Design And Evaluation Of Palonosetron Transdermal Drug Delivery System

Palonosetron is a new 5-HT₃ receptor antagonist approved by FDA for the treatment of delayed nausea and vomiting in 2003.It has a longer half-life and higher affinity and more advantages in preventing acute and delayed vomiting than the first-generation 5-HT₃ receptor antagonists.At present,the commercial preparations of palonosetron are mainly injections and capsules.However,the administration of the injection is inconvenient and its compliance is poor.Multiple injections are likely to cause phlebitis.Oral capsules are not suitable for administration in treating vomiting and are not good for patients who have difficulty swallowing.Transdermal patches show good advantages in terms of convenient administration,maintenance of long-term stable blood concentration and improvement of patient compliance.Previous studies examined the basic prescription of palonosetron transdermal patch,but the cohesive force of the selected pressure-sensitive adhesive was poor,and cold flow phenomenon would occur.Therefore,this study re-designed,optimized and evaluated the palonosetron transdermal drug delivery system to ensure the feasibility of transdermal drug delivery.Firstly,this study performed a methodological validation of the analysis methods of palonosetron transdermal patches to ensure the reliability of the assay.The experimental results showed that the two HPLC methods for the substance and content had good specificity and system applicability.And there was a good linear relationship in a certain concentration range.The sensitivity was high,the precision and accuracy were good,and the analysis methods were proved to meet the detection requirements.Secondly,this study screened out the appropriate drug-loading matrix by examining the adhesion of acrylate pressure-sensitive adhesives PSA-1,PSA-2 and PSA-3 and the stability of the drug in pressure-sensitive adhesives.The experimental results showed that PSA-2 had suitable molecular weight and viscosity,strongest cohesive force,slightly lower peel strength,and better stability of the drug in PSA-2.Therefore,PSA-2 was selected as the drug-loading matrix for transdermal administration of palonosetron.However,in the in vitro permeation experiment,it was found that the penetration rate of drug in PSA-2 was significantly slower than that in PSA-1,so the release and permeation behavior of the system was optimized by adding polyacrylic resins.Through the influencing factors experiment and in vitro permeation experiment of the rat,it was found that the drug had good stability in the patch with polyacrylic resin A and high cumulative penetration rate at 48 h.Therefore,polyacrylic resin A was selected to optimize the system.Then,the content of polyacrylic resin A was investigated,and it was found that the rate of drug permeation increased with the increase of polyacrylic resin A content.When polyacrylic resin A was added to 20 wt%,the penetration rate was not significantly different from those of 30 wt%.Considering that the more the polyacrylic resin A was added,the stickiness of the patch would decrease,so the content of polyacrylic resin A of 20 wt%was used.Finally,the optimized palonosetron transdermal drug delivery system was evaluated by human skin in vitro permeation experiments and in vivo pharmacokinetic experiments.Through human skin in vitro permeation experiments,it was found that the cumulative penetration rate of the optimized system was more than 70%at 120 h and had good in vitro penetration performance.The results of rat pharmacokinetic studies showed that the patch group had longer MRT_（0-t）than the injection group,and the bioavailability was about 33%.Therefore,the results indicated that the palonosetron transdermal drug delivery system had the feasibility of transdermal administration.