目的:探讨羧甲基壳聚糖(CMCS)的取代度对灯盏花素(BRE)鼻黏膜微球体外释药速度的影响.方法:合成取代度分别为40％,60％,80％的CMCS,并进行取代度检测及红外分析.分别以取代度为40％,60％,80％,95％的CMCS为载体,制备BRE微球,并对其体外释药、空白CMCS微球溶蚀及两者之间的关系进行研究.结果:合成得到3种CMCS的取代度分别为(41.60±1.44)％,(59.39±2.15)％,(80.72±2.38)％.当CMCS的取代度分别为40％,60％,80％,95％时,BRE微球体外释药均呈现缓释特性,分别符合Higuchi方程:累积释放度(Q,％)=41.49t1/2-11.66(R2=0.984 3),Q=39.74t1/2-12.82(R2=0.991 6),Q=35.35t1/2-10.89(R2=0.992 8),Q=31.12t1/2-8.80(R2=0.9902);空白CMCS微球溶蚀分别符合Higuchi方程:累积溶蚀量(A,％)=39.25t1/2-10.97 (R2=0.984 0),4=37.59t1/2-12.04(R2=0.990 4),A=33.61t1/2-10.61 (R2=0.992 5),A=29.41t1/2-8.32(R2=0.989 6).释药与CMCS溶蚀之间均呈现高度一致的线性相关性,且随着CMCS取代度的增加,BRE微球体外释药速度逐渐减慢.结论:CMCS取代度对BRE鼻黏膜微球的体外释药有明显的影响,取代度越高,释药越慢,缓释效果越明显.

目的:对N-三甲基壳聚糖(TMC)作为鼻腔给药系统吸收促进剂的作用及安全性进行评价.方法:以苯甲酸利扎曲普坦(RB)为模型药物,采用大鼠在体鼻腔循环法,以RB药液为阴性对照,以含0.5％羧甲基壳聚糖(CMCS) RB药液为阳性对照,对含同用量、不同季铵化程度TMC(TMC20、TMC40、TMC60)的RB药液进行鼻腔吸收实验,筛选出最佳的TMC季铵化程度,同时对筛选出的最佳TMC进行最佳用量的优选,并以生理盐水为阴性对照,1％去氧胆酸钠为阳性对照,对其大鼠鼻黏膜刺激性及对蟾蜍纤毛的影响进行考察.结果:与RB药液相比,0.5％ CMCS及3种TMC均对RB鼻腔吸收有明显的吸收促进作用,与CMCS相比,TMC20促进作用较弱(P＜0.05),TMC40及TMC60均呈现更大的吸收促进作用(P＜0.05),且TMC60作用强于TMC40(P＜0.05).随着TMC60用量的增加,促进吸收作用越大,但1.0％与1.5％ TMC60之间差异无统计学意义(P＞0.05).与生理盐水及RB药液相比,1.0％ TMC60对大鼠鼻粘膜及蟾蜍纤毛运动均无明显影响(P＞0.05).结论:TMCs具有较好的RB鼻腔吸收促进作用,且以1.0％ TMC60最佳,同时安全性较好,值得进一步研究.

目的:对季胺化程度为60％的N-三甲基壳聚糖(TMC60)及羧甲基壳聚糖(CMCS)作为鼻腔给药系统吸收促进剂对苯甲酸利扎曲普坦(RB)脑靶向性促进作用进行比较.方法:SD大鼠随机分为4组,其中3组分别给予同剂量的RB滴鼻剂、RB-TMC60滴鼻剂、RB-CMCS滴鼻剂,第4组静脉给予同剂量的RB注射液.在预定时间点对大鼠血浆及脑组织中RB浓度进行检测,采用DAS2.0软件处理得到药动学参数,并用经鼻给药脑靶向效率(DTE)及脑靶向潜力(DTP)评价脑靶向性.结果:与RB滴鼻剂相比,TMC60及CMCS均可显著增加RB经鼻吸收入脑的药量(P<0.05),且TMC60显著提高RB在血中的药量(P<0.05);与静脉给药相比,RB滴鼻剂、RB-TMC60滴鼻剂、RB-CMCS滴鼻剂的DTE％分别为160％,210％,182％,DTP％分别为37％,52％,45％,说明3种RB滴鼻剂均有一定增加脑靶向性的作用,且TMC60的脑靶向促进作用最佳(P<0.05).结论:与CMCS相比,TMC60对RB鼻腔给药脑靶向促进作用更加显著.

