基于微乳凝胶新载体的丹皮酚经皮给药系统的构建及药代动力学研究

为构建基于微乳凝胶 (microemulsion-based gels, MBGs) 新载体的丹皮酚经皮给药系统, 采用皮肤、血液双位点同步微透析结合LC/MS联用技术测定丹皮酚微乳、微乳凝胶及市售丹皮酚软膏在大鼠皮肤、血液中的药物浓度随时间的变化过程, 并对其药代动力学参数进行比较分析。方法学研究表明, 丹皮酚线性探针体内回收率 (R_{in vivo}) 为 (69.7 ± 4.8) %, 同心圆探针体内回收率为 (51.6 ± 7.2) %。大鼠腹部脱毛, 分别给予丹皮酚微乳 (1% 丹皮酚)、微乳凝胶和市售丹皮酚软膏, 以PBS (pH 7.4) 溶液作为灌流液, 灌流速度为5 μL·mL⁻¹, 每隔20 min收集1次微透析样品, 共收集12 h, 透析液采用LC/MS进行测定。皮肤药动学结果表明丹皮酚微乳、微乳凝胶与市售软膏相比, 显著提高了药物在皮肤组织中的浓度; 血液药动学结果表明微乳凝胶与市售软膏具有相近的生物利用度, 但前者的血药浓度更平稳。本研究所构建的丹皮酚微乳凝胶有望为皮肤湿疹的治疗提供一种新的制剂; 所建立的微透析/LC-MS联用技术能够在体、同步、实时监测大鼠皮肤、血液中的药物浓度, 为经皮给药药代动力学研究提供了新的方法。     

用在体皮肤微透析法研究黄芩苷凝胶经大鼠皮肤吸收的局部药动学

目的建立大鼠在体皮肤微透析技术,研究黄芩苷凝胶经皮吸收局部药动学。方法采用HPLC-MS/MS联用技术测定大鼠皮肤微透析液中黄芩苷的浓度。SD大鼠在麻醉状态下做皮肤微透析预处理,然后将黄芩苷凝胶涂于探针所在皮肤表面,收集皮肤微透析液样品进行黄芩苷浓度测定,绘制黄芩苷浓度-时间曲线,计算经皮吸收局部药动学参数。结果用于定量分析的离子对为m/z 447.3→271.2,黄芩苷在检测浓度范围内线性关系良好,色谱的专属性、精密度等测定结果均符合生物样品测定要求。体内皮下探针对黄芩苷的回收率为（24.40±0.91）%,240 min内各取样点回收率保持稳定;黄芩苷经皮给药后8 h内微透析液中均可检测到黄芩苷的存在,且药物在皮肤组织内浓度持续升高,AUC0-t为（50.04±34.17）（mg·min）/L。结论在体皮肤微透析法可用于黄芩苷经皮吸收局部药动学研究。     

头孢拉定微透析体外回收率及影响因素的研究

目的 测定头孢拉定微透析体外回收率及影响因素。方法 采用微透析浓度差法（减量法、增量法）和液质联用技术（LC-MS/MS）测定头孢拉定的体外回收率,并考察流速、浓度对回收率的影响,以探讨微透析技术用于头孢拉定体内药动学研究的可行性。结果 所建立的方法在要求范围内线性关系良好,方法灵敏可靠。增、减量法测得的回收率无显著性差异。相同条件下,探针体外回收率随流速增大而减小,不受探针周围药物浓度的影响。结论 微透析技术可用于头孢拉定药动学研究,减量法可用于头孢拉定微透析体内回收率和药动学参数的测定。     

在体皮肤微透析的建立及对乌头碱经皮给药药代动力学研究

目的:建立大鼠在体皮肤微透析技术,并用于乌头碱经皮给药药代动力学研究。方法:采用HPLC-MS/MS联用技术建立大鼠血浆和微透析样品中乌头碱的分析方法。体外回收率的测定采用浓差法(增量法、减量法),体内回收率的测定采用减量法,考察流速、浓度对回收率的影响。5只SD大鼠在麻醉状态下,作皮肤微透析预处理后,将乌头碱凝胶涂于探针所在皮肤表面,进行皮肤微透析和颈动脉采血,应用HPLC-MS/MS测定透析液样品及血浆中乌头碱浓度,并绘制血药浓度-时间曲线,并计算药动学参数。结果:乌头碱在检测要求范围内线性关系良好,色谱的专属性、回收率、精密度等测定结果均符合生物样品测定要求。增量法及减量法测定的回收率一致;回收率随灌流速度的增大而减小,探针的回收率与溶媒中乌头碱的浓度无关。体内皮下探针对乌头碱的回收率为(34.48±3.05)%,乌头碱在皮下探针中6 h回收率的变化基本上保持稳定。乌头碱经皮给药后,在皮肤中最大药物浓度为(2723.8±848.8)mg.L-1,AUC(0～t)为(18212.4±4749.1)mg.h.L-1,体内血药浓度比较稳定。结论:本研究提示体内研究的反透析法可作为微透析研究中乌头碱回收率的测定...     

