盐酸昂丹司琼缓释微丸的研究
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摘要
盐酸昂丹司琼(Ondansetron Hydrochloride以下简称OND)是5-HT_3受体的强选择性阻断剂，它对癌症化疗及放疗所致呕吐具有良好防治作用。本文的目的是研究盐酸昂丹司琼一天一次的缓释微丸，并进行体内验证。
建立了紫外分光光度法测定盐酸昂丹司琼的制剂含量和释放度。建立了高效液相色谱法检测体内药物浓度，此法灵敏度高、专属性强。测定主药盐酸昂丹司琼在蒸馏水、人工胃液、人工肠液的溶解度，结果分别为1.42、0.50、0.015g／100ml，且在水中的溶解度随pH的增加而降低。通过对Eudragit NE30D, Eudragit FS30D, Eudragit RS30D, Eudragit RL30D水分散体玻璃化转变温度的测定，可以发现软性高分子(NE30D)的加入对硬性的高分子(FS30D)没有增塑作用，因为硬性高分子的Tg没有降低，软性的高分子形成了连续相而未聚合的硬性的高分子镶嵌在连续相内形成分散相，因此高分子混合膜是不均匀的。通过提高膜热处理温度和减少硬性丙烯酸聚合物的比例，获得均匀透明的高分子膜，作为包衣材料是可行的。
本文采用挤出滚圆法制备微丸，通过Plackett-Burman筛选实验，考察了挤出滚圆法中对微丸收率可能有影响的因素——含水量、捏合时间、筛板孔径、挤出速度、滚圆速度、滚圆时间、滚圆载物量。结果表明，含水量、筛板孔径和滚圆时间对微丸的收率有较大的影响。析因实验优化，结果表明，含水量和滚圆时间的交互作用对微丸的收率和圆整度有相同的影响，滚圆时间增大，同时减少含水量可以获得收率高和圆整度好的微丸，脆碎度则不受含水量、滚圆时间和筛板孔径的影响。
以Eudragit NE30D和Eudragit FS30D为包衣材料对素丸包衣，对包衣
沈阳药科大学硕士学位论文 摘要（中文）
微丸释放度的影响因素进行考察，均匀设计优化了包衣微丸处方，结果表
明，包衣微丸体外释放有明显的缓释特性。通过调整包衣层增重、致孔剂
用量、NE30D与FS30D的比例，可以改变药物的释放速率，使药物的释
放速率不受介质pH值的影响。对制剂稳定性考察结果表明，制剂稳定性
好。
以HPLC方法测定人体内血药浓度，以普通制剂为对照，研究了盐酸
昂丹司琼缓释微丸的家犬体内相对生物利用度和药代动力学。结果表明，
普通胶囊（170mg）与缓释胶囊门）的 AUC分别为 345．sl士34．10ng ．h
／ml、322．22土 17．89ng·h／ml；普通胶囊的 Cm旺、Tm旺分别为 157．39士
35．53fig／ffil、1＊ 土0．14h，缓释胶囊有双峰，Cm肌l、Tin肌l分别为37．37士
4．44ng／ml、gb，Cm帖、Tm叨分别为26＊1上0＊ong／ml、12h，表明与普通胶
囊相比，缓释胶囊血药浓度相对平稳，达峰时间有所延长，峰浓度下降。
缓释胶囊与普通胶囊生物利用度相近。缓释胶囊中体内吸收和体外释放度
之间具有良好相关性。
The research was aiming at the preparation of ondansetron 24h sustained-released pellets and validation in vivo, consisting of preparation methods for pellets, the sustained- release system of coated pellets, stability, pharmacokinetics. The results show: the sustained-release pellets exhibited a marked sustained-release property and the drug was released in vivo over 24h.
Ondansetron (abbr. OND), a highly selective 5-HTj antagonist, has a good effect on prevention of nausea and vomiting induced by cyctotoxic drugs and high dose radiation. Preformulation studies illustrated that solubility of OND HC1 is highly dependent on pH values. In distilled water, simulated gastric liquid and simulated intestinal liquid, its solubility is 1.42, 0.50, 0.015g/l 00ml respectively, which directly leads its slow release in stimulated intestinal liquid. Considering this, different sustained-release oral ondansetron pellets were developed aiming to obtain the most constant and complete release of the drug during transit in gastrointestinal tract.
