马来酸罗格列酮脉冲型小片胶囊的制备与评价
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摘要
马来酸罗格列酮属于第二代噻唑烷二酮类口服抗糖尿病药，它是一种高选择性过氧化酶体增殖活化受体γ(PPARγ)激动剂，可通过提高胰岛素的敏感性而控制血糖水平，用于治疗Ⅱ型糖尿病。该药药效作用强、毒副作用小，因此市场前景广阔。
本文首先有选择性地对马来酸罗格列酮的平衡溶解度、溶液稳定性和表观油／水分配系数等理化性质进行考察，以期为处方设计和药物动力学的研究奠定基础。
应用在体灌流的方法对大鼠的肠吸收动力学进行了研究，通过考察马来酸罗格列酮在肠道各段的吸收情况以及药物浓度和pH值对吸收的影响，对其吸收动力学和吸收机理进行了初步探讨，结果表明其在肠道的吸收呈表观一级动力学过程，吸收机制为被动扩散。
为了提高马来酸罗格列酮的溶出速率、满足脉冲制剂的设计要求，本文以水溶性材料PVP K30为载体，以溶剂法制备了固体分散体。红外光谱和X-射线粉末衍射鉴别马来酸罗格列酮在载体中的存在状态，结果表明马来酸罗格列酮与载体之间没有发生化学反应，但二者有形成氢键的基础；其以无定形状态进行分散。固体分散体能显著增加马来酸罗格列酮的溶出速率，其对温度和强光较为稳定，而对湿度的稳定性较差，需在防潮的容器中保存。
Ⅱ型糖尿病是和进餐相关的疾病，餐后高血糖及总体血糖控制的恶化可引起糖尿病各种并发症特别是心血管病变的发生，因此控制餐后高血糖是治疗糖尿病和预防糖尿病并发症发生、发展的重要环节。本文以马来酸罗格列酮为模型药物，按照时间生物学的原理，根据Ⅱ型糖尿病的病症特
沈阳药科大学硕士学位论文 摘 要
点，以人的饮食习惯和特点为依据，控制餐后高血糖为指导原则进行处方
设计。采用常规辅料和湿法制粒压片的方法制备速释小片，该速释小片可
在30 min内快速释放药物，可实现第一次脉冲的设计要求。以粉末直接压
片的方法制备片芯，以EC为包衣材料，以包衣层的低渗透性和片芯的膨胀
性作为药物释放的时间开关，在综合考察片芯的膨胀力、包衣水平、致孔
剂用量等因素的基础上采用正交试验设计进行处方筛选，结果表明影响释
药时滞的各因素顺序为：包衣水平＞CMSNa用量＞包衣液中HPMC浓度
＞乳糖用量。初步探讨了脉冲小片的释药机理，并通过释药前后衣膜的电
镜扫描对其进行确证。
本文选择速释小片、释药时滞分别为4和sh的脉冲小片填入胶囊制备
一日脉冲三次的小片胶囊，采用荧光分光光度法对其体内药物动力学进行
了研究。结果表明该小片胶囊的相对生物利用度为 100．0％，其在体内的释
药时滞分别为 0、4．5和 gb，分别在 1、6和 11h时达到释药高峰，这与人
的饮食习惯及饭后血糖的达峰时间基本相符，达到了预期的实验要求。
Rosiglitazone maleate is an oral antihyperglycemic agent belonging to a member of the second generation thiazolidinedione class. The drug is a highly selective peroxisome proliferator-activated receptor r agonist and exerts its glucose-lowering effects by increasing insulin sensitivity. According to its potency in the treatment for type II diabetes and little side-effect especially on liver, rosiglitazone maleate owns extensive market potential.
In the study, physical and chemical properties of rosiglitazone maleate such as equilibrium solubility, stability of aqueous solution and apparent oil-water partition coefficient were investigated.
Absorption kinetics and the absorption mechanism of rosiglitazone maleate in rats' intestine were studied utilizing in situ perfusion by investigating intestine segments, drug concentrations and pH values of circulating solution on the absorption. Results indicated that the absorption of rosiglitazone maleate in rats' intestine was via passive diffusion with a one-order mechanism.
