Lipid nanocarriers as skin drug delivery systems: Properties,mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology.Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers.In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.     

美洛昔康醇质体凝胶的研制

目的：制备美洛昔康醇质体凝胶。方法：通过正交设计优选出美洛昔康醇质体的制备工艺,利用HPLC法测定包封率,并对其进行外观粒径评价,从而制备出凝胶剂。结果：制备的醇质体粒径分布均匀,平均粒径为16.95μm,包封率为74.70%。制得凝胶剂为半透明黏稠状胶体,平均含量为2.17 mg/10 g。结论：本实验制备工艺简单,制得的美洛昔康醇质体凝胶有很好的稳定性,具有较好的应用前景。     

Polymeric ethosomal gel loaded with nimodipine: Optimisation,pharmacokinetic and histopathological analysis

This study was performed with the main objective of formulating and evaluating the potential of ethosomesl gel (Etho gel) to deliver nimodipine (NiM) for cardiovascular disease, a potent water insoluble anti-hypertensive drug via skin to reach the deeper layers of skin. The Box-Behnken design (BBD) was used to optimize the NiM-Eth to determine the impact of the independent and depended variables. The effectiveness of drug entrapment, vesicle size, and cumulative drug release were assessed for the NiM loaded ethosomes and NiM-Eth gel using carbopol 934 as a gelling agent. Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Power X-ray diffraction (PXRD), and scanning electron microscopy (SEM) analysis were performed and analysed their physicochemical characters. Rat abdomen skin was used to investigate drug permeability and deposition. As compared to marketed products, NiM-Eth gel produced an improved drug permeability in ex vivo experiments. The mean AUC₀ to AUC_0-∞ of NiM-Eth gel when compared to oral formulation (Nymalize oral preparation) was found to be increased from 4.1 to 5.9 folds which was found to be resulted from first pass effect. Histophatlogical findings revealed that the maximum amount of NiM penetrated the stratum corneum of the skin and create drug depots in the deep layer. In summary, it can be said that NiM might be successfully prepared in NiM-Eth gel for transdermal drug delivery.     

Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: formulation optimization,in vitro evaluation and preclinical assessment

The present investigation aimed for the development and characterization of ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery and effective treatment against vitiligo. The ethosomes were prepared by central composite design (CCD) and characterized for various quality attributes like vesicle shape, size, zeta potential, lamellarity, drug entrapment and drug leaching. The optimized ethosomes were subsequently incorporated int Carbopol® 934 gel and characterized for drug content, rheological behavior, texture profile, in vitro release, ex vivo skin permeation and retention, skin photosensitization and histopathological examination. Ethosomes were found to be spherical and multilamellar in structures having nanometric size range with narrow size distribution, and high encapsulation efficiency. Ethosomal formulations showed significant skin permeation and accumulation in the epidermal and dermal layers. The fluorescence microscopy study using 123 Rhodamine exhibited enhanced permeation of the drug-loaded ethosomes in the deeper layers of skin. Also, the developed formulation showed insignificant phototoxicity and erythema vis-à-vis the conventional cream. The results were cross-validated using histopathological examination of skin segments. In a nutshell, the ethosomes-based hydrogel formulation was found to be a promising drug delivery system demonstrating enhanced percutaneous penetration of methoxsalen with reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.     

Topical delivery of 5-aminolevulinic acid-encapsulated ethosomes in a hyperproliferative skin animal model using the CLSM technique to evaluate the penetration behavior

Psoriasis, an inflammatory skin disease, exhibits recurring itching, soreness, and cracked and bleeding skin. Currently, the topical delivery of 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) is an optional treatment for psoriasis which provides long-term therapeutic effects, is non-toxic and enjoys better compliance with patients. However, the precursor of ALA is hydrophilic, and thus its ability to penetrate the skin is limited. Also, little research has provided a platform to investigate the penetration behavior in disordered skin. We employed a highly potent ethosomal carrier (phosphatidylethanolamine; PE) to investigate the penetration behavior of ALA and the recovery of skin in a hyperproliferative murine model. We found that the application of ethosomes produced a significant increase in cumulative amounts of 5-26-fold in normal and hyperproliferative murine skin samples when compared to an ALA aqueous solution; and the ALA aqueous solution appeared less precise in terms of the penetration mode in hyperproliferative murine skin. After the ethosomes had been applied, the protoporphyrin IX (PpIX) intensity increased about 3.64-fold compared with that of the ALA aqueous solution, and the penetration depth reached 30-80 μm. The results demonstrated that the ethosomal carrier significantly improved the delivery of ALA and the formation of PpIX in both normal and hyperproliferative murine skin samples, and the expression level of tumor necrosis factor (TNF)-α was reduced after the ALA-ethosomes were applied to treat hyperproliferative murine skin. Furthermore, the results of present study encourage more investigations on the mechanism of the interaction with ethosomes and hyperproliferative murine skin.     

