| Risperidone(RIS) is a new generation of atypical antipsychotics for schizophrenia, which has been widely applied as the first-line drug in clinic treatment to control the positive and negative symptoms with several advantages such as low dose, reliable therapeutic efficacy, few extrapyramidal side effects and so on. Presently, the available dosage form of RIS are tablets, capsules, orally disintegrating tablets, drops, etc. As the drug is practically insoluble in water, and its liver first pass effect is significant, the oral bioavailability of the drug in humans was relatively low and thus influence its clinical effect. Human nasal mucosal has large surface area with a large amount of vascular and lymphatic capillary. Some drug has rapid absorption and could avoid hepatic first pass effect by nasal administration, at the same time, nasal drug delivery has characteristic of brain targeting. So the nasal drug delivery may be one of the ideal ways of administration for the drug of some central nervous system diseases. Therefore, this paper proposed to develop the drug nasal gels, in order to achieve purposes of fast absorption and acting, high bioavailability, with certain brain targeting and more convenient to use. In addition, the formulation, quality standard, chemical stability, nasal mucosal ciliotoxicity, pharmacokinetics and relative bioavailability of RIS nasal gel were studied.In chapter one, in the pre-formulation study, a sensitive and precise HPLC method with high selectivity for RIS determination was established, and then the chemical stability, interaction between the drug and cyclodextrin derivatives, the phase solubility and octanol-water partition coefficient of the drug were studied under different p H media. In the study of the chemical stability of the drug, the effect of p H values on drug chemical stability and solubility and the determination of the drug solubility in different solvents were inspected, respectively. The result showed that when the p H is less than 10.0, with the p H values increases, the percentage of RIS degradation increases; with the increase of p H, the solubility of RIS decreased obviously, when p H is above 8.0, RIS is hardly dissolved; in the three solvents of the determination, RIS got the highest solubility in propylene glycol. Then the influence of β-CD derivatives hydroxypropyl-β-CD(HP-β-CD) and sulfobutyl ether-β-CD(SBE-β-CD) on the UV spectroscopy of RIS in aqueous solution was detected, the results showed that the ultraviolet absorption of RIS changed significantly along with an increase in the two β-CDs concentration. The absorption intensity of the drug gradually decreased with an increase in the concentration of the two β-CDs, indicating an obverious inclusion effect of RIS with the two β-CDs in aqueous solution. In the study of phase solubility, the effect of the two β-CDs on the water solubility of the drug was investigated under 25℃, 35℃, 45℃, the results indicated that the solubility of RIS increased linearly in three temperatures with increasing two β-CDs concentrations. The experimental results of thermodynamic parameters showed that the Ka values gradually increased with the rise of temperature, ΔG was negative, ΔH, and ΔS were positive. The inclusion process was an endothermic and entropy-driven process, so high temperature was beneficial to the inclusion reaction. The test results of the RIS partition coefficient showed that the P value of RIS in n-octanol-water system was 1.46; When p H values were under 5.0, the P values of RIS in n-octanol-phosphate buffers system were all less than 1; while the p H values were above 5.0, the P values of RIS were markedly increased with increase of p H values.In chapter two, combined physicochemical properties of RIS with human nasal physiological environment, the prescription composition of RIS nasal gel and preparation process were studied. Carbomer 940 was selected to be the gel matrix due to its good adhesion, safe and stable chemical features, no irritation and allergic reaction.According to the research results of chapter one and reference to the common solvents of topical preparation,propylene glycol was used as solvent and humectant, 2,6-DM-β-CD was chosen as solubilizing agent and absorption enhancer which shows strong solubilization ability, chlorobutanol was selected as the preservative because of its broad spectrum of antibacterial activity and it is suitable for using in weak acidic condition. Screening the prescription by orthogonal test, finally the optimum prescription was decided: 0.5% RIS, 0.35%(w/w) of carbomer 940, 20%(v/w) propylene glycol, 0.5% chlorobutanol, 15%(w/w)2,6-DM-β-CD, p H valus of gel was 6.0. Then three batches of RIS nasal gel were prepared for the further study. The content analysis methods for RIS and chlorobutanol in the drug nasal gel were established, respectively. They all accorded with the relevant requirements for RIS and chlorobutanol determination. Finally, the quality evaluation of RIS nasal gel were performed.In chapter three, the chemical stability test was performed. According to “China Pharmacopoeia”2010 edition relevant requirements of gel, studied the stability of nasal gel under high temperature and light conditions, respectively. By examining the appearance, p H value, content and related substance and dissolution test. The result shows, high temperature condition has some certain influence on the dissolution result, light condition show little effect on the preparation. As a result, the preparation should be stored in low temperature. Accelerated test results showed that p H value of preparation increased slightly, related substances also increased, but it did not exceed the main drug peak area of reference solution, the dissolution degree decreased, drug and preservative content was no change significantly.In chapter four, the pharmacokinetic and relative bioavailability of RIS nasal gel after intranasal administration were studied in rats. A precise, specific and sensitive HPLC method for determining the concentration of RIS in rat plasm was established. Compared with oral administration of RIS mixed suspension solution, pharmacokinetic parameters of intranasal administration and intragastric administration as follows: Tmax were(5.00±0.00)min and(30.00±0.00)min, Cmax were(15.15±3.33) μg·m L-1and(3.68±1.39) μg·m L-1, Ka were(31.05±15.52) h-1 and(3.98±1.63) h-1, AUC0-∞ were(12.85±6.65) μg·h·m L-1 and(7.99±4.48) μg·h·m L-1. The data between the two groups had significant difference(P<0.01). The bioavailability of RIS nasal gel was 1608.26%, it is visible that the perparation showed rapid absorption ability and the relative bioavailability of the preparation were increased significantly.In chapter five, the ciliotoxicity of RIS nasal gel was investigated. The isolated and in vivo toad palate mucous membranes were employed as experiment model, studied the toxicity of the drug gel, 2,6-DM-β-CD and gel only containing drug to the cilia, respectively. The isolated toad palate model experiment proved that the drug gel, 2,6-DM-β-CD and gel only containing drug have a certain ciliotoxicity, but their toxicities were reversible. Additionally, in vivo toad palate model study also showed minor ciliotoxicity of the RIS nasal gel. However, the effect was proved to be reversible. |
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