthogonal design was used to optimize the composition of FP-TDS. Then, step-by-step, different content of drugs, antioxidants and permeation enhancers were chosen in FP-TDS. The FP released from FP-TDS at zero-order through excised nude mouse skin and the cumulative penetrating percentage of FP amounted to 85%. The differential scanning calorimetry (DSC) showed that 8.1% azone in preparation can make the minicrystal of FP disappear and form solid sols.
For the first time, electret was used as substrate layer in FP-TDS. The matrix of FP-TDS can administer to the stability of electret, and electrostatic field of electret can enhance permeation of FP (1.61±0.33 times) .
The content of FP in FP-TDS was measured by spectrophotometric at 247nm after abstracted with PBS (pH7.4) from medical gasoline. FP in dissolution medium was measured by spectrophotometric, too. In 40℃ and relative humidity 75%, the content of FP in FP-TDS and release of FP from FP-TDS kept stable for three months.
FP in plasma of rabbit was measured by HPLC method with KP as an internal standard. The fever was induced by subcutaneous injection of yeast suspention (10%.W/V) 3 mL.Kg-1 and endotoxin (2 μg.mL-1) 0.2 mL.Kg-1. After FP-TDS and FP suspension (25 mg.Kg-1) was administred to rabbit respectively, the inhibition rate (E, %) of rabbit fever and FP in plasma were found correlative and the inhibition rates (E, %) of rabbit fever which administred FP-TDS were placid and persistent. By measuring the content of FP in FP-TDS after administration, it was tested that 58.20%±6.66% FP in FP-TDS was penetrated. Cmax were much lower after a single application of FP-TDS than after FP suspension (mean±SD: 7.11±2.57 μg.mL-1 versus 168.72±23.76 μg.mL-1 respectively), and the mean MRT prolonged (11.87 h±0.79 h and 3.19 h±0.99 h respectively). The mean relative bioavailability of FP from FP-TDS was 48.12%.
本文在分别建立氟比洛芬、酮洛芬、布洛芬、罗索洛芬和萘普生反相高效液相色谱测定方法的基础上，考察了其透皮特性与油水分配系数的关系。从正丁醇到正辛醇随着溶剂极性减小，酮洛芬和氟比洛芬的累计透过量和释药速率增加，提示两者的透皮制剂可能更适合用非极性基质。通过氟比洛芬贴剂和巴布剂的体外透皮行为的比较，验证了此推断。
本文以氟比洛芬作为模型药物，通过正交实验考察各组分对透皮释放速率和物理粘性的影响，并确定了优选处方。在此基础上，逐个考察并选择处方的最佳含药量、抗氧剂和透皮促进剂。最终确定以聚异丁烯为主要组分，含8.1%氮酮的氟比洛芬贴剂，含药0.5 mg.cm-2，体外透皮呈零级释放，24 h累计渗透达78.52%±16.87%。考察了贴剂中促进剂的相互作用。用差示扫描量热分析（DSC）研究处方组分的分散状态，发现氮酮可以使药物微晶体消失，形成固溶胶的高分散状态。
本文首次将驻极体引入贴剂的制备。贴剂的无水基质可以保证驻极体的静电场的稳定，而作为背衬层的驻极体提供的负静电场对氟比洛芬的透皮吸收有极显著促进作用（促进倍数1.61±0.33 ，P=0.0053）。
氟比洛芬贴剂含量采用液液提取后UV法测定，桨碟释放液用UV法直接测定。用加速实验法考察了贴剂在40℃，相对湿度75%环境中放置三个月的稳定性，结果表明制剂含药量和释放度均保持稳定。
以酮洛芬为内标用HPLC法测定氟比洛芬在家兔体内的血药浓度，采用酵母和内毒素诱导家兔的发热模型，同时考察了家兔给予氟比洛芬贴剂和口服混悬剂的血药浓度和体温升高抑制率（E%），结果表明氟比洛芬贴剂降温作用持久平缓，血药浓度和体温升高抑制率具有相关性。通过氟比洛芬贴剂残药量测定，得家兔24h药物吸收百分量为58.20%±6.66%。氟比洛芬口服混悬剂和贴剂的最大血药浓度分别为168.72±23.76 μg.mL-1 和7.11±2.57 μg.mL-1，平均滞留时间（MRT）分别为3.19 h±0.99 h和11.87 h±0.79 h，平均相对生物利用度为48.12%。
Aryl propionic acid derivatives in non-steroidal drugs (flurbiprofen, ketoprofen, ibuprofen, loxoprofen, naproxen, etc.) have anti-inflamatory, antifebrile and analgesic actions which have been using in arthritis, rheumatoid arthritis and chronic pains. However, many patients suffer from gastro-intestinal disturbance when these drugs are administered orally, which limits the application of them. When the active ingredients are delivered transdermally, the topical concentration of them in joint location can increase; gastro intestinal disturbance may be avoided; furthermore, the active ingredients are continuously released at a constant rate. Therefore, much attention has been given to the transdermal delivery system (TDS) of these drugs.
