复方丹参冻干乳剂的制备及其体外溶出特性研究

目的研制复方丹参冻干乳剂,改善复方丹参片中脂溶性成分的溶出。方法采用高速剪切-均质法制备复方丹参液态乳;以物理外观、复溶效果为评价指标,采用均匀设计试验法优选油相比例与支架剂用量,进而以冷冻干燥法制得复方丹参冻干乳剂。以方剂中脂溶性代表成分丹参酮IIA、龙脑为检测指标,分别考察复方丹参冻干乳剂与片剂在人工胃液和人工肠液中的溶出度;以复溶后外观、平均粒径和Zeta电位为指标,考察冻干乳剂长期留样稳定性。结果液态乳油相(中链甘油三酸酯)比例为10%,加入18%麦芽糖和0.25%β-环糊精作为支架剂时,制备的冻干乳剂外观均匀、复溶迅速且完全,稳定性良好。以人工胃液为溶出介质,复方丹参冻干乳剂中的丹参酮IIA、龙脑在30 min时的累积溶出率分别为(94.8±2.8)%、(97.4±2.9)%;而复方丹参片中的丹参酮IIA几乎未溶出,龙脑的累积溶出率也仅为(23.3±3.4)%。以人工肠液为溶出介质,片剂中的丹参酮IIA、龙脑在120 min时的累积溶出率分别为(42.5±2.7)%、(74.4±1.8)%,仍显著低于冻干乳剂的(97.8±1.9)%、(92.7±3.5)%。冻干乳剂室温放置1年后,各项指标均无显著变化。结论与市售片剂相比,冻干乳剂可显著提高复方丹参方剂中脂溶性成分的溶出度,且具有速释特点,其物理稳定性良好。

Preparation and dissolution characteristics of Compound Danshen freeze-dried emulsion

Objective To improve in vitro dissolution of lipophilic constituents in Compound Danshen Tablet, a novel freeze-dried emulsion was designed and developed. Methods Compound Danshen liquid emulsion was prepared by high-speed shearing, following by high pressure homogenization process. The oil phase and cryoprotectants were optimized by uniform design test, using physical appearance and redispersibility as evaluation indexes. The in vitro dissolution profile of tanshinone II_A and borneol in the freeze-dried emulsion and Compound Danshen Tablet was determined in artificial gastric juice and artificial intestinal juice containing 0.5% sodium lauryl sulfate (SDS). Based on the appearance, average particle size and zeta potential, the stability of freeze-drying emulsion was investigated. Results The developed Compound Danshen freeze-dried emulsion had good physical appearance, meanwhile maintained a good redispersibility and stability, when 10% medium chain triglycerides (MCT) was adopted as oil phase of liquid emulsion and 18% maltose combined with 0.25% beta-cyclodextrin was optimized as cryoprotectants. In artificial gastric juice, the accumulated dissolution rates of tanshinone II_A and borneol in Compound Danshen freeze-dried emulsion reached up to (94.8 ± 2.8)% and (97.4 ± 2.9)% at 30 min, respectively. However, the accumulated dissolution rate of borneol in the tablet was only (23.3 ± 3.4)% at 120 min, while tanshinone II_A showing no dissolution. In artificial intestinal juice, the accumulated dissolution rates of tanshinone II_A and borneol in the tablet rose to (42.5 ± 2.7)% and (74.4 ± 1.8)% at 120 min, but they were still much lower than that in the freeze-dried emulsion which reached up to (97.8 ± 1.9)% and (92.7 ± 3.5)%. After one year''s storage, there were no significant changes of the stability evaluation index for freezing dry emulsion.Conclusion The dissolution rates of lipophilic constituents in Compound Danshen freeze-dried emulsion increased significantly and exhibited a fast and fairly complete drug release, which provides a potential and promising formulation to improve bioavailability of the original dosage form of tablet. Its physical stability is good.