目的:对灯盏花素(BRE)鼻黏膜微球的制备工艺进行优化,并对其体外质量进行考察,为进一步体内实验奠定基础.方法:以羧甲基壳聚糖(CMCS)为载体,采用喷雾干燥法制备BRE微球.以包封率及载药量的综合评分为评价指标,采用正交试验优化其处方及制备工艺,并对其形态、粒径及体外释药特性进行考察.结果:优选出的BRE微球最佳制备条件为:CMCS浓度为0.8 9·ml-1,BRE∶CMCS为1∶5(g∶g),CMCS∶三聚磷酸钠(TPP)为15∶1(g∶g),蠕动泵速度为20ml·min-1.BRE微球外形圆整光滑,粒径均匀,体外释药呈明显缓释性,包封率和载药量分别为(68.33±0.35)％和(16.26±0.42)％.结论:BRE-CMCS微球制备简单,体外质量理想,值得进一步研究.

目的:采用HPLC法建立阮氏上清丸指纹图谱定性和7种成分定量分析的测定方法,为阮氏上清丸的质量控制提供更为可靠的方法和依据.方法:采用HPLC法,同时测定阮氏上清丸中没食子酸、迷迭香酸、甘草苷、苦参碱、氧化苦参碱、儿茶素、表儿茶素的含量,采用ZORBAX Eclipse XDB-C18色谱柱(250 mm×4.6 mm,5μm),流动相为甲醇-0.1％磷酸溶液(B),梯度洗脱;检测波长为220 nm、280 nm,柱温为30℃,流速为1.0 ml· min-1,进样量为10μl.选取苦参碱为参照峰,并使用中药色谱指纹图谱相似度评价系统对指纹图谱进行相似性评价.结果:没食子酸、迷迭香酸、甘草苷、苦参碱、氧化苦参碱、儿茶素、表儿茶素检测质量浓度的线性范围分别为2.009～12.050,0.952～5.715,1.016～6.096,4.655～27.930,38.940～233.600,407.600～2 446,232.100～1 393 μg· ml-1(r为0.999 4～0.999 8);定量限分别为1.021,0.936,1.034,1.125,1.305,1.024,1.037μg·ml-1;平均加样回收率分别为99.1％,98.9,98.5％,99.1％,98.5％,99.0％,98.7％(RSD＜2.0％,n=6).10批次阮氏上清丸样品的指纹图谱与其指纹图谱共有模式相比较相似度均大于0.9,标定了共有峰22个,并对其中7个共有指纹峰进行了指认和归属.结论:所建立的HPLC指纹图谱分离效果良好,特征性强,方法稳定简单,多指标成分含量测定同时结合指纹图谱分析能更为全面地对阮氏上清丸的质量进行控制.

目的:对苯甲酸利扎曲普坦(RB)鼻用温度-离子敏感型原位凝胶的体外溶蚀及安全性进行研究.方法:采用体外振荡法检测RB鼻用温度-离子敏感型原位凝胶的基质溶蚀及药物释放特性.以生理盐水为正常对照,1％去氧胆酸钠为阳性对照,观察RB鼻用温度-离子敏感型原位凝胶对蟾蜍上腭纤毛运动及形态的影响,以及对大鼠鼻黏膜形态的影响.结果:RB鼻用温度-离子敏感型原位凝胶的基质溶蚀及释药均为零级动力学过程,溶蚀方程为A=0.0922t+0.1988(r=0.9986),释药方程为Q=0.2460t+1.8462(r=0.9977),且两者有明显的线性相关性:Q=0.3525A-0.4248(r=0.9990).与正常对照组相比,RB鼻用温度-离子敏感型原位凝胶对蟾蜍纤毛运动能力无显著影响(P>0.05),且纤毛分布均匀,排列整齐,同时对大鼠鼻黏膜无明显的毒性.结论:RB从原位凝胶中的释放主要受凝胶溶蚀控制,同时具有良好的鼻用安全性.

