Full metadata record
DC FieldValueLanguage
dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.contributor.advisorWong, Wing-tak (ABCT) ; Chow, Ming-cheung (ABCT)-
dc.creatorXu, Liang-
dc.identifier.urihttps://theses.lib.polyu.edu.hk/handle/200/10452-
dc.languageEnglishen_US
dc.publisherHong Kong Polytechnic University-
dc.rightsAll rights reserveden_US
dc.titleDevelopment of a novel nasal spray for rapid prevention of nausea and vomiting induced by chemotherapy or radiotherapyen_US
dcterms.abstractBackground: Nausea and vomiting are commonly and severely debilitating adverse events in cytotoxic chemotherapy and radiotherapy. The management of chemotherapy-induced and radiotherapy-induced nausea and vomiting (CINV and RINV) has improved greatly since the discovery of 5-HT3 receptor antagonists (5-HT3 RAs). The 5-HT3 RAs are regarded as highly effective antiemetic agents and recommended as the first choice to control CINV and RINV. Granisetron is a potent and highly selective 5-HT3 RA, and is effective and well-tolerated for preventing CINV and RINV. It is currently marketed in various dosage forms including oral tablet/solution, transdermal patch, intravenous injection and subcutaneous injection. The onset of antiemetic effects of oral and transdermal dosage forms of granisetron is relatively slow (> 1 hour for oral granisetron and 24 hours for transdermal granisetron). In addition, oral administration of granisetron tablets may be extremely difficult for patients with compromised swallowing capacity or nausea symptoms. Granisetron injection is an invasive dosage form, so patients will suffer unnecessary pains and potential infection due to injection, which is an important issue in those immune-compromised patients. Therefore, it is imperative to develop an alternative dosage form administered via noninvasive route and with rapid onset for better management of nausea and vomiting. Intranasal administration is a noninvasive route for both local and systemic drug delivery. The nasal mucosa is highly vascularized and permeable, which enables drugs to quickly and completely transport across the mucosa and directly enter into the systemic circulation without first-pass metabolism. Granisetron is a small and lipophilic molecule with high water solubility and stability. Therefore it is an ideal drug candidate for intranasal delivery. Purpose: This project aims to develop novel granisetron intranasal spray for rapid prevention of CINV/RINV. Various granisetron bioadhesive formulations will be prepared and optimized, followed by the pharmacokinetics and brain targeting study. Finally, a Phase I clinical trial will be conducted to confirm the safety and efficacy of granisetron nasal sprays as compared to granisetron intravenous injection and granisetron tablet in healthy volunteers. Methodology: In order to develop granisetron nasal spray, several research objectives have to be achieved: (1) to evaluate the feasibility of delivering granisetron via nasal route; (2) to prepare various formulations utilizing bioadhesive technologies and screen the mucoadhesive capabilities basing on the animal studies; (3) to study the pharmacokinetics and brain distribution of granisetron nasal spray solution in SD rats; (4) to evaluate the pharmacokinetics of granisetron and its major metabolite (7-OH granisetron) in Beagle dogs following intranasal administration; (5) to investigate the pharmacokinetics, safety and tolerability of granisetron nasal spray in healthy volunteers.en_US
dcterms.abstractResults: Various bioadhesive formulations were prepared and screened basing on nasal residence time and bioavailability in rats. After intranasal administration of granisetron formulations containing HPMC at different concentrations, the highest bioavailability was achieved when the concentration of HPMC was 0.25%. The Cmax and AUC0-∞ increased in a dose-proportional manner over the dose range of 0.4 to 1.6 mg/kg in rats and 0.5 to 2.0 mg/dog in Beagle dogs after intranasal administration of granisetron formulations. As compared to oral administration, higher Cmax and shorter tmax, as well as improved bioavailability were observed after intranasal administration of bioadhesive formulations. In the brain distribution study in rats, only limited direct nose-to-brain transport was observed following intranasal administration of granisetron formulation. In a pharmacokinetic study in Beagle dogs, rapid and complete absorption of granisetron was achieved after intranasal administration of bioadhesive nasal spray. Meanwhile, the systemic exposure of the metabolite 7-OH granisetron after intranasal administration was approximate 50% lower than that after oral administration. In Phase I clinical study (open-label and parallel-group), the absolute bioavailability of intranasal granisetron at the doses of 0.5, 1.0, and 2.0 mg were 50.4%, 75.5%, and 64.0%, respectively. The intranasal administration of granisetron bioadhesive spray presented more rapid absorption rate in comparison with oral administration of granisetron tablet (Kytril®). A dose-proportional increase in AUCs was observed in subjects after intranasal administration of granisetron nasal spray over the dose range of 0.5 to 2.0 mg. Conclusion: A rapid absorption of granisetron was achieved through nasal route. The granisetron nasal sprays (0.5 mg, 1.0 mg and 2.0 mg) are generally safe and well tolerated in comparison with intravenous and oral administrations of Kytril® 1.0 mg.en_US
dcterms.extent209 pages : color illustrationsen_US
dcterms.isPartOfPolyU Electronic Thesesen_US
dcterms.issued2020en_US
dcterms.educationalLevelPh.D.en_US
dcterms.educationalLevelAll Doctorateen_US
dcterms.LCSHNausea Preventionen_US
dcterms.LCSHVomiting Preventionen_US
dcterms.LCSHCancer -- Chemotherapy -- Complications -- Treatmenten_US
dcterms.LCSHCancer -- Radiotherapy -- Complications -- Treatmenten_US
dcterms.LCSHHong Kong Polytechnic University -- Dissertationsen_US
dcterms.accessRightsopen accessen_US

Files in This Item:
File Description SizeFormat 
991022381951403411.pdfFor All Users1.5 MBAdobe PDFView/Open


Copyright Undertaking

As a bona fide Library user, I declare that:

  1. I will abide by the rules and legal ordinances governing copyright regarding the use of the Database.
  2. I will use the Database for the purpose of my research or private study only and not for circulation or further reproduction or any other purpose.
  3. I agree to indemnify and hold the University harmless from and against any loss, damage, cost, liability or expenses arising from copyright infringement or unauthorized usage.

By downloading any item(s) listed above, you acknowledge that you have read and understood the copyright undertaking as stated above, and agree to be bound by all of its terms.

Show simple item record

Please use this identifier to cite or link to this item: https://theses.lib.polyu.edu.hk/handle/200/10452