To improve the dissolution rate of rosiglitazone maleate and satisfy the demand of dosage form design, solid dispersions were prepared by the solvent method using PVP K30 as a hydrophilic carrier. Infrared spectra and X-ray powder diffraction spectra were used to identify the existing state of rosiglitazone maleate in the carrier. Results suggested that there were no chemical interactions between the drug and PVP K30 but with the possibility of hydrogen-bond formation, and the drug was amorphously dispersed in the carrier. The solid dispersion could significantly increase the dissolution rate of
the drug, and it was stable to high temperature and light but unstable to humidity suggested to be kept in the dry container.
Type II diabetes is a kind of disease associated with meal. Hyperglycemic after meal and out of control on the total glucose level can induce complications especially pathological changes of vessels. Therefore, the strict control on hyperglycemic after meal will play a very important role on the treatment for the diabetes and prevention to its complications. In the study, based on chronobiology, the characteristic of type II diabetes and the diet habit of human, formulations were designed according to the principle of the strict control on hyperglycemic after meal.
Conventional excipients were used to prepare rapid-released mini-tablets by the conventional method. Rapid-released mini-tablets could quickly release the drug in 30 minutes and realized the demand of the first pulse. Coated mini-tablets were formed by coating cores which were directly compressed by the powder of the mixture containing the rosiglitazone maleate and excipients with EC as the coating material. Low permeability of the coating film and swellability of the cores as the turn-off trigger, influential factors such as swelling of the core, the coating level and the pore former level were evaluated, thereafter orthogonal experiments were performed. The effect of influential factors on the lag time was as following: coating level>CMS-Na content>HPMC concentration>lactose content. Releasing mechanism of coated mini-tablets was explored, and identified with the electroscope photograph of the film before and after the dissolution test. Rapid-released and coated mini-tablets with the lag time of 4 and 8 h were selected to fill into the same hard capsule to form the pulsatile mini-tablet capsule.
Luminescence spectrophotometric method was utilized to determine the plasma level of rosiglitazone maleate. Studies on pharmacokinetics in dogs showed that relative bioavailability of the mini-tablet capsule versus the marketed conventional tablet was 100.0%. Its lag time in vivo were 0, 4.5 and 9 h respectively, and reached the maximum plasma level on the time of 1, 6 and 11 h, which conformed to the glucose peak after meal approximately.
本文首先有选择性地对马来酸罗格列酮的平衡溶解度、溶液稳定性和表观油／水分配系数等理化性质进行考察，以期为处方设计和药物动力学的研究奠定基础。
应用在体灌流的方法对大鼠的肠吸收动力学进行了研究，通过考察马来酸罗格列酮在肠道各段的吸收情况以及药物浓度和pH值对吸收的影响，对其吸收动力学和吸收机理进行了初步探讨，结果表明其在肠道的吸收呈表观一级动力学过程，吸收机制为被动扩散。
为了提高马来酸罗格列酮的溶出速率、满足脉冲制剂的设计要求，本文以水溶性材料PVP K30为载体，以溶剂法制备了固体分散体。红外光谱和X-射线粉末衍射鉴别马来酸罗格列酮在载体中的存在状态，结果表明马来酸罗格列酮与载体之间没有发生化学反应，但二者有形成氢键的基础；其以无定形状态进行分散。固体分散体能显著增加马来酸罗格列酮的溶出速率，其对温度和强光较为稳定，而对湿度的稳定性较差，需在防潮的容器中保存。
Ⅱ型糖尿病是和进餐相关的疾病，餐后高血糖及总体血糖控制的恶化可引起糖尿病各种并发症特别是心血管病变的发生，因此控制餐后高血糖是治疗糖尿病和预防糖尿病并发症发生、发展的重要环节。本文以马来酸罗格列酮为模型药物，按照时间生物学的原理，根据Ⅱ型糖尿病的病症特
沈阳药科大学硕士学位论文 摘 要
点，以人的饮食习惯和特点为依据，控制餐后高血糖为指导原则进行处方
设计。采用常规辅料和湿法制粒压片的方法制备速释小片，该速释小片可
在30 min内快速释放药物，可实现第一次脉冲的设计要求。以粉末直接压
片的方法制备片芯，以EC为包衣材料，以包衣层的低渗透性和片芯的膨胀
性作为药物释放的时间开关，在综合考察片芯的膨胀力、包衣水平、致孔
剂用量等因素的基础上采用正交试验设计进行处方筛选，结果表明影响释
药时滞的各因素顺序为：包衣水平＞CMSNa用量＞包衣液中HPMC浓度
＞乳糖用量。初步探讨了脉冲小片的释药机理，并通过释药前后衣膜的电
镜扫描对其进行确证。
本文选择速释小片、释药时滞分别为4和sh的脉冲小片填入胶囊制备
一日脉冲三次的小片胶囊，采用荧光分光光度法对其体内药物动力学进行
了研究。结果表明该小片胶囊的相对生物利用度为 100．0％，其在体内的释
药时滞分别为 0、4．5和 gb，分别在 1、6和 11h时达到释药高峰，这与人
的饮食习惯及饭后血糖的达峰时间基本相符，达到了预期的实验要求。