The high performance liquid chromatographic (HPLC) method using a reversed-phase column was adopted for determination of flurbiprofen (FP), ketoprofen (KP), ibuprofen (IP), loxoprofen (LP) and naproxen (NP). The relation between the permeation of these drugs through excised rat skin and oil-water partition coefficient was investigated. The cumulative penetrating amount and steady state flux of KP and FP increased when the polarity of alcoholic solvents decreased from n-butyl alcohol to n-octyl alcohol, which indicated that KP and FP in nonpolar polymers can maximize their thermodynamic activity and further increase the skin permeability. It was tested by the comparison of the drug release behavior through excised nude mouse skin between the transdermal delivery system of FP (FP-TDS) with polyisobutylene and FP-patch with hydrophilic matrix.
Orthogonal design was used to optimize the composition of FP-TDS. Then, step-by-step, different content of drugs, antioxidants and permeation enhancers were chosen in FP-TDS. The FP released from FP-TDS at zero-order through excised nude mouse skin and the cumulative penetrating percentage of FP amounted to 85%. The differential scanning calorimetry (DSC) showed that 8.1% azone in preparation can make the minicrystal of FP disappear and form solid sols.
For the first time, electret was used as substrate layer in FP-TDS. The matrix of FP-TDS can administer to the stability of electret, and electrostatic field of electret can enhance permeation of FP (1.61±0.33 times) .
The content of FP in FP-TDS was measured by spectrophotometric at 247nm after abstracted with PBS (pH7.4) from medical gasoline. FP in dissolution medium was measured by spectrophotometric, too. In 40℃ and relative humidity 75%, the content of FP in FP-TDS and release of FP from FP-TDS kept stable for three months.
FP in plasma of rabbit was measured by HPLC method with KP as an internal standard. The fever was induced by subcutaneous injection of yeast suspention (10%.W/V) 3 mL.Kg-1 and endotoxin (2 μg.mL-1) 0.2 mL.Kg-1. After FP-TDS and FP suspension (25 mg.Kg-1) was administred to rabbit respectively, the inhibition rate (E, %) of rabbit fever and FP in plasma were found correlative and the inhibition rates (E, %) of rabbit fever which administred FP-TDS were placid and persistent. By measuring the content of FP in FP-TDS after administration, it was tested that 58.20%±6.66% FP in FP-TDS was penetrated. Cmax were much lower after a single application of FP-TDS than after FP suspension (mean±SD: 7.11±2.57 μg.mL-1 versus 168.72±23.76 μg.mL-1 respectively), and the mean MRT prolonged (11.87 h±0.79 h and 3.19 h±0.99 h respectively). The mean relative bioavailability of FP from FP-TDS was 48.12%.