By DSC, Glass transition temperature of different aqueous acrylic polymer dispersions such as Eudragit NE30D, Eudragit FS30D, Eudragit RS30D, Eudragit RL30D and their blends were tested. It illustrated that the formation of a heterogeneous film is possible either by increasing the drying temperatures above the film forming temperature of the blends or by adding effective plasticizers in order to decrease the Tg values of the hardest polymers.
A Plackett-Burman screening design was employed to isolate critical parameters that influenced the yield of pellets bys Extrusion-spheronization
method. The result of this study found that amount of water, width of sieve and spheronization time had greater influences on the yield of pellets. Then, 23 full factorial design had been used to investigate the main effects and their interactive effects of amount of water, width of sieve and spheronization time on the yield, sphericity and friability. Pellets with good sphericity, high yield and appropriate hardness was produced.
Pellets were coated with aqueous dispersion (Eudragit NE30D and Eudragit FS30D) using mini-fluidized bed spray coater. The effects of process variables and formulation variables on coating pellets preparation were investigated. The results showed: the coated pellets had a marked sustained release property. The coating level, the ratio of NE30D to FS30D and amount of pore-forming agent could alter the release rate of the drug. The stability of the preparation was investigated under 4500Lx light condition, 40 癈 and 75%RH, room temperature and 60%RH. The results showed that the preparation was stable.
A reversed-phase HPLC method was established for determination of OND drug plasma concentration. Pharmacokinetics of ondansetron sustained-release capsule and conventional capsule was studied in three dogs. The AUC of conventional capsule (170mg) and sustained-release capsule(170mg) were 345. 51 34.10ng/ml h, 322.22 17.89ng/ml h respectively. The Cmax and Tmax of conventional capsule were 157.39 35.53ng/ml and 1.16?.14h. The sustained-release capsule had double peaks, Cmax1 and Tmax1 were 37.37.63 4.44ng/ml and 9h, Cmax2 and Tmax2 were 26.01 0.60ng/ml and 12h. The relative bioavailability of OND were 93.3% compared with conventional capsule. It was very significant between in vivo absorption and dissolution in vitro using Wagner-Nelson equation to calculate the in vivo absorption fraction.
Consequently, sustained-release capsule dosed daily was expected to show a
more efficiency than its reference dosed 3~4 times a day.
建立了紫外分光光度法测定盐酸昂丹司琼的制剂含量和释放度。建立了高效液相色谱法检测体内药物浓度，此法灵敏度高、专属性强。测定主药盐酸昂丹司琼在蒸馏水、人工胃液、人工肠液的溶解度，结果分别为1.42、0.50、0.015g／100ml，且在水中的溶解度随pH的增加而降低。通过对Eudragit NE30D, Eudragit FS30D, Eudragit RS30D, Eudragit RL30D水分散体玻璃化转变温度的测定，可以发现软性高分子(NE30D)的加入对硬性的高分子(FS30D)没有增塑作用，因为硬性高分子的Tg没有降低，软性的高分子形成了连续相而未聚合的硬性的高分子镶嵌在连续相内形成分散相，因此高分子混合膜是不均匀的。通过提高膜热处理温度和减少硬性丙烯酸聚合物的比例，获得均匀透明的高分子膜，作为包衣材料是可行的。
本文采用挤出滚圆法制备微丸，通过Plackett-Burman筛选实验，考察了挤出滚圆法中对微丸收率可能有影响的因素——含水量、捏合时间、筛板孔径、挤出速度、滚圆速度、滚圆时间、滚圆载物量。结果表明，含水量、筛板孔径和滚圆时间对微丸的收率有较大的影响。析因实验优化，结果表明，含水量和滚圆时间的交互作用对微丸的收率和圆整度有相同的影响，滚圆时间增大，同时减少含水量可以获得收率高和圆整度好的微丸，脆碎度则不受含水量、滚圆时间和筛板孔径的影响。
以Eudragit NE30D和Eudragit FS30D为包衣材料对素丸包衣，对包衣