Rosiglitazone maleate is an oral antihyperglycemic agent belonging to a member of the second generation thiazolidinedione class. The drug is a highly selective peroxisome proliferator-activated receptor r agonist and exerts its glucose-lowering effects by increasing insulin sensitivity. According to its potency in the treatment for type II diabetes and little side-effect especially on liver, rosiglitazone maleate owns extensive market potential.
In the study, physical and chemical properties of rosiglitazone maleate such as equilibrium solubility, stability of aqueous solution and apparent oil-water partition coefficient were investigated.
Absorption kinetics and the absorption mechanism of rosiglitazone maleate in rats' intestine were studied utilizing in situ perfusion by investigating intestine segments, drug concentrations and pH values of circulating solution on the absorption. Results indicated that the absorption of rosiglitazone maleate in rats' intestine was via passive diffusion with a one-order mechanism.
To improve the dissolution rate of rosiglitazone maleate and satisfy the demand of dosage form design, solid dispersions were prepared by the solvent method using PVP K30 as a hydrophilic carrier. Infrared spectra and X-ray powder diffraction spectra were used to identify the existing state of rosiglitazone maleate in the carrier. Results suggested that there were no chemical interactions between the drug and PVP K30 but with the possibility of hydrogen-bond formation, and the drug was amorphously dispersed in the carrier. The solid dispersion could significantly increase the dissolution rate of
the drug, and it was stable to high temperature and light but unstable to humidity suggested to be kept in the dry container.
Type II diabetes is a kind of disease associated with meal. Hyperglycemic after meal and out of control on the total glucose level can induce complications especially pathological changes of vessels. Therefore, the strict control on hyperglycemic after meal will play a very important role on the treatment for the diabetes and prevention to its complications. In the study, based on chronobiology, the characteristic of type II diabetes and the diet habit of human, formulations were designed according to the principle of the strict control on hyperglycemic after meal.
Conventional excipients were used to prepare rapid-released mini-tablets by the conventional method. Rapid-released mini-tablets could quickly release the drug in 30 minutes and realized the demand of the first pulse. Coated mini-tablets were formed by coating cores which were directly compressed by the powder of the mixture containing the rosiglitazone maleate and excipients with EC as the coating material. Low permeability of the coating film and swellability of the cores as the turn-off trigger, influential factors such as swelling of the core, the coating level and the pore former level were evaluated, thereafter orthogonal experiments were performed. The effect of influential factors on the lag time was as following: coating level>CMS-Na content>HPMC concentration>lactose content. Releasing mechanism of coated mini-tablets was explored, and identified with the electroscope photograph of the film before and after the dissolution test. Rapid-released and coated mini-tablets with the lag time of 4 and 8 h were selected to fill into the same hard capsule to form the pulsatile mini-tablet capsule.
Luminescence spectrophotometric method was utilized to determine the plasma level of rosiglitazone maleate. Studies on pharmacokinetics in dogs showed that relative bioavailability of the mini-tablet capsule versus the marketed conventional tablet was 100.0%. Its lag time in vivo were 0, 4.5 and 9 h respectively, and reached the maximum plasma level on the time of 1, 6 and 11 h, which conformed to the glucose peak after meal approximately.
