Formulation And Preparation Research Of Palonosetron Transdermal Patch

Palonosetron is a highly effective, highly selective 5-HT3 receptor, used as antiemetic in the chemical and radiative treatment of cancer. Compared with the older 5-HT3 receptor antagonists, palonosetron shows a higher affinity to the 5-HT3 receptors. Moreover, palonosetron possesses a significantly longer half-life (approximately 40 hours), a moderate plasma protein binding of 62%, as well as excellent safety. However, there are only two dosage forms of palonosetron in clinic, injections and capsules. Palonosetron capsule caused gastrointestinal tract side effects and undergo first-pass effect; palonosetron injection formulation produced poor patient compliance. Therefore, a new delivery route is demanded to reduce related side effects and improve patient compliance.Transdermal drug delivery system (TDDS) can continuously provide stable drug delivery for a prolonged period of time, thereby reduce the medication frequency. TDDS can also avoid first-pass effect and gastrointestinal tract side effects associated with oral administration, which will largely improve patient compliance. However, the transdermal administration of palonosetron has rarely been reported. So, the purpose of this study is to develop a transdermal patch of palonosetron.Drug-PSA compatibility study and in vitro permeation study were performed to screen a suitable PSA type for palonosetron. The penetration enhancers were evaluated through in vitro permeation study using hairless mouse. Finally, in vivo pharmacokinetics study was carried out in rats to determine pharmacokinetics characteristics of palonosetron patch with injection formulations as control.Drug-PSA compatibility study results showed that the drug loading capacities of PSA-B, C and E are more than 10%(w/w); palonosetron showed good stability in PSA-B and E, less oxidative impurity was produced than that in other PSAs. However, palonosetron showed better permeability in PSA-D and E than that in other PSAs. Based on above results, PSA-E was determined as the desirable matrix for palonosetron. Further study on penetration enhancers showed that No. ? displayed the largest permeability enhancement of palonosetron, resulting in 2.16-fold higher permeation flux than that without enhancer. In addition, the permeation enhancement of No. ? increased with the increase of enhancer concentration, indicating concentration-dependent of this permeation enhancer. So, the concentration of No. ? in palonosetron patch was determined as 10 wt%, at which the largest permeation flux was obtained. It is found that adding antioxidants can't block the appearance of related substances. But wheather filling nitrogen in mixing process is a major factor of wheather related substances appear. The mixing process, coating process, drying process and packaging process were optimized by preparation reasearch. In vivo pharmacokinetics study in rats showed that MRT0-t following transdermal administration were longer than those after injection administration, and transdermal administration could maintain a relative stable plasma drug concentration for a longer time, avoid the initial high plasma drug level associated with injection.