| Studies have shown that nearly 100% of large molecular drugs and 98% of small molecular drugs can not penetrate across the blood-brain barrier (BBB). Drugs will bypass or easily penetrate the BBB and target to the brain through novel administration routes or by new drug delivery systems respectively, which has important meaning to improve the effect of treatment in diseases of central nervous system (CNS).Just because of the BBB. many chemotherapeutics have not been applied to treat brain tumors primary or metastatic. Raltitrexed (RTX), a new anticancer drug put into market in 1996, has never been used to treat brain cancer primary or metastatic due to its poor penetration through the BBB, although it has been demonstrated effective to many kinds of cancers already.This dissertation will study the brain targeting of RTX after its nasal administration and incorporating into SLN respectively, utilizing the new administration route of nose and the new drug delivery system of SLN. Study of RTX's brain targeting from this two aspects are innovations worldwide.Chapter 1, Preformulation study of RTX, including stability and solubility study, has been done. A sensitive and precise HPLC method with high specialty for RTX determination has been established, which is suitable for not only RTX content determination, but also its stability study. Stability study of RTX in solution demonstrated that RTX's stability depended on the pH of solution. RTX's stability increased as the pH of the solution increased from 2.0 to 12.0. Antioxidant sodium hydrosulphite in 0.1mol.L-1NaH2PO4 buffer of pH 8.0 at a concentration of 0.2% also increased RTX's stability. Solubility study of RTX showed that its solubility increased linearly with the concentration of HP-β-CD in distilled water, 20% HP-β-CD increasedRTX's solubility of 1500 times more than distilled water alone did. While in 0.1 mol.L"1NaH2PO4 buffer of pH 8.0, RTX's solubility was increased of 2000 times more than that in distilled water alone, and adding HP-(3-CD into 0.1 mol.L'Nal-bPC^ buffer of pH 8 0 didn't increase RTX's solubility any more because RTX and HP-P-CD were not able to form into inclusion under this condition. After studies above, the main factors affected RTX's stability and solubility were found, which made a base for RTX's formulation and techniques study.Chapter 2, Brain targeting of RTX after its nasal administration was thoroughly studied. Formulation and preparation techniques of RTX's nasal drug delivery system for brain targeting were optimized by formulation and techniques study, a reasonable formulation and feasible techniques were obtained. A sensitive and precise HPLC method with high specialty for RTX determination in both plasma and brain tissues of rats has been established, which could be applied to pharmacokinetic study of RTX in plasma and distribution study of RTX in brain tissues of rats. Brain targeting of three different formulations of RTX's nasal drug delivery systems were evaluated in rats, all of the three formulations demonstrated significant brain targeting tendency following nasal administration compared with intravenous administration, and the rank orders of targeting potential in brain tissues from high to low were olfactory bulb (OB), olfactory tract (OT), cerebrum (CR) and cerebellum. Both 5% HP-p-CD and 5% DM-p-CD in formulations of RTX's nasal administration increased RTX's brain targeting potential. Finally, nasal mucosa cilia toxicity were evaluated by toad palate method in vitro, results showed that RTX itself did have some cilia toxicity for nasal mucosa, but both 5% HP-P-CD and 5% DM-P-CD decreased the toxicity significantly.Chapter 3, Brain targeting of RTX solid lipid nanoparticles (SLN) were evaluated in mouse after intravenous administration. Formulation and preparation techniques of blank SLN were optimized by orthogonal design using average diameter of SLN as an index, the blank SLN with average diameter of 120nm were obtained. RTX-loaded SLN with a narrow particle size distribution and good surface morphology were also prepared, the entrapment efficiency of RTX-loaded SLN was about 27%. Compared...
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