Studies On Intranasal Spray Of Ketamine Hydrochloride

Ketamine hydrochloride (KET-HC1) is a kind of new nonbarbiturate having anaesthesia and analgetic substance. The history of clinical application has exceed for 30 years. Since KET-HC1 has some special properties such as good stability and rapid onset compared to other anesthesia, it has been applied under various clinical conditions. The main dosage forms of KET-HC1 used on domestic clinical practice is injection, however, oral liquid is also performed.In recent years growing attention has been paid to the nose as an alternative route of administration for systemically active drugs, which are poorly absorbed orally or extensively metabolised in the gastrointestinal tract itself or are subjected to first pass metabolism in the liver. The nose is well suited for the absorption of drugs since it has large epithelial surface area available due to numerous microvilli. Furthermore, the subepithelial layer is highly vascularized and venous blood from the nose passes directly into the systemic circulation shortcutting the liver.Because KET-HC1 is mainly applied to children in clinical, in order to facilitate the administration, increase the patients' compatibility and decrease the fear psychology of injection for children, research on nasal spray of KET-HC1 by nasal administration has been carried out in this paper.In this paper we prepared KET-HC1 nasal spray as an intranasal given dosage form to avoid first pass metabolism and prolong the residence time in the nasal cavity in attempt to get high bioavailability.Based on the research of general characteristics of KET-HC1, We studied transmucosa absorption of KET-HC1. It was concluded that KET-HC1 had good inherent absorbent quality through nasal mucosa. We investigated the effects of pH value and permeation enhancers on transmucosa of KET-HC1. It was showed that the absorption was rising with the increases of pH. pH value of 7 was decided to be used for the formulation and EDTA is selected for permeation enhancer. We studiedthe nasal mucosa of two species. The permeation coefficients of dog nasal mucosa is very larger than those of rabbit.The formulation of KET HCl spray was optimized by orthogonal design experiment.The result of ciliotoxicity study appeared that this preparation had no ciliotocity.The pharmacokinetics of intranasal administration of KET-HC1 and intravenous administration of KET-HC1 solution were performed on 6 rabbits in an open randomized crossover manner. The drug plasma concentrations were determined by HPLC. The concentration time curves conformed to 1-compartment model with a first-order absorption. Tmax and Cmax was 2.83 min and 69.07 ng ml-1 respectively. The absolute bioavailability of KET HCl was 42.29 %.