pH-sensitive lyotropic liquid crystal beads designed for oral zero-order extended drug release

The present study introduces a novel formulation approach for utilizing Lyotropic Liquid Crystals (LLCs) as sustained oral delivery systems. For this purpose, a novel bottom-up fabrication process was developed, enabling the casting of LLC beads with precise control over their diameter. Predetermining the effective diffusional interfacial surface of the beads enables regulation of the release rate of solubilized drugs from the LLCs. To prevent bead coalescence throughout shelf life, the LLC beads are embedded in a heat-sensitive gelatin-chitosan coacervate. Additionally, the study focuses on LLC beads formulated as pH-responsive systems, designed to attenuate the Higuchian primary diffusional burst in a gastric environment while enhancing the release of the solubilized load at an elevated pH (6.4).

To demonstrate the applicability of the pH-responsive systems, the LLC beads were loaded with a lipophilic low water solubility (< 5 µg/mL) model drug, Celecoxib (CLXB). Although the water solubility of CLXB is not pH dependent, the Higuchian release constant of CLXB increased from 9.31 at pH 1.5 to 15.03 at pH 6.4. The pH dependency of CLXB release was achieved by the co-solubilization of additional compounds in the LLC structure, creating a pH-dependent environment that influences both the LLC structure and the release of the co-solubilized compounds. The enhanced release of CLXB in an elevated pH environment enables gaining a zero-order (R² > 0.99) sustained release profile extending beyond 10 h in a release medium simulating the gastrointestinal (GI) tract environment.

Additionally, the study investigated the association between the release of co-solubilized compounds and the micellar structure using techniques such as small-angle X-ray diffraction, nuclear magnetic resonance, and electron paramagnetic resonance. The results revealed a co-dependent relationship between the release of lipophilic compounds and changes of the LLC's curvature at different pH levels, suggesting that a compensatory mechanism operates between these two processes. These insights, combined with the innovative bottom-up fabrication method for LLC beads, provide valuable tools for controlling the release of lipophilic compounds from LLCs and for enhancing their effectiveness as controlled oral delivery systems.