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油酸对罗美昔布泊洛沙姆凝胶流变学性能及体外释放的影响。

Influence of oleic acid on the rheology and in vitro release of lumiracoxib from poloxamer gels.

机构信息

School of Pharmacy, Pharmaceutical Technology Laboratory, Department of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

出版信息

J Pharm Pharm Sci. 2010;13(2):286-302. doi: 10.18433/j34880.


DOI:10.18433/j34880
PMID:20816013
Abstract

PURPOSE: Transdermal delivery of anti-inflammatory lumiracoxib (LM) could be an interesting strategy to avoid the side effects associated with systemic delivery, but it is ineffective due to the drug poor skin penetration. We have investigated the effects of oleic acid (OA), a lipid penetration enhancer, on the in vitro release of LM from poloxamer-based delivery systems (PBDS). The rheological behavior (shear rate dependent viscosity) and gelation temperature through measurements of optimal sol-gel transition temperatures (Tsol-gel) were also carried out in these systems. METHODS: In vitro release studies of LM from PBDS were performed using cellulose acetate as artificial membrane mounted in a diffusion system. The amount of LM released was divided by exposition area (microg/cm2) and these values were plotted as function of the time (h). The flux of the drug across the membrane (J) was calculated from the slope of the linear portion of the plot and expressed as microg/cm2. h -1. The determination of viscosity was carried out at different shear rates (gamma) between 0.1- 1000 S-1 using a parallel plate rheometer. Oscillatory measurements using a cone-plate geometry rheometer surrounded by a double jacket with temperature varying 4-40 degrees C, was used in order to determine Tsol-gel. RESULTS: Increase of both polymer and OA concentrations increases the viscosity of the gels and consequently reduces the in vitro LM release from the PBDS, mainly for gels containing OA at 10.0% compared to other concentrations of the penetration enhancer. Tsol-gel transition temperature was decreased by increasing viscosity; in some cases the formulation was already a gel at room temperature. Rheological studies showed a pseudoplastic behavior, which facilitates the flow and improves the spreading characteristics of the formulations. CONCLUSIONS: Taken together, the results showed that poloxamer gels are good potential delivery systems for LM, leading to a sustained release, and also have appropriate rheological characteristics. Novelty of the work: A transdermal delivery of non-steroidal antinflammatory drugs like lumiracoxib (LM) can be an interesting alternative to the oral route of this drug, since it was recently withdraw of the market due to the liver damage when systemically administered in tablets as dosage form. There are no transdermal formulations of LM and it could be an alternative to treat inflammation caused by arthritis or arthrosis. Then, an adequate delivery system to LM is necessary in order to release the drug properly from the PBDS as well as have good characteristics related to semi-solid preparations for transdermal application, which were evaluated through in vitro release studies and rheological behavior in this paper, respectively.

摘要

目的:透皮递送抗炎药物鲁米昔布(LM)可能是避免全身递送相关副作用的一种有趣策略,但由于药物皮肤渗透不良,该策略效果不佳。我们研究了油酸(OA)作为一种脂质渗透增强剂对泊洛沙姆为基础的递送系统(PBDS)中 LM 体外释放的影响。还通过测量最佳溶胶-凝胶转变温度(Tsol-gel),对这些系统的流变行为(剪切率依赖性粘度)和凝胶化温度进行了研究。 方法:使用纤维素乙酸酯作为人工膜,将其安装在扩散系统中,进行 PBDS 中 LM 的体外释放研究。释放的 LM 量除以暴露面积(μg/cm2),并将这些值作为时间(h)的函数绘制。从线性部分的斜率计算药物穿过膜的通量(J),并以μg/cm2·h-1表示。使用平行板流变仪在 0.1-1000 S-1 之间的不同剪切率(γ)下进行粘度测定。使用带有温度在 4-40°C 之间变化的双夹套的锥板流变仪进行振荡测量,以确定 Tsol-gel。 结果:增加聚合物和 OA 浓度都会增加凝胶的粘度,从而降低 PBDS 中 LM 的体外释放,对于含有 10.0%OA 的凝胶与其他渗透增强剂浓度的凝胶相比,这种效果更为明显。溶胶-凝胶转变温度随粘度的增加而降低;在某些情况下,制剂在室温下已经是凝胶。流变学研究表明,该制剂表现出假塑性行为,这有利于制剂的流动和改善其铺展特性。 结论:综上所述,结果表明泊洛沙姆凝胶是 LM 的良好潜在递送系统,可实现药物的持续释放,并具有适当的流变学特性。 工作新颖性:将非甾体抗炎药(如鲁米昔布(LM))经皮递送可能是该药物口服途径的一种有趣替代方案,因为最近由于全身给予片剂时肝损伤,该药物已被撤出市场。目前尚无 LM 的透皮制剂,它可能是治疗关节炎或骨关节炎引起炎症的一种替代方法。因此,为了使药物从 PBDS 中适当释放,以及使与经皮应用的半固体制剂相关的良好特性,有必要采用适当的 LM 递送系统,本文分别通过体外释放研究和流变学行为对其进行了评估。

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