| Objective: To prepare a naltrexone nasal spray with high bioavailability, fast onset and low or without toxicity.Content and Method: First, the solubility and pKa of naltrexone were determined. Then, the influence of pH on the stability of naltrexone, the air tightness of the dispenser and the precise of spray volume were studied respectively. Then isolated sheep nasal mucous was employed to evaluate the influence of kinds of absorption enhancers and their concentrations on the penetration enhancement effect of the model drug in vitro; "Ex vivo toad palate mucoas method" was used to assay the ciliotoxicity of the model drug and the excipients. Meanwhile, the influence of pH and osmslarity on the ciliary movement was investigated. And mucous membrane irritation test of rabbit eyes was used to estimate physical irritation of the formulation. Next, technique process study was made and a quality specification protocol of naltrexone nasal spray was developed. In the research of formulation stability, the package and storage condition were investigated as well. Finally, in vivo study was carried out with beagle dogs to make pharmacokinetics and bioavailability research on the naltrexone nasal spray.Results: The solubility of naltrexone was about 100mg·mL-1 at acid or neutral condition and 6.7mg·mL-1 at weak base condition. The pKa of naltrexone was 5.78. The naltrexone nasal spray was stable in a pH range from 3.5 to 4.5. The results of transmucoas absorption test and ex vivo toad palate mucosa study showed that a nice enhanced penetration effect was reached with low ciliotoxicity and protection to nasal mucosa when the concentration of the penetration enhancer B was 2.5%. Moreover, PBS of pH4.0 was selected as solvent and 0.5% acetone chloroform as preservative. The established formulation and technique process were confirmed by the quality study of three repeated batches with promising results. Long term storage study under ambient temperature showed that the nasal spray was very stable. Isolated toad palate mucosa study showed the ciliotoxicity of the formulation was low and reversible. Acceptable osmotic pressure was attained with the NaCl concentration from 0.3% to 1.8 due to its little ciliotoxicity. For the same reason, the pH range was preferable from 4 to 10. The result of the mucous membrane irritation test of rabbit eyes revealed the nasal spray hardly causing any mucosa irritation. The results of pharmacokinetic study indicated that nasal spray fit with two compartment model in vivo with Tmax (12.5±2.74)min, about 5 times higher than that of conventional tablets; Cmax (145.32±47.33)ng·mL-1, around 2.5 folds than that of conventional tablets; the relative bioavailability was (148.51±40.6)% compared with conventional tablets.Conclusion: The naltrexone nasal spray developed in this study was confirmed with coherent formulation, controllable quality, repeatable technique process, good stability, little ciliotoxicity, quick absorption and higher relative bioavailability etc., which basically met the aim and requirements of this study.
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