目的:对苯甲酸利扎曲普坦(RB)鼻用温度-离子敏感型原位凝胶的脑靶向性进行研究.方法:SD大鼠随机分为3组,其中两组分别给予同剂量的RB滴鼻剂、RB鼻用温度-离子敏感型原位凝胶,第3组静脉给予同剂量的RB注射液.在预定时间点测定各组大鼠血浆中及脑组织中RB浓度,绘制药时曲线,采用DAS2.0软件处理得到主要药动学参数,并用脑靶向性指数(BTI)评价两种RB鼻用制剂的脑靶向性.结果:RB滴鼻剂的BTI为1.71,RB鼻用温度-离子敏感型原位凝胶的BTI为2.12,均显示有一定的脑靶向性,且原位凝胶的脑靶向性更为显著,同时原位凝胶的达峰时间及半衰期均延长,显示明显的缓释性及长效性.结论:RB鼻用温度-离子敏感型原位凝胶具有较好的脑组织靶向性.

目的:探讨苯甲酸利扎曲普坦(RB)鼻用温度-离子敏感型原位凝胶对偏头痛大鼠的行为、痛域及血管活性物质的影响.方法:采用电刺激法在清醒大鼠体内建立偏头痛模型.将模型大鼠按数字法随机分为3组:RB鼻用温度-离子敏感型原位凝胶(2.5 mg·kg-1)组、RB溶液(2.5 mg·kg-1)组、模型(生理盐水)组,每组10只,于电刺激前用50μl平头微量注射器经鼻给予相应药物.另取10只未造模大鼠设为空白组.各组分别施加频率为6 Hz、电压为3 V、脉宽为0.25 ms的电刺激,持续时间为1 h,连续5 d.对电刺激后大鼠行为、痛域及降钙素基因相关肽(CGRP)、内皮素(ET)、一氧化氮(NO)含量进行观测.结果:与模型相比,RB两种鼻用制剂均可明显改善电刺激后大鼠行为,增加机械及温度刺激痛域,并显著降低血浆中CGRP、ET、NO含量(P<0.05或P<0.01);与RB溶液相比,RB原位凝胶呈现更好的改善作用(P<0.05).结论:RB鼻用温度-离子敏感型原位凝胶在偏头痛大鼠模型中有较好的治疗作用.

目的:研制苯甲酸利扎曲普坦(RB)鼻用温度-离子敏感型原位凝胶,并考察其体外性质.方法:筛选合适的吸收促进剂,并对泊洛沙姆407及去乙酰结冷胶的最佳用量进行考察,制备RB温度-离子敏感型原位凝胶,对其胶凝温度、胶凝时间、胶凝强度、生物黏附力及体外释药特性进行测定.结果:最佳吸收促进剂为1.0％的羧甲基壳聚糖(CMCS),泊洛沙姆407用量为18％,去乙酰结冷胶用量为0.3％,胶凝温度为(32.6±0.3)℃,胶凝时间为(25.6±1.8)s,胶凝强度为(122.4±1.5)s,生物黏附力为(152.25±12.76)(×102dyne·cm-2),体外释药符合Higuchi方程:Q=5.5856t1/2+0.3260(r=0.9942).结论:RB鼻用温度-离子敏感型原位凝胶具有较好的温度、离子敏感性,并具有明显的缓释性.

