Date of Award

2026

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Abu T.M. Serajuddin

Second Advisor

Bu Pengli

Third Advisor

Ketan D Patel

Abstract

Clofazimine (CFZ), a highly effective antibiotic for leprosy and multidrug-resistant tuberculosis (MDR-TB), with additional activity against cryptosporidiosis, SARS-CoV-2, and cancer, is on the WHO Essential Medicines List. However, no optimally bioavailable CFZ product exists; its only formulation, Lamprene®, was withdrawn from the US market presumably due to poor solubility-driven bioavailability. This dissertation presents a lipid-based formulation (LBF) using lipid digestion products (LDP) to improve clofazimine (CFZ) solubility and enable rapid microemulsion dispersion upon aqueous dilution. The LDP consisted of a 2:1 molar ratio of oleic acid and glyceryl monooleate. Common lipid excipients (glyceryl monooleate, glyceryl trioleate, Tween 80, Kolliphor EL) gave low CFZ solubility (< 15 mg/g), but oleic acid in the LDP achieved ~500 mg/g. This high solubility in oleic acid was leveraged to develop a self-emulsifying drug delivery system (SEDDS), and the final formulation contained a 1:1 w/w mixture of LDP and surfactants, achieving a higher drug loading of 100 mg/g. The developed formulation was dispersed rapidly and completely in simulated gastric and intestinal fluids and showed high cell viability, supporting in vivo safety. Since the unsaturated LDP (oleic acid and glyceryl monooleate) used were liquids, the aforementioned formulation was encapsulated in soft gelatin capsules. To enable tablet dosing, a solid SEDDS (S-SEDDS) was developed via hot-melt extrusion (HME) by combining saturated LDP (myristic acid, glyceryl monomyristate) with unsaturated LDP at a 4:6 molar ratio, along with poloxamer 188 and Kollidon VA64, and extruded at 80°C. CFZ converted to an amorphous form with good powder-processing properties and achieved ~95% release within 2 h at pH 6.8. Both liquid and solid SEDDS caused precipitation of CFZ HCl salt at gastric pH via the common-ion effect, so an enteric coating was used to bypass gastric exposure and ensure intestinal release. Collectively, these findings demonstrate that LDP-based strategies enhance drug loading of poorly soluble, weakly basic CFZ by overcoming conventional lipid excipient limitations and reducing cosolvent dependence. The developed LBFs, as liquid SEDDS and solid SEDDS, formed microemulsions in aqueous media and maintained the drug in a supersolubilized state, demonstrating a formulation strategy broadly applicable to other poorly water-soluble basic drugs.

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