羟基积雪草酸固体脂质纳米凝胶的制备及体内外透皮特性研究

Preparation and Transdermal Permeability in vitro and in vivo of Madecassic Acid Solid Lipid Nanoparticles Gel

目的:研究羟基积雪草酸固体脂质纳米凝胶(MA-SLN-gel)最佳工艺处方,考察其在动物体内外的透皮特性。方法:正交设计试验优化MA-SLN-gel处方并考察其初步稳定性。以羟基积雪草酸普通凝胶(MA-gel)为对照完成以下试验:采用透析袋法进行体外释放试验;Franz扩散池法进行离体透皮试验,并测定皮内滞留量及组织学评价;在活体小鼠体表进行透皮试验,考察新制剂的透皮性能。结果:MA-SLN-gel的最佳处方工艺:取1%卡波姆、12.5%甘油及10%丙二醇制成空白凝胶,与羟基积雪草酸纳米粒按1∶1比例混合得半透明状纳米凝胶。MA-SLN-gel的24 h累积释放率(75.8%)只有MA-gel的80%,具有缓释性;MA-SLN-gel经皮稳态渗透速率(2.7098μg^(-1)·cm^(-2)·h^(-1))是MA-gel的2.7倍,皮内滞留总量(2.5353μg^(-1)·cm^(-2))是MA-gel的1.2倍,且主要聚集在真皮层抑制成纤维细胞增殖发挥药效;组织学评价未发现淋巴细胞聚集,说明羟基积雪草酸抑制了炎症发生;在体小鼠经皮给药后,MA-SLN-gel较MA-gel渗透快且更多滞留在真皮层,与离体透皮试验结果一致。结论:MA-SLN-gel制备工艺简单,质量稳定且具有良好的透皮性能,有望成为应用羟基积雪草酸局部治疗瘢痕增生的新剂型。

Objective:To prepare a novel drug delivery system of madecassic acid solid lipid nanoparticles loaded gel(MA-SLN-gel),and to investigate its transdermal permeability in vitro and in vivo.Methods:Orthogonal design test was used to optimize the formulation of madecassic acid solid lipid nanoparticles gel.The preliminary stability was also investigated.The following experiments were carried out with common gel(MA-gel)as control:in vitro release test was carried out in a dialysis bag;transdermal absorption test in vitro was carried out by using Franz diffusion cells,the skin retention amount of madecassic acid was determined and histological evaluation was carried out;transdermal test was carried out in living mice to investigate the transdermal performance of the new preparation.Results:The optimum gel formulation was as follows:1%carbomer,12.5%glycerol and 10%propylene glycerol were used to prepare the blank gel,and then mixed with madecassic acid solid lipid nanoparticles to obtain the semi-transparent nanoparticles gel.The cumulative drug release rate of MA-SLN-gel in 24 hours(75.8%)was 80%of that of MA-gel.The steady-state permeation rate of MA-SLN-gel(2.7098μg^(-1)·cm^(-2)·h^(-1))was 2.7 times of that of MA-gel.The intradermal retention(2.5353μg·cm^(-2))of MA-SLN-gel was 1.2 times of that of MA-gel,and the MA-SLN-gel aggregation in dermis inhibited the fibroblast proliferation.Histological evaluation showed no lymphocyte aggregation,indicating no inflammation.After transdermal administration on living mice,MA-SLN-gel penetrated faster than MA-gel and retained more in dermis.The results were consistent with those of in vitro transdermal test.Conclusion:The preparation of MA-SLN-gel is simple and stable with good transdermal properties.It is expected to become a new form of topical application for madecassic acid in the treatment of scar hyperplasia.