氨甲环酸醇质体的制备及体外评价

目的：制备氨甲环酸醇质体（TA@ES）,并初步考察其体外透皮性能。方法：采用乙醇注入-挤出法制备TA@ES。通过单因素考察和Box-Behnken设计-响应面法对处方进行筛选及优化;按最优处方制备TA@ES,对其进行质量评价,并进行体外透皮试验。结果：优化后的TA@ES处方脂药比为3.20∶1,胆固醇用量为0.62%,乙醇用量为19.37%。制得的TA@ES为类球形,平均粒径为（194.3±4.1）nm,Zeta电位为（-32.2±2.6）mV,包封率为（17.20±0.89）%。体外透皮试验结果表明,与氨甲环酸水溶液相比,TA@ES不仅提高了药物经皮渗透量（4.98倍）,而且还增加了深层皮肤滞留量（1.74倍）。结论：制备的TA@ES能够提高氨甲环酸的经皮渗透量和深层皮肤滞留量,有望成为黄褐斑治疗药物的新载体。     

新型藏药“扎颉俄色”总黄酮醇质体凝胶剂的制备和药效学研究

目的 制备藏药生发复方“扎颉俄色”总黄酮提取物（ZJESF）醇质体及其凝胶剂,并考察其对脱发模型小鼠毛发生长的影响。方法 采用乙醇注入法制备“扎颉俄色”总黄酮提取物醇质体 , 以卡波姆为基质制备“扎颉俄色”总黄酮提取物醇质体凝胶剂并优化制备工艺。 以C57BL/6J小鼠建立动物脱发模型,观察“扎颉俄色”总黄酮提取物醇质体凝胶剂对C57BL6脱发模型小鼠毛发生长及毛发周期的影响。结果 优选的制剂处方和工艺制得了均匀、细腻、稠度适中、涂展性较好的浅黄色半透明状ZJESF醇质体凝胶。其中“扎颉俄色”总黄酮提取物醇质体凝胶外观为淡黄乳状液,平均粒径为（296.6±5.8）nm,Zeta电位为（-14.4±2.3）mv,平均包封率为72.2%。动物实验中醇质体凝胶中与阴性对照组相比,“扎颉俄色”总黄酮提取物醇质体凝胶可加快小鼠生发进程,并可达到阳性对照相似效果。结论 “扎颉俄色”总黄酮提取物醇质体凝胶剂的处方及制备工艺合理可行,质量稳定可控。“扎颉俄色”总黄酮提取物醇质体凝胶剂可诱导小鼠毛囊进入生长期,可促进脱发模型小鼠毛发生长,且具有一定的皮肤毛囊皮脂腺靶向性。     

Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: A comparative assessment

The objective of work was to formulate, evaluate and compare the transdermal potential of novel vesicular nanocarriers: ethosomes and ultradeformable liposomes, containing clotrimazole (CLT), an anti-fungal bioactive. The ethosomal formulation (ET₄) and ultradeformable liposomal (UL) formulation (TT₃) showed highest entrapment 68.73 ± 1.4% and 55.51 ± 1.7%, optimal nanometric size range 132 ± 9.5 nm and 121 ± 9.7 nm, and smallest polydispersity index 0.027 ± 0.011 and 0.067 ± 0.009, respectively. The formulation ET₄ provided enhanced transdermal flux 56.25 ± 5.49 μg/cm²/h and decreased the lag time of 0.9 h in comparison to TT₃ formulation (50.16 ± 3.84 μg/cm²/h; 1.0 h). Skin interaction and FT-IR studies revealed greater penetration enhancing effect of ET₄ than TT₃ formulation. ET₄ formulation also had the highest zone of inhibition (34.6 ± 0.57 mm), in contrast to TT₃ formulation (29.6 ± 0.57 mm) and marketed cream formulation (19.0 ± 1.00 mm) against candidal species. Results suggested ethosomes to be the most proficient carrier system for dermal and transdermal delivery of clotrimazole.     

Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption,photostability, biocompatibility and anti-psoriatic activity

Tretinoin (TRE) is a widely used retinoid for the topical treatment of acne, psoriasis, skin cancer and photoaging. Despite unmatchable efficacy, it is associated with several vexatious side effects like marked skin erythema, peeling and irritation, eventually leading to poor patient compliance. Its photo-instability and high lipophilicity also pose challenges in the development of a suitable topical product. The present study, therefore, aims to develop biocompatible lipid-based nanocarriers of TRE to improve its skin delivery, photostability, biocompatibility and pharmacodynamic efficacy. The TRE-loaded liposomes, ethosomes, solid lipid nanoparticles (SLNs) and nanostructured lipidic carriers (NLCs) were prepared and characterized for micromeritics, surface charge, percent drug efficiency and morphology. Bioadhesive hydrogels of the developed systems were also evaluated for rheological characterization, photostability, ex vivo skin permeation and retention employing porcine skin, and anti-psoriatic activity in mouse tail model. Nanoparticulate carriers (SLNs, NLCs) offered enhanced photostability, skin transport and anti-psoriatic activity vis-à-vis the vesicular carriers (liposomes, ethosomes) and the marketed product. However, all the developed nanocarriers were found to be more biocompatible and effective than the marketed product. These encouraging findings can guide in proper selection of topical carriers among diversity of such available carriers systems.     

盐酸青藤碱醇质体凝胶与脂质体凝胶体外经皮渗透动力学比较研究

目的:比较盐酸青藤碱醇质体凝胶（SHEG）与其脂质体凝胶（SHLG）的体外经皮渗透行为,以期为筛选出较优的盐酸青藤碱（SH）经皮吸收制剂奠定基础。方法:制备SHEG与SHLG;以离体鼠皮为屏障,采用Franz扩散池法对其体外经皮渗透行为进行比较研究。结果:两种制剂的经皮渗透动力学均符合Higuchi方程,即SHLG:Q=27.22t^1/2-16.04（r=0.996 5）;SHEG:Q=33.46t^1/2-19.59（r=0.995 0）,稳态透皮速率J分别为27.22μg·cm^-2·h^-1和33.46μg·cm^-2·h^-1,在经皮渗透24 h后,皮肤内的蓄积量分别为21.05μg·cm^-2和18.95μg·cm^-2,凝胶中的残留量为53.44μg·cm^-2和48.09μg·cm^-2。两种SH制剂比较,以上参数差异均有统计学意义（P<0.05）。结论:与SHLG相比,SHEG在促进药物经皮吸收方面具有更好的效果。