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" Development and Characterization of Novel Sulforaphane-Enabled Self-Emulsifying Drug Delivery Systems for Taxanes and Curcumin "
Kamal, Mohammad Mostafa
Nazzal, Sami M.
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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1051359
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TL50476
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| Main Entry
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Kamal, Mohammad Mostafa
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| Title & Author
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Development and Characterization of Novel Sulforaphane-Enabled Self-Emulsifying Drug Delivery Systems for Taxanes and Curcumin\ Kamal, Mohammad MostafaNazzal, Sami M.
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| College
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University of Louisiana at Monroe
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| Date
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2019
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| Degree
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Ph.D.
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2019
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| Note
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203 p.
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| Abstract
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The quest for discovering new drug molecules has led to the development of highly lipophilic and low water soluble drug candidates. Poor water solubility of drugs limits their bioavailability, which results in therapeutic failure. Self-emulsifying drug delivery systems (SEDDS) emerged as a promising platform for the delivery of drugs with poor water solubility. SEDDS is a pre-concentrated blend of drugs in suitable oil, and surfactant/co-surfactant blend in which the oil phase serves as a solubilizer for the lipophilic/water-insoluble drugs. While screening for an ideal oil phase, sulforaphane was found to have a high capacity to solubilize a large number of potent drug molecules in significantly viable drug to solubilizer ratio. Sulforaphane (4-methylsulfinybutyl isothiocyanate, SFN) is an oily sulfur-containing isothiocyanate phytochemical derived from cruciferous vegetables, such as broccoli and brussels sprouts, cabbage, and cauliflower. A set of 24 drugs were screened for their solubility in SFN, of which paclitaxel, docetaxel, and curcumin were selected for subsequent SEDDS formulation development, utilizing SFN as a common solubilizer. SEDDS formulations of paclitaxel (PTX) and docetaxel (DTX) with significantly lower excipient content were developed by a high-throughput screening process. SFN-SEDDS formulations were developed utilizing a stepwise screening method that enabled the selection of the most efficient surfactants and co-surfactants to yield transparent microemulsions by microscopic analysis and absorbance data. PTX and DTX are highly effective chemotherapeutic agents against breast and other cancers. The high excipient content in the existing taxane formulations, however, were found to cause a multitude of side-effects. SFN enabled the development of highly concentrated PTX and DTX SEDDS. A highly sensitive isocratic HPLC-UV analytical method was developed and validated per International Conference on Harmonisation (ICH) guidelines for the simultaneous detection and quantification of PTX and SFN. The separation of the analytes was performed with the aid of a reversed phase C18 column at ambient temperature using a 60:40 mixture of acetonitrile and KH2PO4 buffer (pH 5.0) as the mobile phase. PTX and SFN peaks were detected at 202 nm with high resolution without interference from excipients. 98-100% of the injected samples were recovered with relative standard deviation of 0.06-0.68% indicating the suitability of the method for the simultaneous detection and analysis of the molecules in dissolution media. Optimized formulation contained vitamin E TPGS and transcutol. It resulted in the formation of transparent microemulsions (< 20 nm) in water. When tested in vitro against MDA-MB-231 and MCF7 cancer cells by IncuCyte® live cell analysis and CellTiter-Blue® assay, taxane/SFN microemulsions showed similar activity as the commercial taxanes injection solutions. SFN was synergistic with taxanes cytotoxicity only at higher concentrations. SFN-SEDDS formulation was also developed for curcumin (CUR), which was characterized by DSC and FTIR. When tested for CUR release in a controlled dissolution study, more than 95% of the drug was found to dissolve within 10 min in both simulated gastric and intestinal fluids. CUR-SEDDS was subsequently entrapped in solid carriers to produce free-flowing powders. Entrapment of SEDDS into a solid carrier offer several advantages as it combines the features of liquid and solid dosage forms. The suitability of soluplus®, a hydrophilic polymer, as a carrier for the entrapment of CUR-SEDDS by the spray-drying process was investigated. Soluplus® was compared with neusilin® US2, a hydrophobic high-capacity adsorbent as a control. Both carriers produced free flowing powders with high CUR entrapment efficiency. SEM studies confirmed the incorporation of CUR SEDDS, where SEDDS was shown to adsorb on the surface of neusilin® US2 but encapsulate in soluplus®. When filled into capsules and tested for CUR release in water, almost 100% of CUR was dissolved from the soluplus® powder within 150 min and only 55% from the neusilin® US2 based powder. When the powders were compressed into tablets, a slow CUR release was observed over 24 h, which varied as a function of compression force and the percentage of disintegrant used. CUR-SEDDS were also formulated into a flexible film by entrapping the liquid into soluplus® by the solvent casting technique. A 9-run, 2-factor 3-level response surface methodology (RSM) was used to investigate the effect of SEDDS loading and film thickness on the release profile, tensile strength, ultimate elongation, and adhesiveness of the resultant films. Both variables were found to have a statistically significant (p<0.05) effect on tensile strength, ultimate elongation, and adhesiveness. All films, nonetheless, led to a sustained CUR-SEDDS release up to 6 h. Overall, these studies demonstrated the utility of SFN in developing highly concentrated SEDDS for poorly soluble drugs and the efficiency of soluplus® in trapping liquid SEDDS for the formulation of free flowing powder and flexible films. In conclusion, solubilization capacity of SFN was discovered and this property was utilized for developing SEDDS formulations for a number of water insoluble drugs. Soluplus®, a novel amphiphilic polymer was successfully used to solidify liquid SEDDS into solid dosage forms to enhance stability and provide manufacturing advantages.
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| Descriptor
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Pharmaceutical sciences
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Nazzal, Sami M.
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University of Louisiana at Monroe
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