沈阳药科大学硕士学位论文 摘要（中文）
微丸释放度的影响因素进行考察，均匀设计优化了包衣微丸处方，结果表
明，包衣微丸体外释放有明显的缓释特性。通过调整包衣层增重、致孔剂
用量、NE30D与FS30D的比例，可以改变药物的释放速率，使药物的释
放速率不受介质pH值的影响。对制剂稳定性考察结果表明，制剂稳定性
好。
以HPLC方法测定人体内血药浓度，以普通制剂为对照，研究了盐酸
昂丹司琼缓释微丸的家犬体内相对生物利用度和药代动力学。结果表明，
普通胶囊（170mg）与缓释胶囊门）的 AUC分别为 345．sl士34．10ng ．h
／ml、322．22土 17．89ng·h／ml；普通胶囊的 Cm旺、Tm旺分别为 157．39士
35．53fig／ffil、1＊ 土0．14h，缓释胶囊有双峰，Cm肌l、Tin肌l分别为37．37士
4．44ng／ml、gb，Cm帖、Tm叨分别为26＊1上0＊ong／ml、12h，表明与普通胶
囊相比，缓释胶囊血药浓度相对平稳，达峰时间有所延长，峰浓度下降。
缓释胶囊与普通胶囊生物利用度相近。缓释胶囊中体内吸收和体外释放度
之间具有良好相关性。
The research was aiming at the preparation of ondansetron 24h sustained-released pellets and validation in vivo, consisting of preparation methods for pellets, the sustained- release system of coated pellets, stability, pharmacokinetics. The results show: the sustained-release pellets exhibited a marked sustained-release property and the drug was released in vivo over 24h.
Ondansetron (abbr. OND), a highly selective 5-HTj antagonist, has a good effect on prevention of nausea and vomiting induced by cyctotoxic drugs and high dose radiation. Preformulation studies illustrated that solubility of OND HC1 is highly dependent on pH values. In distilled water, simulated gastric liquid and simulated intestinal liquid, its solubility is 1.42, 0.50, 0.015g/l 00ml respectively, which directly leads its slow release in stimulated intestinal liquid. Considering this, different sustained-release oral ondansetron pellets were developed aiming to obtain the most constant and complete release of the drug during transit in gastrointestinal tract.
By DSC, Glass transition temperature of different aqueous acrylic polymer dispersions such as Eudragit NE30D, Eudragit FS30D, Eudragit RS30D, Eudragit RL30D and their blends were tested. It illustrated that the formation of a heterogeneous film is possible either by increasing the drying temperatures above the film forming temperature of the blends or by adding effective plasticizers in order to decrease the Tg values of the hardest polymers.
A Plackett-Burman screening design was employed to isolate critical parameters that influenced the yield of pellets bys Extrusion-spheronization
method. The result of this study found that amount of water, width of sieve and spheronization time had greater influences on the yield of pellets. Then, 23 full factorial design had been used to investigate the main effects and their interactive effects of amount of water, width of sieve and spheronization time on the yield, sphericity and friability. Pellets with good sphericity, high yield and appropriate hardness was produced.
Pellets were coated with aqueous dispersion (Eudragit NE30D and Eudragit FS30D) using mini-fluidized bed spray coater. The effects of process variables and formulation variables on coating pellets preparation were investigated. The results showed: the coated pellets had a marked sustained release property. The coating level, the ratio of NE30D to FS30D and amount of pore-forming agent could alter the release rate of the drug. The stability of the preparation was investigated under 4500Lx light condition, 40 癈 and 75%RH, room temperature and 60%RH. The results showed that the preparation was stable.
