In vitro and in vivo Evaluation of Ibuprofen Nanosuspensions for Enhanced Oral Bioavailability

IntroductionThe objectives were to prepare, characterize, and evaluate different ibuprofen (IBU) nanosuspensions.MethodsThe nanosuspensions produced by ultrahomogenization were compared with a marketed IBU suspension for particle size, in vitro dissolution, and in vivo absorption. Five groups of rabbits were orally administered with 25 mg/kg of IBU nanosuspension, nanoparticles, unhomogenized suspension, marketed product, and untreated suspension. A sixth group received 5 mg/kg IBU intravenously. Blood samples obtained were analyzed by chromatography.ResultsThe nanosuspensions showed significant decrease in particle size. Polyvinylpyrrolidone (PP) K30 profoundly increased aqueous solubility of IBU. Addition of Tween 80 (TW), in equal amount as PP (IBU:PP:TW, 1:2:2 w/w), resulted in much smaller particle size and better dissolution rate. The C_max values achieved were 14.8 ± 1.64, 11.1 ± 1.37, 9.01 ± 0.761, 7.03 ± 1.38, and 3.23 ± 1.03 μg/mL, and the t_max values were 36 ± 8.2, 39 ± 8.2, 100 ± 17.3, 112 ± 15, and 105 ± 17 min for the nanosuspension, nanoparticle, unhomogenized suspension, marketed IBU suspension, and untreated IBU suspension in water, respectively. Bioavailability of the different formulations relative to the marketed suspension was found to be in the following sequence: nanosuspension > unhomogenized suspension > nanoparticles > untreated IBU suspension.ConclusionIBU/PP/TW nanosuspension showed enhanced in vitro and in vivo performance as compared to the marketed product. Nanosuspensions prepared by the ultrahigh-pressure homogenization technique can be used as a good formulation strategy to enhance the rate and extent of absorption of poorly soluble drugs.     

普罗布考对高脂兔脂肪肝形成的影响

 目的 观察普罗布考对高脂兔脂肪肝形成的影响,并探讨其可能机制.方法 16只新西兰大白兔给予高脂饲养8周后,随机分为2组:(1)淀粉组(n=8):饲以高脂饲料及1%淀粉;(2)普罗布考组(n=8):在饲以高脂饮食基础上给予1%普罗布考;另选8只兔为正常饮食组(n=8),给予普通饮食.14周末结束实验.测定血清脂质、超氧化物歧化酶(SOD)、丙二醛(MDA)和转氨酶水平,测定肝脏的脂质含量并进行病理学检测.结果 (1)高脂饮食8周后总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇的含量明显升高,普罗布考可明显降低上述指标,均为P＜0.01;(2)普罗布考对SOD活性无明显影响,但与淀粉组比较,普罗布考组MDA的含量[(9.2±3.3) μg/ml vs (12.6±4.4) μg/ml,P＜0.01]明显降低;(3)普罗布考组血清转氨酶水平[ALT(45.3±12.9)U/L, AST (49.5±13.0)U/L]较淀粉组[ALT(67.20±14.3)U/L,AST(81.6±21.8)U/L]明显降低,均为P＜0.01;(4)普罗布考干预6周后可明显降低肝脏中胆固醇和甘油三酯的含量,肝脏脂肪病变明显减轻.结论 普罗布考具有降脂、抗氧化和护肝作用,能抑制高脂饮食所致的脂肪肝形成.     

阿托伐他汀联合葡萄籽原花青素预防兔动脉硬化的研究

目的探讨阿托伐他汀与葡萄籽原花青素(grape seed proanthocyanidin extract, GSPE)联合应用后对兔动脉硬化的预防作用。方法应用电化学发光法测定甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-c）及高密度脂蛋白胆固醇（HDL-c）水平,应用硫代巴比妥酸法（TBA）检测血清丙二醛（MDA）含量;应用免疫组织化学法和扫描、透射电镜观察各组标本变化。结果联合用药组与阿托伐他汀组比较,TG、TC、LDL-c和HDL-c两组之间差异无统计学意义（P＞0.05）,而血清MDA则显著降低(P＜0.05）。GSPE和阿托伐他汀联合应用较阿托伐他汀组可减轻兔主动脉内皮和心肌的损害。结论阿托伐他汀和GSPE联合应用后能明显减轻动脉硬化斑块的发生。     

谷胱甘肽对肝缺血再灌注损伤细胞因子的影响

 目的观察炎性细胞因子在家兔肝缺血再灌注(Ischemia-reperfusion,I/R)损伤中的变化及谷胱甘肽的保护机制.方法将30只健康家兔随机分为对照组、I/R组和谷胱甘肽保护组,制备肝缺血再灌注损伤模型,测定3组血清或血浆和肝组织中ALT、MDA、TNF-α、IL-1β、IL-6、IL-8含量,观察肝脏病理变化和肝组织中PMN浸润数.结果肝I/R组损伤后,ALT、MDA、TNT-α、IL-1β、IL-6、IL-8含量相继明显升高,肝组织中中性粒细胞(PMN)浸润明显增多(P＜0.05),肝脏出现明显的病理变化;使用谷胱甘肽后,上述指标的异常变化均明显减轻,差异有显著性意义(P＜0.05).结论炎性细胞因子参与了肝I/R损伤,甘胱甘肽通过清除氧自由基,减少炎性细胞因子的生成,减轻PMN在病变部位聚集,对肝I/R损伤有积极的保护作用.     