引文
[1] 王丽纳，吕心阳，林晓闽．2型糖尿病微血管病变患者的胰岛素分泌功能分析．中国糖尿病杂志，2001，9(5)：279～281．
[2] Polondky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med, 1998, 318(19): 231～1239.
[3] Otsuka M, Matsuda Y. Controlled release of highly water-soluble pentoxifylline from time-time disintegration-type wax matrix tablets. Pharmaceutical Research, 1994, 11(2):351～357.
[4] Conte U, Maggi L, Torre ML, et al. Press-coated tablets for time-programmed release of drugs. Biomaterials, 1993, 14(2):1017～1013.
[5] 张军，陆彬．脉冲式给药系统的研究进展．国外医药-合成药·生化药·制剂分册，1998，19(5)：317～319．
[6] Possi F, Forlani P, Gazzaniga A, et al. The time clock system: a new oral dosage form for fast and complete release of drug after a predetermined lag time. J controlled release, 1994, 31(1):99～108.
[7] Hata T, Shimazaki Y, Kagayama A, et al. Development of a novel drug delivery system, time controlled explosion system (TES): V. animal pharmacodynamic study and human bioavailability study. International J of Pharmaceutics, 1994, 110(5): 1～8.
[8] 张强．脉冲定时给药系统的研究及应用．第四届中国新医药博士论坛论文集．北京．1999：15～16．
[9] 范田园，王杰，魏树礼．阿司匹林包衣脉冲片剂的研究．北京医科大学学报，2000，32(3)：232～234．
[10] 齐美玲，王鹏，郑俊民，等．盐酸尼卡地平定时释放片研究，药学学报，1999，34(9)：710～715．
[11] Lin SY, Lin KH, Lin MJ. Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet. J Controlled Release, 2001,70(6):321～325.
[12] 邹豪，蒋雪涛，郭涛．盐酸维拉帕米脉冲控式释片的理化性质研究．解放军药学
学报，2000，10(5)：236～239．
[13] Binns J, Steve H, Mewen J, et al. The tolerability of multiple oral doses ofpulsincap capsules in healthy volunteers. J Controlled Release, 1996, 38(8): 151～157.
[14] 郝钦，岗艳云，朱家壁．硝酸异山梨酯脉冲控释微丸的研制．中国医药工业杂志，1999，30(3)：109～112．
[15] 赵圣印．糖尿病治疗药物的研究进展．国外医药-合成药·生化药·制剂分册，1999，20(3)：130～135．
[16] Sorbera LA, Rabasseda X, Gastaner J. Rosiglitazone maleate. Drugs of the future, 1998, 23(9):977～985.
[17] Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes, 1998, 47(3):507～714.
[18] 梁桂贤，刘谦民．药物吸收方法研究近况．国外医学-合成药·生化药·制剂分册，1998，19(4)：251～252．
[19] 杨正管，朱家璧，岗艳云．盐酸地尔硫卓大鼠肠吸收动力学及在口服缓释制剂设计中的意义．中国药科大学学报，1998，29(3)：179～182．
[20] Schurger N, Bijdendijk J, Tukker J. Comparision of four experimental techniques for studing drug absorbance kinetics in the anesthetized rat in situ. J Pharm Sci, 1986, 75(2):117～128.
[21] Artursson P, Karisson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun, 1991, 175(3):880～885.
[22] 毛凤斐，屠锡德，朱家壁，等．黄芩甙大鼠小肠吸收的研究．南京药学院学报，1984，15(1)：61～63．
[23] 陆彬 主编．药剂学实验 第1版．北京：人民卫生出版社，1994：131．
[24] 黄志宏，方积乾 主编．数理统计方法．北京：人民卫生出版社，1987：143．
[25] 崔福德 主编．药剂学．北京：中国医药科技出版社，2002：439．
[26] 毕殿洲 主编．药剂学 第4版．北京：人民卫生出版社，1999：117．
[27] 刘丽鹃，邹立家．一种优良的片剂崩解剂．山东医药工业，1999，18(3)：20～21．
[28] 姬静，郭圣荣，方晓玲．乙基纤维素在药物制剂中的应用．中国医药工业杂志，2000，31(2)：89～92．
[29] 魏树礼 主编．生物药剂学与药物动力学．北京：北京医科大学／中国协和医科大学联合出版社，1997：73．
[30] 魏淑香，张振清．反相高效液相色谱法测定血浆中罗格列酮的含量．药物分析杂志，2001，21(5)：365～366．
[31] Ann-marie M, Susan F, Paul R. Automated high-performance liquid chromatography method for the determination of rosiglitazone in human plasma. Journal of Chromatography B, 2001, 752(1):77～84.
