格列吡嗪胶囊人体药动学及相对生物利用度的研究

目的研究格列吡嗪胶囊人体药物代谢动力学及相对生物利用度.方法用HPLC法测定10名受试者单剂量交叉口服5mg格列吡嗪胶囊和片剂后的血药浓度,MC-PKP药动学程序拟合,得药动学参数,计算胶囊剂的相对生物利用度(F).结果胶囊剂的Cmax为(456±60)ng/ml、Tmax为(2.9 5±0.6)h、AUC为(2335±180)h*ng/ml.以上参数经双单侧t检验等统计分析,与片剂比无显著差异.F值为(103±4)%.结论格列吡嗪(2.95±0.6)h血药浓度达高峰,峰浓度为(456±60 )ng/ml.且胶囊与片剂为生物等效制剂.     

克拉霉素对家兔体内格列吡嗪药动学特征的影响

目的研究克拉霉素在健康和糖尿病家兔体内对格列吡嗪片代谢的影响。方法健康新西兰家兔和实验性糖尿病家兔各5只,每只口服格列吡嗪5 mg,经2周清洗期后,每只家兔予克拉霉素0.25 g,ig,bid,持续3 d,第4天口服相同剂量格列吡嚎。在给予格列吡嗪前及给药后O.5、1.5、3、5、7、9、11、24、35 h,经耳缘静脉采血,用HPLC法测定各点格列吡嗪的血药浓度,用3P97数据处理软件计算药动学参数。采用自身对照法分析给予克拉霉素前后格列吡嗪药动学的变化。结果正常组家兔单用格列吡嗪,其t₁/2_ke、ρ_max、AUC分别为（3.99±1.52）h、（4.05±0.89）mg·L^-1、（68.54±15.67）mg.h·L^-1,加用克拉霉素后又分别为（4.26±1.29）h、（5.41±1.64）mg·L^-1、（74.25±18.94）rag·h·L^-1。糖尿病组家兔单用格列毗嗪,其t₁/2ke、ρ_max、AUC分别为（3.81±0.89）h、（4.19±1.25）mg·L^-1、（70.24±13.21）mg·h·L^-1,加用克拉霉素后又分别为（4.28±O.91）h、（5.31±1.47）mg·L^-1、（79.48±17.69）mg·h·L^-1。给予克拉霉素前后格列吡嗪的t₁/2ke、ρ_max、AUC差异均存有统计学意义（P<0.5）。结论克拉霉素对家兔体内格列吡嗪的药动学有明显的影响。     

酸-碱溶析分散技术及在格列吡嗪制剂中的应用

酸-碱溶析分散技术是一种依次加入酸化剂和碱化剂,使难溶性药物溶解后,在后续过程中析出而分散于载体材料的制剂技术;与预粉碎方法相比,采用该方法可减小难溶性药物格列吡嗪在颗粒剂中的粒径。结果表明,本法能显著减小颗粒中格列吡嗪的粒径,并具有良好的工艺重现性。     

格咧吡嗪缓释微囊的制备及其释药特性考察

采用喷雾干燥法，以乙基纤维素为囊材，制备格咧吡嗪缓释微囊，并对其体外释药特性进行考察。实验结果表明，所得微囊能延缓药物释方，药物释放速率随其含量增加而增加，随着介质ｐＨ值升高而增加，随着微囊粒径的增大而减少。     

The effect of sulphonylurea on the in vivo tissue uptake of glucose in normal rats

Summary To evaluate the effect of sulphonylurea on in vivo tissue uptake of glucose, the arterial injection tissue-sampling technique of Oldendorf [9] was used to measure the glucose uptake of brain; liver; subcutaneous fat; and of three skeletal muscles, the masseter, femoris and soleus. Rats gavaged with glipizide 5 mg/kg daily for 5 days were compared to vehicletreated rats. The serum glucose levels at the time of the experiment were identical in the two groups (10.36±0.42 mmol/l vs 10.38±0.36 mmol/l). Glipizide treatment did not result in an increase in glucose uptake by the various tissues studied. It is concluded that, under physiological conditions in non-fasted rats, sulphonylureas do not significantly alter tissue uptake of glucose.     

格列吡嗪双层渗透泵片在比格犬体内的药动学

目的考察格列吡嗪双层渗透泵片在比格犬体内的药动学过程,评价其生物等效性及体内体外相关性。方法建立格列吡嗪比格犬血浆样品的UPLC/MS/MS测定方法,以市售格列吡嗪控释片(瑞易宁)为参比制剂,对自制格列吡嗪控释片进行了比格犬体内药动学研究。结果建立了测定格列吡嗪UPLC/MS/MS方法,方法灵敏度高,分析速度快。自制格列吡嗪控释片中格列吡嗪的相对生物利用度为(85.37±26.69)%。结论受试制剂和参比制剂生物不等效,但体内外相关性较好。     