目的:制备转铁蛋白(Tf)修饰的甲基莲心碱(Nef)纳米脂质体(NefNL),并考察其脑部靶向性.方法:以二硬脂酰基磷脂酰胆碱(DSPC)、胆固醇、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)及二硬脂酰磷脂酰乙醇胺-聚乙二醇2000-羧基(DSPE-PEG200-COOH)为成膜材料,采用薄膜分散法制备NefNL,并将Tf共价结合于DSPE-PEG200-COOH的COO-上制备Tf修饰的NefNL(Tf-NefNL).HPLC法测定小鼠中血浆及脑部Nef浓度.以同剂量的NefNL为对照,测定Tf-NefNL给药后不同时间点小鼠血浆及脑部的Nef浓度,并利用DAS2.0软件计算主要药动学参数,并用相对摄取率(re)、靶向效率(te)及峰浓度比(Ce)3个指标评价其脑靶向性.结果:与同剂量的NefNL相比,Tf-NefNL在小鼠脑组织中的峰浓度(Cmax)及曲线下面积(AUC)明显增加,达峰时间(Tmax)缩短(P<0.05),re、te、Ce分别为1.90、1.37、2.0.结论:Tf修饰的纳米脂质体可显著增加Nef在小鼠脑部的浓度,加快达峰,具有明显的脑靶向性.

Objective:To optimize the formula and preparation of exendin W /O/W multiple emulsion , and study the main proper-ties in vitro to lay foundation for the development of exendin prolonged action preparation .Methods:Using multiple emulsion yield and centrifugal separation time as the comprehensive index , the formula and preparation of exendin multiple emulsion were optimized by or-thogonal tests, and the morphology, particle size, stability, encapsulation efficiency and drug release in vitro were studied.Results:The optimal formula was as follows:the volume ratio of W1 phase to O phase was 1:1.2, the quality percentage of emulsifierⅠin the O phase was 10％, poloxamer 407 in W2 phase was 10％, and the quantity ratio of W1/O to W2 phase was 1:1.The optimal prepara-tion conditions were as follows:the stirring speed for W1/O was 10000 r· min-1 , and the stirring time was 10 min, and that for W1/O/W2 was 2500 r· min-1 with the stirring time of 3 min.The multiple emulsion was spherical with the mean size of (46.3 ±2.6)μm, and the centrifugal and viscosity stability were both promising .The drug encapsulation efficiency was above 90％, and the drug release in vitro accorded with a Higuchi equation: Y=13.7930X+5.5981(r=0.9883), showing notable sustained and prolonged property .Conclusion:The optimal formula and preparation process of exendin multiple emulsion are simple with high drug content , good stability and notable sustained release property in vitro.

目的:制备N-三甲基壳聚糖(TMC)包衣伏立康唑(VCZ)脂质体冻干品,对其体外性质进行考察.方法:采用薄膜分散法制备VCZ脂质体(VCZL),以季铵化程度60％的TMC(TMC60)对其进行包衣.处方采用正交试验进行优化,并筛选出最优的冻干保护剂制备冻干品.考察其形态、粒径及Zeta电位,并用透析袋法研究体外释药特性.结果:TMC60包衣VCZL最优处方组成为质量比卵磷脂∶胆固醇4∶1,药物∶类脂1∶20,TMC60溶液浓度为0.15 mg·ml-1,PBS的pH为7.4.TMC60包衣VCZL形态圆整,平均粒径为(590.4±16.0) nm,冻干复水化后平均粒径为(503.2±20.5) nm;VCZL的Zeta电位为-46.4 mV,TMC60包衣后为+54.9 mV,冻干复水化后为+52.6 mV;冻干前后平均包封率无明显变化;体外释药符合Higuchi方程.结论:TMC60包衣VCZL粒径均匀,带正电荷,包封率较高,具有缓释性,冻干对其主要性质无显著影响.

Objective:To improve the stability of exendin W/O/W multiple emulsion.Methods:The amount of electrolyte sodium chloride in the internal water phase and that of thickener PVP in the external water phase were both screened for exendin W/O/W mul-tiple emulsion,and the cryoprotectant in the freeze-drying process was optimized in order to further optimize the formula and preparation of exendin W/O/W multiple emulsion. Verification experiment was carried out to study the main properties of the optimized exendin W/O/W multiple emulsion in vitro. Results: The optimal quality volume percentage concentration of sodium chloride in the internal water phase was 0.10%,and that of PVP in the external water phase was 0.15%,and the best cryoprotectant was 10% mycose. The main in vitro properties of exendin W/O/W multiple emulsion showed no significant changes before the freeze-drying and after the rehy-dration. Conclusion:Through the optimization of the internal and external water phase of exendin W/O/W multiple emulsion,the sta-bility is enhanced,which lays foundation for the in vivo studies.

