| Nalmefene hydrochloride (NMF) is a selective narcotic antagonist. It has been widely applied in clinic treatment of anaethetic and alcoholism, shock, opioid detoxification and so on. It was considered to be effective while has few side effects. Presently, the available dosage form of NMF is injection which is mainly used in domestic and aboard clinical treatment, while NMF tablet is undergoing the clinical phaseⅢat present. Intravenous administration of NMF needs special environment and the patients have to suffer from the injury of injection. Tablet takes on action slowly so it is not suitable for emergency use. In this paper, NMF is chosen as a model drug to develop a nasal drug delivery system which aiming to take on action quickly and to rescue opioid overdose and alcoholism. In this paper, the pharmaceutics, toxicity, pharmacokinetics and pharmacodynamics aspects of NMF nasal delivery system were studied.In the beginning of pre-formulation study, a sensitive and precise HPLC method with high selectivity for NMF determination was established, and then the stability and octanol-water partition coefficient were studied which were related to formulation research. In the stability study of NMF solution, the effect of solution pH value, ionic strength and HP-β-CD were investigated. The study on the effect of pH value indicated that NMF's stability depended on the pH value of the solution, and the stability of NMF declined with the increasing of pH value. The study on the effect of ionic strength of the solution showed that the NMF concentration of samples didn't change under 60℃after five days, which meant that the ionic strength had little relation to the stability of NMF. The study on HP-β-CD indicated that HP-β-CD can affect the stability of NMF under certain conditions. The octanol-water partition coefficient study showed that the octanol-water partition coefficient of NMF was depending on the pH value of solution and increased with the pH value increases. When the pH value of the solution was less then 6, NMF was mainly ionic and distribute in the water phase. Finally, the drug permeability across different regions of the ovine nasal mucosa was investigated, thus established the foundation for the permeability study in vitro.In chapter two, the NMF nasal delivery system was developed and studied. Firstly, based on the findings we got in chapter one, middle turbinate mucosa was chosen as the in vitro penetration model for the screening of absorption enhancers. The model mentioned above was employed to screening a enhancer within HP-β-CD,DM-β-CD,α-CD and SEM-β-CD. As a result, HP-β-CD showed the highest enhancing ability. Then the enhancement of HP-β-CD under concentrations of 1%, 3%, 5% were studied, and the enhancement was found to be increasing with concentration of HP-β-CD. Since the package of NMF nasal spay was multi-doses, chlorbutanol was selected as the bacterial inhibitor according to the references. The effect of drug concentration and solution pH value on the NMF nasal absorption was carried out by employing in situ recirculation method, furthermore, the NMF nasal absorption kinetics was also evaluated. It implied that the octanol-water partition coefficient had correlation to the nasal absorption of NMF. Based on former studies, the preliminary formulation was presented, and the quality of two sprayers was studied. One of the sprayers was chosen for the package of NMF nasal spray, and then the quality evaluation and stability test were performed.In chapter three, the toxicity of dosage was researched extensively. Firstly, the isolated toad palate was employed as experiment model to investigate the influencing factors on ciliotoxicity, it was found that osmotic pressure, pH value, HP-β-CD and excipient solution had effect on the lasting time of ciliary movement, and the cilia from the toxicity of chlorbutanol could be protected by HP-β-CD. The protecting mechanism of HP-β-CD was investigated and the effect of HP-β-CD on the bacteriostatic action of chlorbutanol was also discussed. The bacteriostatic action of chlorbutanol solution decreased with the increasing concentration of HP-β-CD, but when the concentration of HP-β-CD was below 3%, it had little effect on the bacteriostatic action. Furthermore, the in situ toad palate and nasal local irritation test, which are more similar to in vivo situation, were used to investigate the toxicity of NMF nasal spray. In this chapter, several toxicity tests were performed for deeply investigating the toxicity of model drug, excipients and formulation. According to the results of toxicity research, the influencing factors of the toxicity of NMF nasal spray were determined and the final formulation was found to be safe and had no toxicity.In chapter four, the pharmacokinetics of NMF after administered through different routes (i.e. intravenous, intramuscular and nasal delivery) were studied. HPLC method for determining the concentration of NMF in rabbit plasm was established. The Cmax and bioavailability of three routes were compared, and it was found that NMF nasal delivery had relative high bioavailability and would take action quickly. Besides this, the pharmacodynamics of NMF for antialcoholism was discussed. The pharmacodynamics study was accomplished to compare the intramuscular route with nasal route, and the effect of NMF solutions with three different concentrations i.n. were evaluated in the test. |
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