Varshika Endabetla, Prabhakar Kandadi, Kishan Veerabrahma
Department of Pharmaceutics, University College of Pharmaceutics Sciences, Kakatiya University, Warangal, Andhra Pradesh, India 506009.
PDA J Pharm Sci Technol. 2009 Sep-Oct;63(5):380-9.
The aim of the present study was to develop stable parenteral submicron lipid emulsions (SLEs) for sustained delivery of diclofenac acid, used to treat arthritic conditions, to minimize dosing frequency. The SLEs of diclofenac acid were prepared using soybean oil, egg lecithin, and cholesterol. They were heated and processed by homogenization and ultrasonication. The influence of formulation variables, such as the change in proportion of oil and cholesterol, were studied, and optimized formulations were developed. The stability of the optimized formulations SM-A (no cholesterol), SM-I (0.05% cholesterol), and SM-II (0.1% cholesterol) was studied during autoclaving, centrifugal stress, desorption stress (dilution effect), and on storage. The creaming volume percentage was found during the storage and centrifugal stress studies. The effect of dilution on zeta potential and size was noted in the desorption studies. The total drug content and entrapment efficiency was determined using high-performance liquid chromatography. In vitro release studies were performed in phosphate buffer using dialysis method for 12 h. The in vivo anti-inflammatory activity (reduction in paw volume of optimized SLEs) was tested in a 1% carrageenan-induced rat paw oedema model and compared with a diclofenac injection (Voveran). Stable SLEs of diclofenac were developed with a mean size ranging from 200-250 nm and a zeta potential of -31 +/- 1 mV. The cholesterol concentration did not significantly affect the prepared SLEs' size and zeta potential. The optimized formulations, SM-A, SM-I, and SM-II, were relatively stable during centrifugal stress, dilution stress, and storage. The drug content was found to be 2.45 +/- 0.26 mg/mL for SM-A, 2.46 +/- 0.34 mg/mL for SM-I, and 2.42 +/- 0.01 mg/mL for SM-II. The entrapment efficiency was 98.91 +/- 0.13%, 99.01 +/- 0.12%, and 99.27 +/- 0.1% for SM-A, SM-I and SM-II, respectively. The in vitro drug release was zero-order and the cumulative amount of drug released within 12 h was 80% (SM-A), 57% (SM-I), and 42% (SM-II. During in vivo studies, the optimized formulations initially revealed a sustained anti-inflammatory activity occurring up to 12 h, with a maximum activity occurring after 2 h. In the case of the diclofenac injection, the maximum activity persisted up to 5 h and then gradually decreased. No such decrease was noticed regarding the optimized formulations for a period extending up to 12 h. Beyond 12 h, activity persisted up to 24 h with a slight reduction in effect.
本研究的目的是开发稳定的肠胃外亚微米脂质乳剂（SLEs），用于持续递送双氯芬酸，以治疗关节炎病症并尽量减少给药频率。双氯芬酸的SLEs采用大豆油、蛋黄卵磷脂和胆固醇制备。它们经过加热，并通过均质化和超声处理。研究了配方变量的影响，如油和胆固醇比例的变化，并开发了优化配方。在高压灭菌、离心应力、解吸应力（稀释效应）及储存过程中，对优化配方SM-A（无胆固醇）、SM-I（0.05%胆固醇）和SM-II（0.1%胆固醇）的稳定性进行了研究。在储存和离心应力研究过程中测定了乳析体积百分比。在解吸研究中记录了稀释对ζ电位和粒径的影响。使用高效液相色谱法测定总药物含量和包封率。采用透析法在磷酸盐缓冲液中进行了12小时的体外释放研究。在1%角叉菜胶诱导的大鼠足肿胀模型中测试了优化后的SLEs的体内抗炎活性（足体积减小），并与双氯芬酸注射液（扶他林）进行了比较。开发出了双氯芬酸的稳定SLEs，其平均粒径为200 - 250 nm，ζ电位为-31±1 mV。胆固醇浓度对所制备的SLEs的粒径和ζ电位没有显著影响。优化配方SM-A、SM-I和SM-II在离心应力、稀释应力和储存过程中相对稳定。SM-A的药物含量为2.45±0.26 mg/mL，SM-I为2.46±0.34 mg/mL，SM-II为2.42±0.01 mg/mL。SM-A、SM-I和SM-II的包封率分别为98.91±0.13%、99.01±0.12%和99.27±0.1%。体外药物释放为零级，12小时内药物累积释放量分别为80%（SM-A）、57%（SM-I）和42%（SM-II）。在体内研究中，优化配方最初显示出长达12小时的持续抗炎活性，2小时后出现最大活性。对于双氯芬酸注射液，最大活性持续至5小时，然后逐渐下降。在长达12小时的时间段内，优化配方未出现这种下降情况。12小时后，活性持续至24小时，效果略有降低。