引文
1. 吴君丽. 非甾体抗炎镇痛药的临床应用. 颈腰痛杂志，1999，20(1):65~66
2. 梁秉文. 经皮给药制剂. 中国医药科技出版社，1992：83~87
3. 丁平田，刘军田，郑俊民. 用油/水分配系数预测药物的经皮渗透性. 中国医药工业杂志，1998，29(4):186~190
4. Bernharo PW, Bernharo CL. Skin penetration of nonsteroidal antiinflammatory drugs out of a lipophilic vehicle: influence of the viable epidermis. J. Pharm. Sci., 1999, 88(12)1326~1331
5. Choi HK, Cho YJ. Composition for transdermal delivery system containing nonsteroidal anti-inflammatory drug as an active ingreduent [P]. EP 0827741, 1998-3-11
6. 钟延强，王春燕. 新型非甾体抗炎药—氟比洛芬制剂学研究进展. 药学实践杂志，1999, 17(2): 97~101
7. 郑俊民. 经皮给药新剂型. 人民卫生出版社，1997：6~13，255~270
8. 夏钟福. 驻极体的研究现状. 压电与声光，1997, 19(4): 242~246
9. 钟极根，龚肖崎，张亚霖，等. 驻极体对皮肤烫伤后微循环和血液粘度的影响. 第二军医大学学报，1994, 15(3): 263~267
10. 莉莉，张崇义，驻极体（I、II型）对骨折动物某些血液指标的影响. 中华骨科杂志，1995, 15(8): 535~537
11. 郝岚，张明利，江键，等. 驻极体对金黄色葡萄球菌感染创面影响的实验研究. 实用美容整形外科杂志，1997, 8(3): 122~124
12. 王信良，张志刚，王岳兴，等. 驻极体穴位刺激对家兔生殖力影响. 中国医学物理学杂志，1997, 14(1): 7~9
13. 王怡，翁维良，刘剑刚，等. 用驻极体技术改进脂质体包封血红蛋白制备的实验研究. 微循环学，1998, 8(1): 25~27
14. 崔丽丽、江健. 第十届国际驻极体大会. 波兰
15. 葛庆华，张焱，陈庆华. 缓释微丸及血浆中酮洛芬的HPLC测定. 中国医药工业杂志，1994, 25(11):505~507
16. 孙华君，胡晋红，朱全刚. 脂质体对酮洛芬体外透皮特性的影响. 第二军医大学学报，1999, 20(6):371~373
2. 梁秉文. 经皮给药制剂. 中国医药科技出版社，1992：83~87
3. 丁平田，刘军田，郑俊民. 用油/水分配系数预测药物的经皮渗透性. 中国医药工业杂志，1998，29(4):186~190
4. Bernharo PW, Bernharo CL. Skin penetration of nonsteroidal antiinflammatory drugs out of a lipophilic vehicle: influence of the viable epidermis. J. Pharm. Sci., 1999, 88(12)1326~1331
5. Choi HK, Cho YJ. Composition for transdermal delivery system containing nonsteroidal anti-inflammatory drug as an active ingreduent [P]. EP 0827741, 1998-3-11
6. 钟延强，王春燕. 新型非甾体抗炎药—氟比洛芬制剂学研究进展. 药学实践杂志，1999, 17(2): 97~101
7. 郑俊民. 经皮给药新剂型. 人民卫生出版社，1997：6~13，255~270
8. 夏钟福. 驻极体的研究现状. 压电与声光，1997, 19(4): 242~246
9. 钟极根，龚肖崎，张亚霖，等. 驻极体对皮肤烫伤后微循环和血液粘度的影响. 第二军医大学学报，1994, 15(3): 263~267
10. 莉莉，张崇义，驻极体（I、II型）对骨折动物某些血液指标的影响. 中华骨科杂志，1995, 15(8): 535~537
11. 郝岚，张明利，江键，等. 驻极体对金黄色葡萄球菌感染创面影响的实验研究. 实用美容整形外科杂志，1997, 8(3): 122~124
12. 王信良，张志刚，王岳兴，等. 驻极体穴位刺激对家兔生殖力影响. 中国医学物理学杂志，1997, 14(1): 7~9
13. 王怡，翁维良，刘剑刚，等. 用驻极体技术改进脂质体包封血红蛋白制备的实验研究. 微循环学，1998, 8(1): 25~27
14. 崔丽丽、江健. 第十届国际驻极体大会. 波兰
15. 葛庆华，张焱，陈庆华. 缓释微丸及血浆中酮洛芬的HPLC测定. 中国医药工业杂志，1994, 25(11):505~507
16. 孙华君，胡晋红，朱全刚. 脂质体对酮洛芬体外透皮特性的影响. 第二军医大学学报，1999, 20(6):371~373
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