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Toxicity Study Of 0.5% Podophyllotoxin-loaded Nanostructured Lipid Carriers On Vaginal Mucosa

Posted on:2020-06-28Degree:MasterType:Thesis
Country:ChinaCandidate:L S LiuFull Text:PDF
GTID:2404330575989515Subject:Dermatology and Venereology
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1.BackgroundThe 0.5%podophyllotoxin tincture(POD-T)is one of the first-line drugs in the guidelline by the World Health Organization(WHO)for the treatment of condyloma acuminate(CA)[1].However,its alcoholic carrier inevitably exerts significant irritation to the mucous membranes and subsequently destroys the natural epithelial barrier of mucous membranes,thereby causing poison of podophyllotoxin(POD)via blood circulation.Additionally,compared to nanostructure lipid carrier(NLC),alcoholic carrier has a poor local targeting of drugs,hence,the drugs cannot be accumulated and the action time is short.Therefore,POD-T is recommended for CA in mucosal areas by the WHO.To combine the pharmacological action of POD and the advantages of NLC,we have modified the drug carrier of POD into POD-NLC,aiming to make it suitable for CA in genital tract,urethra and other mucosal areas.Our team has completed the synthesis prescription optimization,pharmacodynamic studies,in vitro drug release kinetics,drug release stability,targeted distribution of cervical nucosa and pharmacokinetics of POD-NLC.In this study,toxicological test of 0.5%POD-NLC was conducted to provide important basis for the the safety of clinical applications.2.ObjectivesThe study was designed to explore the irritation,acute toxicity and long-term toxicity of 0.5%POD-NLC.3.Materials and methods(1)Irritation assay:A total of 12 New Zealand rabbits were divided into three groups:saline control group,0.5%POD-T group and 0.5%POD-NLC group.Briefly,2ml drugs were daily administered to the vagina.After 10 consecutive days,the animals were sacrificed by anesthesia and the vagina was resected for histopathological examinations to assess and obtain irritation intensity grade by the Eckstein scoring systern.(2)Acute toxicity assay:Twenty SD female rats were randomly assigned into two groups according to body weight:vehicle group and 0.5%POD-NLC group.In brief,rats were vaginally administered with drugs at a dose of 300 times of that in human for multiple times within 24 hours.After 14 days of continuous observation,the vagina was dissected,the organ was weighed,and the organ coefficient was calculated.(3)Long-term toxicity assay:Eighty SD female rats were randomly divided into four groups according to body weight:vehicle group,low-dose POD-NLC group,middle-dose POD-NLC group and high-dose POD-NLC group.Rats in every experimental group were vaginally administered with drugs once a day,which continued for 3 months.At the end of the experiment,blood was collected from 2/3 of the animals in each experimental group,followed by blood routine tests and blood biochemical tests.Subsequently,the animals were sacrificed by anesthesia,organs were dissected and weighed,and the organ coefficient was calculated.The pathological morphology of organ tissues in the control group and the high-dose POD-NLC group were examined.In the case of pathological changes in a certain organ,the specific organ in other groups were correspondingly examined.The remaining 1/3 of the rats in each group were observed for another 2 weeks.During this period,the same procedure was conducted,except that no test substance was given.4.Results and analysis(1)Irritation assay:Eckstein evaluation criteria,recognized by WHO,was used to comprehensively assess the response of vaginal mucosa to drug irritation in each group.As a result,the positive control group(POD-T)minus the negative control group was 10.917<12 points,indicating moderate irritation;the test group(POD-NLC)minus negative control group was 2.417<5 points,suggesting extremely light irritation.(2)Acute toxicity assay:The organ coefficients of lung,heart,thymus,kidney,adrenal glands,lung,spleen,ovary,uterus,and brain were not statistically different between the two groups(P>0.05).(3)Long-term toxicity:There was no statistical significance of behavior and activity,body weight,blood examination and organ coefficient among the control group(vehicle),low-dose POD-NLC(15-fold of clinical dose),middle-dose POD-NLC(30-fold of clinical dose)and high-dose POD-NLC(60-fold of clinical dose),neither was there statistical significance of the above indicators in intra-group comparison at the 13th and 15th week(P>0.05).5.ConclusionsIn this study,we evaluated the toxic effects of POD-NLC through irritation assay,acute toxicity assay and long-term toxicity assay on rodents.As a result,the irritation of 0.5%POD-NLC is very small compared to that of 0.5%POD-T,which would not damage the original structure of vaginal mucosa or lead to serious local toxic side effects.A short-term 300-fold od clinical dose was not likely to affect the system.In addition,there was no statistical significance of behavior and activity,body weight,blood examination and organ coefficient in the long-term administration of 15-fold,30-fold and 60-fold of POD-NLC.Therefore,POD-NLC is speculated to be relatively safe for administration in the vaginal mucosa.
Keywords/Search Tags:Podophyllotoxin, Nanostructure lipid carrier, Irritation, Acute toxicity, Long-term toxicity, Condyloma acuminate
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