| Objective:Dexmetomidine（DEX）is a highly selectiveα~2-adrenoceptor agonist with sedative,analgesic and anti-anxiety effects.It was first approved to market in FDA in1999.It is widely used in sedation,preoperative auxiliary anesthesia and anti-anxiety in critically ill patients.At present,there are only injections on the market at home and abroad,and the injection is poorly tolerated to patients,especially in children.This study intends to develop a new way of administration of dexmedetomidine,which can be absorbed quickly and take effect quickly,so as to achieve an ideal sedative effect.it is suitable for short-term sedation in diagnosis,examination and therapeutic operation of children and adolescent patients.Methods:Firstly,the physical and chemical properties of dexmetomidine were studied,and the HPLC analysis method of dexmetomidine content and related substances was established,and then according to the physical and chemical properties of dexmetomidine and the characteristics of each mucosal drug delivery system,the kinds of excipients were selected and the compatibility test of raw materials and excipients was carried out.The formulation of each mucosal administration preparation of dexmedetomidine was drawn up,the prescription was optimized,and the quality study,in vitro evaluation and in vivo pharmacokinetic study were carried out.Results:A HPLC method for the determination of dexmetomidine and its related substances was established and verified by methodology.the method is simple,accurate,sensitive and specific.Through the properties and compatibility tests of raw materials and excipients,rectal gel was determined to be rectal gel,which was composed of DEX,HPMC,propylene glycol and water;oral administration was composed of oral spray,which was composed of DEX,pH regulator a,pH regulator b,bacteriostatic a,taste correction and water;and nasal delivery preparation was nasal spray,which was composed of DEX,bacteriostatic c,sodium hydroxide,appropriate amount of sodium chloride,and water.The best prescription dosage was determined by laboratory small-scale test,and the influence factor test was carried out.through the influence factor test,the mucosal administration preparation of DEX was stable under the condition of high temperature 60℃and light（4500±500lx）,and the content and related substances were qualified.Through the pharmacokinetic test in rats,the results showed that the absorption effect was rapid after nasal administration,the Tmax was only 5 min,while the overall absorption of rectal administration was less,and the systemic exposure was very low.Through the pharmacokinetic test in beagle dogs,the results showed that the Tmax,Cmaxand AUC were 15 min,4.43±1.19 ng/mL and 8.92±2.07h ng/mL;after intranasal administration,respectively.After oral spray was administered through buccal mucosa and sublingual mucosa,the Tmax,Cmax and AUC of buccal mucosa were60 min,2.87±0.69 ng/mL and 7.99±1.77 h ng/mL,respectively.The Tmax,Cmax and AUC of sublingual mucosa were 60 min,2.70±0.41 ng/mL and 7.01±2.09 h ng/mL,respectively.Conclusion:This study provided a basis and prescription basis for the development of various mucosal drug formulations through pharmacological studies.Through animal pharmacokinetic tests,the mucosal absorption of dexmedetomidine was studied and compared,and dexmedetomidine was found.Nasal cavity absorption is the most complete and rapid,followed by the cheek and sublingual mucosa,and the rectal mucosa is basically not absorbed.Therefore,the development of rectal mucosa preparation is difficult,it is necessary to screen the appropriate absorption promoter.Although the cheek and sublingual mucosa are absorbed more slowly than the nasal mucosa,there is no significant difference in AUC,and both can achieve the desired anesthetic effect.Therefore,the development of dexmedetomidine nasal spray and oral spray is of great significance for the clinical short-term sedation of pediatric patients. |