18α-甘草酸固体脂质纳米粒的药动学研究

目的 对18α-GL固体脂质纳米粒(18α-GL-SLN)的药动学进行研究。方法 在大鼠股静脉和肝脏同时植入探针,尾静脉给药后,同步微透析采样10 h,HPLC测定透析液中18α-GL的浓度,推算血液及肝脏中真实18α-GL药物浓度,拟合药-时曲线,计算药动学参数,并进行统计分析。结果 大鼠尾静脉给予18α-GL-SLN和18α-GL后血液和肝脏的主要药动学参数C_max、AUC_0→T(n)、AUC_extra和MRT差异均有统计学意义。与18α-GL水溶液相比,18α-GL-SLN的血液C_max显著降低,肝脏C_max显著升高,MRT显著延长,AUC显著增高。结论 18α-GL-SLN给药后药物在大鼠肝脏中的浓度显著升高,存留时间显著延长,提示18α-GL-SLN具有显著的肝脏靶向特性。     

黄芩苷对大鼠体内硝苯地平的药动学的影响

目的 研究黄芩苷对大鼠体内硝苯地平药动学以及大鼠肝微粒体CYP3A活性的影响。方法 雄性Wistar大鼠分别ig 0.2、0.6 g/kg黄芩苷和硝苯地平10 mg/kg,采用LC-MS法测定血浆中硝苯地平的质量浓度,比较药动学参数。黄芩苷和硝苯地平经大鼠肝微粒体共孵育后,LC-MS法测定孵育液中氧化硝苯地平的质量浓度,比较CYP3A活性。结果 ig 0.6、0.2 g/kg黄芩苷后,硝苯地平质量浓度-时间曲线下面积(AUC_0-t)均显著增大,表现为硝苯地平的生物利用度升高。黄芩苷0.6 g/kg组硝苯地平的达峰浓度(C_max)显著升高、药物清除率(CLz)和表观分布容积(Vz)显著降低。黄芩苷0.2 g/kg组硝苯地平的上述药动学参数无显著变化。30、90μg/mL黄芩苷可降低大鼠肝微粒体孵育体系中氧化硝苯地平的生成量,抑制大鼠肝微粒体CYP3A活性。结论 黄芩苷可改变大鼠体内硝苯地平药动学特征,提高生物利用度,这与黄芩苷对CYP3A活性的抑制作用有关。     

京尼平苷体内外微透析回收率的研究

目的 探究京尼平苷在自制线性微透析探针上的体内外回收率与灌流速度、药物浓度、透析膜长之间的关系。方法 采用HPLC测定微透析样品浓度,考察不同灌流速度、不同药物浓度和不同透析膜长对体外正向和体外反向回收率、体内反向回收率的影响。结果 自制探针性质稳定;探针回收率与京尼平苷的药物浓度无关,与灌流速度成反比,随透析膜长增加而增加;体外的正向与反向探针回收率有显著性差异（P<0.01）,而体内反向回收率低于体外反向回收率,与体外正向回收率无显著性差异;新探针体内回收率大于使用过1次的探针体内回收率（P<0.05）。结论 在京尼平苷的皮肤药动学研究中,宜采用体内反向回收率或体外正向回收率作为药物的探针回收率来校正。     

氧化苦参碱凝胶体外经皮渗透及大鼠药动学研究

目的 研究氧化苦参碱凝胶的体外经皮渗透影响因素,并对其在大鼠体内的药动学进行研究。方法 采用Valia-Chien 双室扩散池,以大鼠离体皮肤为渗透屏障,HPLC测定氧化苦参碱浓度,以药物累积渗透量为指标,对药物及渗透促进剂的浓度进行筛选。结果 氧化苦参碱经皮凝胶的最优处方12 h累积渗透量为(18.094±1.253)mg·cm^-2,大鼠静注与经皮给药的血浆药动学研究表明,经皮给药的AUC_(0-t)是注射给药的1.9倍(P<0.01)。结论 氧化苦参碱凝胶的经皮吸收能力良好,能长时间持续释放药物,有望成为新的给药剂型。     

