Supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) has recently been utilized to enhance the oral absorption of poorly water-soluble drugs. S-SMEDDS forms drug-incorporated microemulsions (MEs) during aqueous dispersion with the formation of drug supersaturation in the bulk water phase. However, the liquid–liquid phase separation (LLPS) behavior of the supersaturated drugs within MEs has not been well studied. This study investigated the impact of S-SMEDDS components on the LLPS of the supersaturated drug and the achievable supersaturation level of the drug in MEs. Fenofibrate (FFB)-loaded S-SMEDDS formulations composed of different oils, Labrafil M 1944 CS (M1944) and Labrafac PG (PG), were prepared and dispersed into water to form MEs (M1944 ME and PG ME). Cryo-TEM measurements revealed the coexistence of swelling micelles and nanosized FFB-rich droplets in highly FFB-loaded MEs, indicating that FFB underwent LLPS even in the MEs. The FFB-rich droplet size was significantly reduced in PG ME. NMR-based quantification of the solubilized FFB in swelling micelles and phase-separated FFB revealed that apparent amorphous solubility of FFB increased with increasing M1944 components in MEs, while that was almost constant regardless of PG contents. On the other hand, PG was largely partitioned into the FFB-rich phase, resulting in the reduction of the chemical potential of FFB in the FFB-rich phase and the maximum free FFB concentration in the bulk water phase. The mixing of PG with the FFB-rich phase would work to maintain the FFB-rich droplet as a smaller size. Meanwhile, M1944 was minimally distributed to the FFB-rich phase, keeping the maximum supersaturation level of FFB. This study highlights that the impact of S-SMEDDS oil components on the physicochemical properties of the drug-rich phase formed via LLPS and achievable drug supersaturation should be considered when designing S-SMEDDS formulations to enhance drug absorption.
Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate.
Cyclodextrin (CD) has been widely used as a solubilizing agent for poorly water-soluble drugs. In the present study, the effect of CD on the amorphous drug solubility and the maximum thermodynamic activity of the drug in the aqueous phase when the drug concentration exceeded the liquid–liquid phase separation (LLPS) concentration was investigated using three chemically diverse CDs, β-cyclodextrin (β-CD), dimethyl-β-CD (DM-β-CD), and hydroxypropyl-β-CD (HP-β-CD). The amorphous solubility of ibuprofen (IBP) increased substantially linearly with the increase in the CD concentration due to IBP/CD complex formation. Surprisingly, although the crystalline solubility of IBP in the β-CD solution reached a plateau at β-CD concentrations above 3 mM (BS-type solubility diagram) because of the limited crystalline solubility of the IBP/β-CD complex, the amorphous solubility of IBP increased linearly even when the β-CD concentration was higher than 3 mM. The amorphous solubility of IBP in CD solutions was influenced primarily by the phase separation of the IBP-supersaturated solution to the aqueous phase and the other phase mainly composed of IBP, namely, the IBP-rich phase, via LLPS. NMR spectroscopy revealed that DM-β-CD was distributed into the IBP-rich phase when the IBP concentration exceeded its amorphous solubility, while β-CD and HP-β-CD showed minimal mixing with the IBP-rich phase. NMR diffusometry showed that the maximum free IBP concentration was reduced in the DM-β-CD solution compared to that in the buffer. The mixing of DM-β-CD with the IBP-rich phase reduced the chemical potential of IBP in the IBP-rich phase, which in turn reduced the maximum thermodynamic activity of IBP in the aqueous phase. In contrast, the maximum free IBP concentration was unchanged when β-CD or HP-β-CD was present. The hydrophobic nature of the DM-β-CD substituent may contribute to its partitioning into the IBP-rich phase. The present study highlights the impact of CD on the maximum thermodynamic activity of drugs as well as the apparent amorphous solubility of the drug. This aspect should be considered for improving the effective absorption of poorly water-soluble drugs.