Objective: To study the status of indomethacin (IDM) in IDM enteric-coated dropping pills and its interaction with PEG 6000.Methods: IDM, PEG 6000, their physical mixture and IDM enteric-coated dropping pills were respectively studied by DSC, IR, X-ray diffraction and SEM.Results: In the map of DSC, the endothermic peak of IDM enteric-coated dropping pills disappeared at 164℃, and the endothermic peak of PEG 6000 at 57℃ shifted forward.In the map of IR, the carbonyl stretching vibration peak of IDM in IDM enteric-coated dropping pills disappeared, and a new peak appeared at 1 680 cm-1.In the map of X-ray diffraction, there was no diffraction peak in IDM enteric-coated dropping pills.SEM showed the morphology of IDM in the base was much smaller than that of IDM raw material.Conclusion: IDM in IDM enteric-coated dropping pills is dispersed in the matrix with an amorphous or molecular form, and there is hydrogen bond between IDM and PEG 6000.

Objective:To study the pharmacokinetics of indometacin (IDM) enteric-coated dropping pills.Methods:Beagle dogs were used as the experimental animals and the marketed IDM enteric-coated tablets were applied as the control,the pharmacokinetics of IDM enteric-coated dropping pills was studied after a single oral administration.DAS software was used for the model fit and parameter calculation,and the bioequivalence was also evaluated.Results:Both IDM enteric-coated dropping pills and tablets were fitted a one-compartment model.Compared with those of IDM enteric-coated tablets,the Cmax,Tmax,AUC0-∞and Tlag of IDM enteric-coated dropping pills all showed notable differences (P<0.05),and the former two increased significantly,and the latter two were shortened significantly.The relative bioavailability of the dropping pills was (121.0±7.7)%.Conclusion:Compared with IDM enteric-coated tablets,IDM enteric-coated dropping pills are with significantly enhanced absorption and shortened lag time,which is worthy of further studies and development.

Objective: To prepare mesalazine thermosensitive liquid suppositories and study the in vitro properties. Methods:Poloxamer 407 (P407) and poloxamer 188 (P188) were used as the temperature-sensitive materials, and mesalazine thermosensitive liquid suppositories were prepared by a cold method. The optimal ratio of P407 and P188 was screened using gel temperature as the in-dex. The gel strength and bioadhesive force of mesalazine thermosensitive liquid suppositories were studied, and the in vitro gel erosion and drug release were investigated as well. Results:The optimal ratio of P407 and P188 was 20%: 2. 5%, and the gel temperature was (36.9 ±0.2)℃, the gel strength was (115.1 ±3.2)s and the bioadhesive force was (130.7 ±5.8) ×102 dyne·cm-2. The drug release and gel erosion in vitro were both fitted first-order kinetics, and the two had promising linear relationship, suggesting good sustained-release property based on gel erosion mechanism of mesalazine liquid suppositories. Conclusion:The preparation of mesala-zine liquid suppositories is simple, and the gelation, bioadhesion and sustained-release of the suppositories are promising. Mesalazine liquid suppositories are valuable to be studied further.

