Vyas S P, Kannan M E, Jain Sanyog, Mishra V, Singh Paramjit
Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, MP 470 003, India.
Int J Pharm. 2004 Jan 9;269(1):37-49. doi: 10.1016/j.ijpharm.2003.08.017.
The present study was aimed at preparation, characterization, and performance evaluation of rifampicin-loaded aerosolized liposomes for their selective presentation to alveolar macrophages, that being the most dense site of tuberculosis infection. Egg phosphatidylcholine (PC)- and cholesterol (Chol)-based liposomes were modified by imparting negative charge (using dicetylphosphate, DCP) or by coating them with alveolar macrophage-specific ligands (maleylated bovine serum albumin, MBSA; and O-steroyl amylopectin, O-SAP). The prepared formulations were characterized in vitro for vesicle morphology, mean vesicle size, and percent drug entrapment. Pressurized packed systems based on preformed liposomal formulations in chlorofluorocarbon aerosol propellants were prepared. In vitro airway penetration efficiency of the liposomal aerosols was determined by percent dose reaching the base of the lung, it was recorded 1.5-1.8 times higher as compared to plain drug solution-based aerosol. Percent viability of Mycobacterium smegmatis inside macrophages (in vitro) after administration of drug (in vivo) was in the range of 7-11% in the case of ligand-anchored liposomal aerosols, while it was recorded to be 45.7 and 31.6% in case of plain drug and plain neutral liposomal aerosol (based on PC:Chol)-treated macrophages. Results suggest the preferential accumulation of MBSA- and O-SAP-coated formulations in the lung macrophages, which was further reflected in the periodically monitored in vivo tissue distribution studies. Higher lung drug concentration was recorded in case of ligand-anchored liposomal aerosols and negatively charged liposomal aerosols (based on PC:Chol:DCP) as compared to plain drug and plain liposome-based aerosols. The drug was estimated in the lung in high concentration even after 24h. The drug localization index calculated after 6h was nearly 1.4- and 3.5-fold, respectively, for both ligand-appended liposome-based systems as compared to negatively charged and plain neutral liposome-based aerosolized systems. These results suggest that the ligand-anchored liposomal aerosols are not only effective in rapid attainment of high-drug concentration in lung with high population of alveolar macrophages but also maintain the same over prolonged period of time. The significance of targeting potential of the developed systems was established.
本研究旨在制备、表征和评估负载利福平的雾化脂质体，使其能够选择性地递送至肺泡巨噬细胞，因为肺泡巨噬细胞是结核病感染最密集的部位。以鸡蛋磷脂酰胆碱（PC）和胆固醇（Chol）为基础的脂质体通过赋予负电荷（使用磷酸二鲸蜡酯，DCP）或用肺泡巨噬细胞特异性配体（马来酰化牛血清白蛋白，MBSA；以及O-硬脂酰支链淀粉，O-SAP）包被进行修饰。对制备的制剂进行体外囊泡形态、平均囊泡大小和药物包封率的表征。制备了基于在氯氟烃气雾剂推进剂中的预制脂质体制剂的加压包装系统。脂质体气雾剂的体外气道渗透效率通过到达肺底部的剂量百分比来确定，与基于普通药物溶液的气雾剂相比，其记录值高1.5 - 1.8倍。给药（体内）后巨噬细胞内耻垢分枝杆菌的存活百分比（体外），在配体锚定脂质体气雾剂的情况下为7 - 11%，而在普通药物和普通中性脂质体气雾剂（基于PC:Chol）处理的巨噬细胞中分别记录为45.7%和31.6%。结果表明，MBSA和O-SAP包被的制剂在肺巨噬细胞中优先积累，这在定期监测的体内组织分布研究中得到进一步体现。与普通药物和普通脂质体气雾剂相比，配体锚定脂质体气雾剂和带负电荷的脂质体气雾剂（基于PC:Chol:DCP）在肺中的药物浓度更高。即使在24小时后，肺中药物浓度仍很高。与带负电荷和普通中性脂质体气雾剂系统相比，两种基于配体连接脂质体的系统在6小时后计算出的药物定位指数分别接近1.4倍和3.5倍。这些结果表明，配体锚定脂质体气雾剂不仅能有效地在含有大量肺泡巨噬细胞的肺中迅速达到高药物浓度，而且能在较长时间内保持这一浓度。已确定所开发系统靶向潜力的重要性。
