Preparation And Pharmaceutical Application Of Palmatine-phospholipid Complex

Palmatine, one of the primary ingredients of Common Fibrauea Stem, is an isoquinoline quaternary ammonium alkaloid, and has been considered as the standard component of Fibrauea Tablets in the latest edition of Chinese Pharmacopeia. Many pharmacological activities have been reported, such as antibiotic activity against bacteria, fungi and viruses, and enhancing immunity. However, Fibrauea presents a very poor oral bioavailability, as far as we are concerned, which may be due to its extremely low lipid solubility. Therefore, the aim of this project is to find a simple and feasible method to increase lipid solubility of Fibrauea, so that it can be easily absorbed after oral administration with a proper lipid/water distribution coefficient.Phospholipid, an amphiphilic material and one of the important components of biological cell membrane, plays a very important role in the activities of cells. Considering phospholipid is an endogenetic agent, numerous novel drug carriers based on phospholipids are investigated extensively, especially Chinese medicine research of phospholipid-complex. Thus, Fibrauea combining with phospholipid would be a rational method to increase lipid solubility of Fibrauea due to the amphiphilic character of phospholipids.First, Palmatine was extracted from Fibrauea Stem and purified using macroporous adsorptive resins (purity higher than95%). Palmatine-phospholipid complex was prepared in aprotic solvent. Influence of material ratio、reation temperature、concentration of reactants、solvent and reaction time on the quality of product was investigated. Formation of phospholipid complex was certified by differential scanning calorimetry (DSC), infrared scanning (IR), ultraviolet scanning (UV) and X-ray diffraction (XRD). Solubility study showed that n-octanol solubility of Palmatine-phospholipid complex was about15folds higher than that of Palmatine.Then, oral bioavailability was studied by intragastric administration of Palmatine-complex suspension and Palmatine aqueous solution to S.D. rats. After oral administration the peak plasma concentration (Cmax) of Palmatine given by the complex was31.69±6.20ng/ml which was much higher than that of Palmatine sample (Cmax=19.8±5.30ng/ml), with Tmax of3.2±1.09h,2.8±0.98h and AUC of392.7±61.9and215.4±43.6μg/L*h, respectively. And the relative bioavailability (F) reached182.31%.In conclusion, with regard to the water soluble drugs with low oral bioavailability, combining them with phospholipid would be effective in increasing lipid solubility and even enhancing bioavailability after preparation of phospholipid. It provides a new and potent platform for solving the problem of low bioavailability of this kind of drugs.