A reversed-phase HPLC method was established for determination of OND drug plasma concentration. Pharmacokinetics of ondansetron sustained-release capsule and conventional capsule was studied in three dogs. The AUC of conventional capsule (170mg) and sustained-release capsule(170mg) were 345. 51 34.10ng/ml h, 322.22 17.89ng/ml h respectively. The Cmax and Tmax of conventional capsule were 157.39 35.53ng/ml and 1.16?.14h. The sustained-release capsule had double peaks, Cmax1 and Tmax1 were 37.37.63 4.44ng/ml and 9h, Cmax2 and Tmax2 were 26.01 0.60ng/ml and 12h. The relative bioavailability of OND were 93.3% compared with conventional capsule. It was very significant between in vivo absorption and dissolution in vitro using Wagner-Nelson equation to calculate the in vivo absorption fraction.
Consequently, sustained-release capsule dosed daily was expected to show a
more efficiency than its reference dosed 3~4 times a day.
引文
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[2] Gralia RJ. Approaches to management of emesis. Clinician 1988; 6: 26-39.
[3] Blackwell CP, Harding SM. The clinical pharmacology of ondansetron. Eur J Cancer Clin Oncol 1989; 25 (Suppi 1): S21-S24.
[4] Hsyu P-Horitchard JF Bozigian HP et al. Comparison of the pharmacokinetics of an Ondansetron solution (8mg) when administered intravenously, orally, to the colon, and to the rectum. Pharm Res, 1999,11 (1) :156-160.
[5] 曾万勇 周际昌 孙燕等。联合应用止吐药控制高剂量顺铂引起的胃肠道反应的初步报告。实用肿瘤杂志，1990，5(3)：146-147．
[6] Tsavaris N Fountzilas G Mylonakis N et al. A randomized comparative study of antiemetic prophylaxis with Ondansetron in a single 32mg loading dose versus 8mg every 6h in patients undergoing cisplatin-based chemotherapy. Oncology, 1998,55(6):513-517.
[7] 梁德荣 徐楠 张辉明，盐酸奥丹西隆注射剂Ⅰ期临床药物耐受性试验．华西医学，1995，10(3)：280-291．
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[10] 包泳初，陈庆华，潘家祯等，挤出滚圆法制备药用微丸．中国医药工业杂志．1999,30(1)：18-21．
[11] 陈庆华．现代微丸制备与包衣装置的类型与应用微丸．中国医药工业杂志．1999，30(1)：18-21．
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[14] 张立超，胡晋红．聚合物水分散体包衣技术的进展．药学实践．1999，17(3)：144-147．
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[2] Gralia RJ. Approaches to management of emesis. Clinician 1988; 6: 26-39.
[3] Blackwell CP, Harding SM. The clinical pharmacology of ondansetron. Eur J Cancer Clin Oncol 1989; 25 (Suppi 1): S21-S24.
[4] Hsyu P-Horitchard JF Bozigian HP et al. Comparison of the pharmacokinetics of an Ondansetron solution (8mg) when administered intravenously, orally, to the colon, and to the rectum. Pharm Res, 1999,11 (1) :156-160.
[5] 曾万勇 周际昌 孙燕等。联合应用止吐药控制高剂量顺铂引起的胃肠道反应的初步报告。实用肿瘤杂志，1990，5(3)：146-147．
[6] Tsavaris N Fountzilas G Mylonakis N et al. A randomized comparative study of antiemetic prophylaxis with Ondansetron in a single 32mg loading dose versus 8mg every 6h in patients undergoing cisplatin-based chemotherapy. Oncology, 1998,55(6):513-517.
[7] 梁德荣 徐楠 张辉明，盐酸奥丹西隆注射剂Ⅰ期临床药物耐受性试验．华西医学，1995，10(3)：280-291．
[8] Cunningham D Hawthorn J Pople A et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT_3 receptor antangonist. The Lancet, 1987,1461-1473.
[9] 潘家祯，孙晓明，陈庆华等．挤出滚圆法制备药用微丸．中国医药工业杂志．1998,29(8)：378-380．
[10] 包泳初，陈庆华，潘家祯等，挤出滚圆法制备药用微丸．中国医药工业杂志．1999,30(1)：18-21．
[11] 陈庆华．现代微丸制备与包衣装置的类型与应用微丸．中国医药工业杂志．1999，30(1)：18-21．
[12] 钱方，蒋雪涛，王安文．微丸的进展，中国医药工业杂志．1996，27(1)：41～46．
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