Design And Evaluation Of Granisetron Transdermal Drug Delivery System

Granisetron,a potent selective 5-hydroxytryptamine 3(5-HT3)receptor antagonist,is frequently used to prevent nausea and vomiting induced by chemotherapy(CINV).Domestically,the available dosage forms of granisetron are tablets,capsules and injections.However,the effectiveness of oral delivery of this antiemetic drug may be severely compromised by the extensive hepatic metabolism effect and by the very nausea it is intended to prevent,whereas the i.v.route requires qualified medical personnel and causes discomfort.As compared to the conventional delivery routes,transdermal drug delivery systems(TDDS)is able to eliminate first pass hepatic metabolism and provide sustained drug release for a prolonged period of time.A granisetron transdermal patch named Sancuso(?)was approved by FDA in September 2008.Unfortunately,this preparation is costly and is available only in some developed countries.The object of this work is to design a granisetron transdermal patch in low price,and to evaluate its safety and efficiency.Granisetron free base(GRN-B)was first prepared from granisetron hydrochloride(GRN-H).The formation of GRN-B was demonstrated by differential scanning calorimetry thermogram,and the physicochemical property of granisetron relevant to transdermal delivery was determined.The n-octanol/water partition coefficient of GRN-B extracted by chloroform is 1.39,which makes it a good candidate for TDDS.A diffusion cell consisting of two chambers and excised rabbit abdominal skin were introduced to investigate the permeation behavior of granisetron and to evaluate the potency of different chemical penetration enhancers.It was demonstrated that,the permeability of GRN-B was superior to that of GRN-H,and the donor vehicle isopropyl myristate(IPM)prompted the percutaneous absorption of GRN-B.Among the enhancers in the concentration of 5%(w/w),2-isopropyl-5-methylcyclohexyl heptanoate(M-HEP)produced the highest enhancement effect.Except M-HEP,an inverse linear correlation between the difference in solubility parameter and the enhancement ratio with respective enhancer was raised with a regression r=0.86.Aiming to select a proper pressure sensitive adhesive(PSA),dosage of granisetron and the most potent penetration enhancers,formulation of the patch was screened by the single-factor research method.According to the cumulative amount of GRN-B permeated and the steady-state flux,the optimized formulation was determined to be 5%(w/w)GRN-B,5%(w/w)M-HEP,5%(w/w)IPM and 85%(w/w)DURO-TAK(?)87-9301PSA.Transdermal behavior of GRN-B from the optimized patch was investigated over a period of 168 h across rabbit skin and porcine skin,respectively.Permeation profile of the drug across porcine corresponded to a Higuchi equation with an average flux of(2.60±0.40)?g·cm-2·h-1.The pharmacokinetic studies of granisetron in Bama miniature pigs were conducted,and a LC-MS/MS system was employed for the determination of graniseton plasma level.After i.v.injection,the values of Cmax,AUC0-12 and MRT were(31.8±3.9)ng·mL-1,(31.8±2.1)ng·mL-1·h-1 and(1.79±0.37)h,respectively.When the transdermal patch was applied,the Cmax value decreased to(14.7±5.6)ng·mL-1,AUC0-t value increased to(1.21±0.36)×103 ng·mL-1·h-1 and the MRT was prolonged to(87.8±8.4)h.The plasma level of granisetron declined slowly after patch removal.The observed steady-state plasma concentration of granisetron after transdermal administration(6.74 ng-mL-1)in pigs was comparable with the predicted value(6.14 ng·mL-1)obtained from the in vitro permeation data.This indicates that in vitro experiments with porcine skin may be used for further transdermal drug delivery studies with granisetron.Skin irritation of the gransietron patch in rabbits was estimated by observing erythema and edema of the skin surface.The irritation tests suggested that neither granisetron nor the excipients in the formulation cause safety problem,therefore,the granisetron patch would improve patient compliance.Quality evaluations of the granisetron patch were carried out by tack strength,shear strength,peel strength,drug content and drug release rate studies.These results provided references for the quality standard of the patch.The above findings indicated that the patch for granisetron transdermal delivery was promising in practice and the prospective goal of this investigation was satisfactorily achieved.