Electronic Theses and Dissertations

Date of Award


Document Type


Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Michael A. Repka

Second Advisor

Mitchell A. Avery

Third Advisor

Seongbong Jo

Relational Format



Delta-9- Tetrahydrocannabinol (THC) is the primary active ingredient of the plant Cannabis sativa (marijuana), responsible for the majority of the pharmacological effects. The most promising clinical applications of THC approved by the Food and Drug Administration (FDA) are for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of AIDS patients suffering from anorexia and wasting syndrome. The only dosage form currently approved by FDA is an oral, soft gelatin capsule (e.g. Marinol®). In addition, orally administered THC from Marinol® has shown slow and variable absorption due to low oral solubility and first pass metabolism. Our strategy towards developing THC transmucosal formulations involved development of hydrophilic prodrugs of THC and solubilization and stabilization of prodrugs in oral formulations. In the present study, the hemisuccinate ester of THC (THC-HS) has been investigated for its potential to form inclusion complexes with modified synthetic beta-cyclodextrins (CDs). The formation of 1:1 inclusion complexes of THC-HS with random methylated beta-cyclodextrin (RAMEB) and 2-hydroxypropyl beta-cyclodextrin (HPBCD) was demonstrated by an AL type curve with the slopes less than unity by the phase solubility method. We evaluated the effect of RAMEB and HPBCD on chemical and enzymatic stability and in vitro permeation across excised buccal mucosa of THC-HS. There was a significant reduction in chemical hydrolysis of complexed prodrug as compared to free prodrug. RAMEB afforded better stability profile and lower degradation rate constants as compared to HPBCD at all the pHs tested and in enzymatic conditions too. In vitro permeation experiments demonstrated almost 63-fold increase in the permeability of THC-HS across excised buccal mucosa, in the presence of RAMEB as compared to the surfactants. Lyophilized solid dispersions of THC-HS with RAMEB and HPBCD were evaluated for their stability and drug release characteristics. RAMEB proved superior to HPBCD in enhancing the stability of THC-HS in solid dispersions as well as the rate of release of the prodrug from the solid dispersions. Finally design of experiments approach was implemented by proposing a 23 factorial design to identify critical formulation variables required in the development of transmucosal polymeric films of THC-HS with enhanced solubility and stability.





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