Development of Pharmaceutical Additives-Evaluation of Protein and Polysaccharide Hydrolysates as Carrier to Enhance Absorption Rate of Drug

蛋白质和多糖如水溶性明胶、蛋清蛋白、酪蛋白水解物、低分子壳聚糖和海藻酸盐是各种药物制剂中首选的药物载体。然而，使用天然聚合物改善药物的溶出和吸收还没有得到充分的研究。因此，本研究旨在探讨酪蛋白水解物、蛋清蛋白等天然聚合物作为增溶剂改善难溶药物吸收的可能性。1)利用腐植酸酶和Na2S从水牛的角和蹄中制备了两种碎裂角蛋白(FKS)，并考察了它们在小鼠体内的理化和生物药理性质。FKS的全身急性毒性明显低于超氧化物歧化酶。在血浆中，酶解角蛋白的速度很慢，但在肝和肾的匀浆中，它的Hydr…略快一些。更多的溶解。相反，碎裂的明胶在所用的任何介质中都没有被水解。2)在蛋清的存在下，dl-a-生育酚(VE)的溶解度增加了300倍。卵白蛋白固体分散体中VE的表观溶出度明显高于单独VE。口服蛋清蛋白固体分散体，尤其是含有肉豆蔻酸的蛋清蛋白固体分散体后，VE的平均血药浓度显著高于单独给药。3)用酶解酪蛋白制备了酪蛋白A(平均肽长3.3)和酪蛋白B(平均肽长17.4)两种酪蛋白水解物，并考察了它们对药物体外溶出度和口服生物利用度的影响。三种药物(双氯芬酸、安定、强的松龙)与酪蛋白A、B混合捏合后的体外溶出行为较单用药物显著改善。血药浓度-时间曲线表明，强的松龙在酪蛋白A捏合液和强的松龙溶液中均能迅速完全吸收。此外，与强的松龙粉相比，强的松龙与酪蛋白B捏合的混合物在给药后1小时内更难被吸收。较少

Protein and polysaccharides such as water-soluble gelatin, egg albumin, casein hydrolysate, low molecular chitosan and alginate are the preferred carriers of drugs in various pharmaceutical formulations. However, improvents of the dissolution and absorption of drugs using natural polymers have been not fully studied. Thus, the present study was undertaken to investigate the possible use of natural polymers such as casein hydrolysate, egg albumin as solubilizing agents to improve the absorption of poorly water soluble drugs. The results obtained here are summarized as follows :1)Two types of fragmented keratin (FKs) were prepared from buffalo horn and hoof using savinase and Na_2S,and their physicochemical and biopharmaceutical properties were examined in mice. The systematic acute toxicity of FKs was significantly lower than that of superoxide dismutase. In plasma, enzymatically fragmented keratin was hydrolyzed slowly, but in liver and kidney homogenates it showed slightly faster hydr … More olysis. In contrast, fragmented gelatin was not hydrolyzed in any of the media used here.2)The solubility of dl-a-tocopherol (VE) was increased by 300-fold in the presence of egg albumin. The apparent dissolution rate of VE from solid dispersion with egg albumin was markedly enhanced in comparison with VE alone. The mean serum levels of VE following oral administration of egg albumin solid dispersions, especially egg albumin solid dispersion containing myristic acid, were significantly higher than those of the drug alone.3)Two types of casein hydrolysates, casein A (mean peptide length 3.3) and casein B (mean peptide length 17.4) were prepared by the enzymatic hydrolysis of casein, and their effects on in vitro dissolution rates and oral bioavailability of drugs were evaluated. The in vitro dissolution behavior of the kneaded mixture of three drugs (diclofenac acid, diazepam, and prednisolone) with caseins A and B were significantly improved compared to the drugs alone. The plasma concentration-time profile showed that prednisolone was completely and rapidly absorbed from the casein A kneaded mixture as well as the prednisolone solution. In addition, prednisolone in the kneaded mixture with casein B was more difficult to absorb up to 1 hr after administration in comparison to prednisolone powder. Less