穿透角膜移植术各屈光变量及其相互关系

目的〓〖HTK〗研究穿透性角膜移植（penertrating keratoplasty,PKP）术后各屈光变量间的数量关系,探讨PKP引起眼球屈光状态变化的规律。〖HTW〗方法〓〖HTK〗32只新西兰大白兔随机分为A、B、C、D四组分别行PKP术,植孔大小均为7mm,植片直径依次为7、7.25、7.5和8.0mm,将屈光变量植片差值、角膜屈折力、角膜厚度、前房深度、晶状体厚度依次设为自变量X1、X2、X3、X4、X5,眼轴长度为应变量Y,分别在术前、术后1周、2周、1月、2月、3月进行观察测量并建立Y与各自变量间的数学模型。〖HTW〗结果〓〖HTK〗术前各屈光变量在各组间无显著差异（P＞0.05）。综合各时间点的参数获得了屈光变量间的回归方程,如：术后3月Y=15.238+0.199X1+0.544X2-0.060X3+0.129X4-0.094X5。〖HTW〗结论〓〖HTK〗PKP术中应用不同植片/植孔大小差值可以引起眼球屈光状态的改变。所建立的回归方程数学模型对PKP术后屈光状态的控制具有一定指导作用。     

动脉瘤夹不同夹闭时间对兔颈总动脉管壁的影响

目的探讨一次性使用永久动脉瘤夹不同夹闭时间对兔颈总动脉管壁的影响。方法选用健康雄性日本大耳白兔60只,按数字随机法分为两组,一次性使用永久动脉瘤夹分别夹闭颈总动脉30 min和60 min,每组各30只,分别取动脉瘤夹夹持部位颈总动脉标本30段,采用Mann-Whitney U检验,进行血管壁组织病理学损伤程度的比较。结果一次性使用动脉瘤夹夹闭30 min和60 min所致的血管壁损伤均可见中层弹力板形变和内皮细胞脱落,夹闭时间60 min组血管壁出现局部坏死伴发炎性反应,甚至管壁破裂。夹闭30 min组和夹闭60 min组血管壁总体损伤程度(U=324.00,P=0.045)和重度损伤率[0%(0/30)比20.0%(6/30),P=0.031]差异均有统计学意义。结论一次性使用永久动脉瘤夹夹闭时间60 min比30 min对血管壁的损伤更重,术中应注意缩短夹闭颈动脉时间。     

适于磁共振成像研究房水循环兔模型的建立

目的:建立适宜于房水循环MRI研究的动物模型。方法:新西兰白兔12只,随机分为2组,每组6只;实验组前房注入Gd-DTPA,对照组注入等量生理盐水后30s、30min、1h行MRI检查。结果:实验组不同时间点前房信号不同,对照组前房信号无变化。结论:该模型适于MRI对房水循环研究。     

超氧物歧化酶冻干制剂及脂质体制剂的研究

设计了十一种冻干制剂的配方,通过外观检查和稳定性考查,从中筛选出最佳配方,即以乳糖为赋形剂且冻干前浓度为2.5％的制剂。探讨了各种条件对制备SOD脂质体的影响,选出了提高包嵌率的较好条件。改进了测定SOD活性的极谱法,测定了SOD水溶液和两种SOD脂质体在兔血内SOD活性的变化,初步证实所制得的脂质体可延长SOD在体内的停留时间。     

Ophthalmic bioequivalence of steroid/antibiotic combination formulations

This study compared the relative ocular bioavailability in rabbits of the antibiotic/steroid combination of 0.3 per cent tobramycin and 0.1 per cent fluorometholone acetate to each of the two single-entity products. Two separate studies were conducted, one measuring fluorometholone acetate in cornea and aqueous humour through 240 min and the other measuring tobramycin in the cornea through 120 min. The results for fluorometholone acetate show that the combination product is 15 per cent higher in AUC for the cornea than the single-entity product (0.05 less than p less than 0.1). However, the combination product is only 4.4 per cent higher in AUC when aqueous humour levels are compared (N.S.). The single-entity fluorometholone acetate ointment yielded cornea and aqueous humour levels which were 20 per cent (p less than 0.01) and 6 per cent (N.S.) higher in AUC than the same tissues measured after topical instillation of the suspension. Statistical treatment of the data indicated that the suspension and ointment products, were bioequivalent with respect to fluorometholone acetate in aqueous humour, but not with respect to corneal concentrations. Tobramycin was measured in the cornea following instillation of either the single-entity solution or the combination suspension. Per cent bound (tobramycin to rabbit antibodies determined in vitro from the radioimmunoassay results) was used for statistical analyses of all group means and standard errors. The results indicated that the products were bioinequivalent.     

Improving the ocular absorption of phenylephrine

An oxazolidine prodrug of phenylephrine and the base form of phenylephrine were synthesized, suspended in sesame oil, and tested for mydriatic activity against phenylephrine HCl. The HCl salt was formulated as a viscous aqueous solution and as a sesame oil suspension. A dosing volume of 10 microliter was instilled into rabbit eyes and the pupillary diameter was measured over time. A 0.045 M prodrug suspension was judged equal in mydriatic activity to a 0.45 M viscous solution of phenylephrine HCl with the exception that the time of maximum response occurred 60 min earlier with the prodrug. When phenylephrine base was suspended in sesame oil at 0.045, 0.12, and 0.45 M, the mydriatic activity was also greater than equimolar suspensions of phenylephrine HCl. The pH of tear fluids was also measured over time and found to rise 1.1, 0.70, and 0.30 pH units for 0.45, 0.12, and 0.045 M suspensions of the base form but remain unchanged when phenylephrine HCl was instilled in the rabbit eye. The greater activity associated with the base form of phenylephrine was judged a result of the change in pH to favour the absorption of phenylephrine. This latter approach should be applicable to either weak acids or weak bases with pKa values outside of the normal pH range (7-8) of the tears and in concentrations greater than 0.045 M suspended in a non-aqueous vehicle.