[32] Rao NV, Madhusudana R, Biju B, et al. HPLC method for the determination of rosiglitazone in human plasma and its application in a clinical pharmacokinetic study. Arzneim-Forsch/Drug Res, 2002, 52(7):560～564.
[2] Polondky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med, 1998, 318(19): 231～1239.
[3] Otsuka M, Matsuda Y. Controlled release of highly water-soluble pentoxifylline from time-time disintegration-type wax matrix tablets. Pharmaceutical Research, 1994, 11(2):351～357.
[4] Conte U, Maggi L, Torre ML, et al. Press-coated tablets for time-programmed release of drugs. Biomaterials, 1993, 14(2):1017～1013.
[5] 张军，陆彬．脉冲式给药系统的研究进展．国外医药-合成药·生化药·制剂分册，1998，19(5)：317～319．
[6] Possi F, Forlani P, Gazzaniga A, et al. The time clock system: a new oral dosage form for fast and complete release of drug after a predetermined lag time. J controlled release, 1994, 31(1):99～108.
[7] Hata T, Shimazaki Y, Kagayama A, et al. Development of a novel drug delivery system, time controlled explosion system (TES): V. animal pharmacodynamic study and human bioavailability study. International J of Pharmaceutics, 1994, 110(5): 1～8.
[8] 张强．脉冲定时给药系统的研究及应用．第四届中国新医药博士论坛论文集．北京．1999：15～16．
[9] 范田园，王杰，魏树礼．阿司匹林包衣脉冲片剂的研究．北京医科大学学报，2000，32(3)：232～234．
[10] 齐美玲，王鹏，郑俊民，等．盐酸尼卡地平定时释放片研究，药学学报，1999，34(9)：710～715．
[11] Lin SY, Lin KH, Lin MJ. Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet. J Controlled Release, 2001,70(6):321～325.
[12] 邹豪，蒋雪涛，郭涛．盐酸维拉帕米脉冲控式释片的理化性质研究．解放军药学
学报，2000，10(5)：236～239．
[13] Binns J, Steve H, Mewen J, et al. The tolerability of multiple oral doses ofpulsincap capsules in healthy volunteers. J Controlled Release, 1996, 38(8): 151～157.
[14] 郝钦，岗艳云，朱家壁．硝酸异山梨酯脉冲控释微丸的研制．中国医药工业杂志，1999，30(3)：109～112．
[15] 赵圣印．糖尿病治疗药物的研究进展．国外医药-合成药·生化药·制剂分册，1999，20(3)：130～135．
[16] Sorbera LA, Rabasseda X, Gastaner J. Rosiglitazone maleate. Drugs of the future, 1998, 23(9):977～985.
[17] Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes, 1998, 47(3):507～714.
[18] 梁桂贤，刘谦民．药物吸收方法研究近况．国外医学-合成药·生化药·制剂分册，1998，19(4)：251～252．
[19] 杨正管，朱家璧，岗艳云．盐酸地尔硫卓大鼠肠吸收动力学及在口服缓释制剂设计中的意义．中国药科大学学报，1998，29(3)：179～182．
[20] Schurger N, Bijdendijk J, Tukker J. Comparision of four experimental techniques for studing drug absorbance kinetics in the anesthetized rat in situ. J Pharm Sci, 1986, 75(2):117～128.
[21] Artursson P, Karisson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun, 1991, 175(3):880～885.
[22] 毛凤斐，屠锡德，朱家壁，等．黄芩甙大鼠小肠吸收的研究．南京药学院学报，1984，15(1)：61～63．
[23] 陆彬 主编．药剂学实验 第1版．北京：人民卫生出版社，1994：131．
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