微透析技术用于化疗药物——吉西他滨体内药动学的初步研究

目的：建立以微透析法（microdialysis,MD）为采样技术的肿瘤化疗药物在体检测方法,并进行药动学研究。方法：以吉西他滨（GEM）为研究对象,大鼠为实验动物,采用尾静脉注射为给药方式,通过微透析技术进行血管内取样,对血药浓度进行在线、实时、连续监测,求算相关药动学参数。结果：GEM在大鼠体内血液中的探针回收率为（11.9±2.0）%,经大鼠尾静脉给药后GEM体内过程为二室模型,其消除和分布为一级动力学过程。实验过程中大鼠未见明显副作用。结论：微透析技术可用于活体动物体内GEM浓度的连续监测,提示微透析技术可用于抗肿瘤药物的局部药动学研究。     

精氨酸双糖苷检测方法的建立及药动学研究

目的 建立快速、灵敏、高效的精氨酸双糖苷的测定方法并研究精氨酸双糖苷在大鼠体内的药动学。方法 以乌苯美司作为内标,采用LC-MS/MS检测方法测定血浆中精氨酸双糖苷浓度,利用DAS2.0软件计算药动学相关参数,并分析方法的可靠性。结果 空白血浆对检测物质不产生干扰,在20~20 000 ng/mL符合线性关系,方法学中RSD以及RE值均小于15%。结论 采用LC-MS/MS方法检测精氨酸双糖苷方法合理可靠,精氨酸双糖苷的绝对生物利用度为（4.50±3.75）%。     

Development of transferosomal gel for trans-dermal delivery of insulin using iodine complex

Abstract

The main object of this current research was to examine transferosomes as a transdermal delivery system for insulin, to overwhelm the difficulties related with its subcutaneous delivery. Transferosomal gel formulations were prepared by rotary evaporation sonication technique. The result revealed that insulin was successfully entrapped (78%) in optimized formulations (2.5 I.U. of the drug and 25% of sodium cholate) with cumulative percent drug release (83.11?±?3.782). The glucose lowering study revealed that the transferosomal gel with chemical penetration enhancer showed better glucose lowering effect as compared to the control gel. Consequently, this study authenticated that the transferosomal gel can be used as a possible substitute to the conventional formulations of insulin with progressive permeation characteristics for transdermal application.     

Pharmacological evaluation of membrane-moderated transdermal system of glipizide

1. Membrane-moderated transdermal systems of glipizide were prepared using drug-containing carbopol gel (drug reservoir) and ethyl cellulose, as well as Eudragit RS-100, Eudragit RL-100 (Rohm Pharma, Darmstadt, Germany) and ethylene vinyl acetate (EVA; 2, 9 and 19% vinyl acetate content) rate-controlling membranes, and were subsequently evaluated in vitro (drug content and drug permeation studies) and in vivo (acute and long-term hypoglycaemic activity, effect on glucose tolerance, biochemical and histopathological studies, skin irritation test and pharmacokinetic studies in mice). 2. The drug content of the systems was found to be more than 99%. Variations in drug permeation patterns were observed among the formulations containing different rate-controlling membranes. 3. The system with the EVA (19% vinyl acetate) rate-controlling membrane was selected for in vivo experiments. This transdermal system produced better improvement with respect to hypoglycaemic activity, glucose tolerance and tested biochemical, histopathological and pharmacokinetic parameters all compared with oral administration and exhibited negligible skin irritation. 4. The transdermal system successfully prevented severe hypoglycaemia in the initial hours and it was also effective for chronic application.     

The effect of formulation vehicles on the in vitro percutaneous permeation of ibuprofen

Background

The transdermal application of substances represents an elegant approach to overcome side effects related to injections or oral treatment. Due to benefits like a constant plasma level, no pain during application and a simple therapeutic regime, the optimization of formulations for transdermal drug delivery has gained interest in the last decades. Ibuprofen is a non-steroidal anti-inflammatory compound which is nowadays often used transdermally. The objective of this work was to conduct a study on the effect of different 5% ibuprofen containing formulations (Ibutop^? cream, Ibutop^? gel, and ibuprofen solution in phosphate buffered saline) on the in vitro-percutaneous permeation of ibuprofen through skin to emphasise the importance of the formulation on percutaneous permeation and skin reservoir.