Objective To prepare Levodropropizin(LP) Effervescent Dropping Pills and to investigate its quality. Methods With water-soluble high polymer material PEG6000 and PEG4000 as the main matrix,sodium bicarbonate and tartaric acid ( 3:2 ) as the efferves-cent agents,LP Effervescent Dropping Pills was prepared. With the proportion of qualified product in the dropping pills as the evaluation index,the orthogonal design was adopted to optimize the formula and technology. The quality was investigated with the character,pill weight difference,time-limit of dissolution,content and stability as the investigation indexes. Results The optimal formula was as fol-lows:the ratio of PEG6000 and PEG4000 was 2. 5 :1,the ratio of drug and matrix was 1:4,and the temperature of drug liquid was 95 ℃. The character,pill weight difference,content and stability of LP Effervescent Dropping Pills met the relative require-ments. Compared with LP Dropping Pills,the time-limit of dissolution of LP Effervescent Dropping Pills was significantly decreased,and the difference had statistical significance( P < 0. 01). Conclusion LP Effervescent Dropping Pills has simple formula and simple tech-nology,ideal quality and more rapid dissolution,which is worthy to be further studied.

目的:研制汉防己甲素(Tet)眼用脂质体(L)-原位凝胶(ISG),并对其体外性质进行考察.方法:采用薄膜超声分散法制备Tet脂质体(TetL);以泊洛沙姆407(P407)和泊洛沙姆188(P188)为ISG基质,以胶凝温度为指标,筛选P407与P188的最佳配比,与TetL混合制备TetL-ISG;对其外观、粒径、Zeta电位等体外性质进行考察,并采用无膜溶出模型对其体外释药、凝胶溶蚀特性及其相关性进行研究.结果:当P407与P188的处方用量分别为21％及6％时,胶凝温度最接近人眼表温度(34℃);TetL-ISG的平均包封率为(82.51±2.63)％(n=3),外形球形圆整,粒径均匀[(292.2±12.4)nm],Zeta电位较大[(-38.5±5.9)mV],TetL-ISG体外药物释放及凝胶溶蚀速度均呈现零级特征,且两者相关性良好.结论:TetL-ISG具有包封率高,胶凝温度合适,稳定性较好,缓释等特性,为其角膜滞留性及药效学研究研究奠定了实验基础.

目的 系统比较布地奈德和美沙拉嗪对活动期炎症性肠病的疗效和安全性,为其临床治疗提供最佳证据方法.方法 计算机检索PubMed、Cochrane Central Register of Controlled Trials、CENTRAL、EMbase、Google Scholar、CNKI、CBM 和WanFang Data,查找所有比较布地奈德与美沙拉嗪治疗活动期炎症性肠病的随机对照试验(RCT),检索时限均为建库至2012年12月30日,同时手工检索纳入文献的参考文献.按纳入和排除标准进行文献筛选、资料提取和质量评价后,采用RevMan 5.1软件进行Meta分析.结果 最终纳入5个RCT,共计1 166例患者.Meta分析结果 显示:布地奈德治疗活动期溃疡性结肠炎的临床缓解疗效劣于美沙拉嗪[OR=0.54,95%CI:0.38~0.75,P=0.003),布地奈德与美沙拉嗪对活动期克罗恩病的临床缓解疗效比较差异无统计学意义(OR=1.20,95%CI:0.75~1.90,P=0.45);治疗炎症性肠病患者过程中引起的不良反应比较,布地奈德与美沙拉嗪比较差异无统计学意义(OR=0.94,95%CI:0.73~1.22,P=0.66);而布地奈德引起溃疡恶化的风险高于美沙拉嗪(OR=0.3.98,95%CI:1.53~10.37,P=0.005).结论 对活动期溃疡性结肠炎的临床缓解疗效,美沙拉嗪优于布地奈德,而对克罗恩病患者差异无统计学意义;此外,布地奈德在治疗活动期溃疡性结肠炎时,其导致溃疡恶化的风险较美沙拉嗪高.

目的:建立高效液相色谱法测定喷昔洛韦乳膏含量方法:采用Alltima C_(18)(53 mm×7 mm,3μm)色谱柱,0.02 mol·L~(-1)磷酸二氢钾溶液-甲醇(95:5)为流动相,流速为2.0 ml·min~(-1),检测波长252 nm。结果:喷昔洛韦在0.02~0.2 mg·ml~(-1)范围内呈良好线性关系(r=0.999 9),平均回收率为99.62%,RSD为1.0%(n=9)结论:改进后的方法快速、科学、合理、重复性好,可用于该药的质量控制。