孚来迪治疗2型糖尿病临床观察

目的：评价孚来迪治疗2型糖尿病的有效性和安全性。方法：将40例未接受胰岛素治疗的2型糖尿病病人随机分成两组，用孚来迪治疗的为观察组(n＝20)，用美吡达治疗的为对照组(n＝20)，观察两组病人的血糖、糖化血红蛋白的变化和药物副作用。结果：观察组阵糖有效率与对照组比较无显差异性(有效率分别为90．0％和85．0％，P＞0．05)，但观察组FBG和HbAlC降低较对照组强(P＜0.05)，2hFBG降低较对照组弱(P＜0．05)，而服药后低血糖发生率明显低于对照组(发生率分别为0和15％，P＜0．05)。对肝肾功能和血压无不良影响。结论：口服孚来迪治疗2型糖尿病安全有效。     

格列吡嗪和格列奇特对MIN6细胞的影响

目的:研究不同磺脲类药物对胰岛素分泌细胞的影响及机制。方法:不同浓度格列吡嗪和格列奇特干预MIN6细胞一定时间后,MTT法检测细胞活力变化,运用ROS捕获剂双氢溴乙啶(HE)、双氢-乙酰乙酸二氯荧光黄(DCFH-DA)和双氢罗丹明123(DHR123)孵育细胞,用荧光显微镜观察细胞内荧光、流式细胞仪检测MIN6细胞的平均荧光强度(MFI)而测得细胞内ROS水平。用Annexin-vFITC和PI双标记细胞凋亡检测法通过流式细胞仪测定细胞凋亡情况。结果:格列吡嗪干预MIN6细胞后,细胞活力明显被抑制(P<0.05);细胞内的MFI明显增加;细胞凋亡率明显增加;而且,细胞活力下降、MFI和细胞凋亡率与药物作用浓度和时间呈正相关。而格列奇特干预MIN6细胞后,细胞活力无明显抑制(P>0.05);细胞内的MFI无明显增加;细胞凋亡率亦无明显增加。结论:格列吡嗪可诱导MIN6细胞发生氧化应激,诱导MIN6细胞凋亡,说明临床上磺脲类药物治疗糖尿病出现失效可能与磺脲类药物诱发胰岛细胞衰竭相关,然而,格列奇特不诱导MIN6细胞损害,说明并非所有磺脲类药物对β细胞都有损害作用。     

基于单池药物溶出/吸收仿生系统评价格列吡嗪不同制剂的释药特征及其体内外相关性

[目的]考察格列吡嗪片及其缓释片在单池药物溶出/吸收仿生系统(Single cell-DDASS)的释放特征,以及与比格犬体内吸收程度的相关性。[方法]采用《中华人民共和国药典》(以下简称《药典》)溶出度法和Single cell-DDASS法对格列吡嗪片及其缓释片进行体外释放度实验,用Wagner-Nelson方程计算不同格列吡嗪制剂在体内的吸收百分数,并与相应时间点体外累积释放度进行线性回归,进一步考察其体内外相关性(IVIVC)。[结果]格列吡嗪缓释片体外释放度的最优拟合方程是一级动力学方程,释放机制为溶蚀机制。格列吡嗪片在《药典》溶出法中释放过快,无法建立体内外相关性,而Single cell-DDASS法中累积释放度与比格犬体内吸收百分数之间存在相关性(r=0.773 2,P0.05)。格列吡嗪缓释片在《药典》溶出法中累积释放度与比格犬体内吸收百分数之间密切相关(r=0.811 5,P0.05)。格列吡嗪缓释片在Single cell-DDASS法中累积释放度与比格犬体内吸收百分数之间极密切相关(r=0.987 7,P0.01)。[结论]格列吡嗪片及其缓释片在Single cell-DDASS法中累积释放度与比格犬体内吸收百分数之间的相关性明显优于《药典》溶出法释放百分数与比格犬体内吸收百分数的相关性,表明Single cell-DDASS能够良好预测格列吡嗪不同制剂在体内的动力学特征。     

Characterization,quantification and stability of differently prepared amorphous forms of some oral hypoglycaemic agents

The study deals with the investigation of possible differences induced in the physicochemical properties within the amorphous forms prepared by different methods. Enthalpy of solution measured by solution calorimetry was utilized to highlight the differences prevailing within the amorphous forms and to determine the percentage of amorphous content. Emphasis is laid on the quantification and physical stability of these forms. Amorphization was induced in poorly water-soluble oral hypoglycaemic agents (repaglinide, gliclazide and glipizide), by quench cooling, vaporization under reduced pressure and lyophilization. The amorphous nature was evident from a halo pattern in powder X-ray diffraction. A glass transition event is evident in differential scanning calorimetry thermograms of the amorphous forms of the three drugs. As expected, the amorphous forms show improvement in solubility and dissolution profiles. On subjecting these amorphous forms to different relative humidities at 25°C for three months and subsequent analysis showed that amorphous form of repaglinide prepared by quench cooling is most stable and has the potential to be formulated without any additive while amorphous form of gliclazide tends to devitrify pointing towards its unstable nature.