Methods

The permeation experiments were conducted in Franz-type diffusion cells according to OECD guideline 428 with 2 mg/cm² ibuprofen formulation on each skin sample. Ibuprofen was analysed in the receptor fluid and extracted skin samples by UV-VIS high-performance liquid-chromatography at 238 nm. The plot of the cumulative amount of ibuprofen permeated versus time was employed to calculate the apparent permeability coefficient, the maximum flux and the lagtime, all of which were statistically analysed by One-way ANOVA.

Results

Although ibuprofen permeation out of the gel increases rapidly within the first four hours, the cream produced the highest ibuprofen delivery through the skin within 28 hours, followed by the solution and the gel. A significant shorter lagtime was found after gel treatment compared with the cream and the solution. After 28 hours 59% of the applied ibuprofen was found in the receptor fluid of the cream treated samples, 26% in the solution treated samples and 21% in the samples treated with the gel. Fourfold higher ibuprofen reservoirs were found in the solution and gel treated skin samples compared to the cream treated skin samples.

Conclusion

The present study demonstrates the importance of the formulation on transdermal drug delivery of ibuprofen and emphasises the differences of drug storage within the skin due to the formulation. Thus, it is a mistaken assumption that formulations comprising the same drug amount are equivalent regarding skin permeability.     

Proniosomal transdermal therapeutic system of losartan potassium: development and pharmacokinetic evaluation

The purpose of the current study was to investigate the feasibility of proniosomes as transdermal drug delivery system for losartan potassium. Different preparations of proniosomes were fabricated using different nonionic surfactants, such as Span 20, Span 40, Span 60, Span 80, Tween 20, Tween 40, and Tween 80. Different formulae were prepared and coded as PNG-1 (proniosomal gel-1) to PNG-7. The best in vitro skin permeation profile was obtained with proniosomal formulation PNG-2 in 24?h. The permeability parameters such as flux, permeability coefficient, and enhancement ratio were significant for PNG-2 compared with other formulations (P?<?0.05). This optimized PNG-2 was fabricated in the form of transdermal patch using HPMC gel as a suitable base. Proniosomal transdermal therapeutic system (PNP-H) was found to be the optimized one as it gave better release of drug and better permeation in a steady-state manner over a desired period of time, that is, 24?h through rat skin. In vivo pharmacokinetic study of PNP-H showed a significant increase in bioavailability (1.93 times) compared with oral formulation of losartan potassium. The formulation appeared to be stable when stored at room temperature (30?±?2°C) and at refrigeration temperature (4?±?2°C) for 45 days.     

正交试验优选硫酸铵梯度法制备苦参碱脂质体的工艺研究

目的 以包封率为指标优选苦参碱脂质体的制备工艺.方法 以氢化大豆卵磷脂(HSPC)和胆固醇(Ch)为膜材,采用薄膜超声-硫酸铵梯度法制备脂质体.通过正交设计优化处方工艺,葡聚糖凝胶法分离游离药物,HPLC法测定月旨质体中苦参碱的包封率.结果 最佳工艺为:HSPC:Ch=3∶1,探头超声10 min,药脂比为1:15,包封率均值为50.68％.结论 优化后的工艺可提高苦参碱脂质体的包封率,此工艺条件简单,可操作性强,适于实验室条件下制备苦参碱脂质体.     

Controlled Release of a Contraceptive Steroid from Biodegradable and Injectable Gel Formulations: In Vitro Evaluation

Purpose. The purpose of this study was to investigate the effects of formulation factors including varying wax concentration, drug loading and drug particle size, on drug release characteristics from both pure oil and gel formulations prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl palmitostearate (Precirol ATO 5), using levonorgestrel as a model drug. Methods. The effects of varying drug loadings, different drug particle sizes, and wax (Precirol) concentrations on in-vitro drug release rates were evaluated, and the mechanisms of drug release from the gels were determined. Results. Zero-order drug release rates from the 10% Precirol gel formulations containing 0.25, 0.50 and 2.00% w/v drug loadings were lower than those observed for oil formulations containing identical drug loadings. Higher zero-order release rates were observed from formulations containing smaller drug particles suspended in both oil and gel formulations. The mechanism of drug release from gels containing less than 0.25% w/w drug was diffusion-controlled. Increasing the wax concentrations in the gels from 5% w/w to 20% w/w significantly decreased the diffusivity of the drug through the gel formulations and markedly increased the force required to inject the gels from two different sizes of needles. Conclusions. This study shows how modification of the physicochemical properties of the gel formulations by changing the drug particle size, wax concentration and drug loading, affects drug release characteristics from the system.