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.
We describe multicomponent chemical analysis of pharmaceuticals using a sample chamber cooled by a cryostat. THz chemical imaging (TCI) measurement at low temperature sharpens spectral peaks and/or shifts peak frequencies, enabling us to determine the distribution of several kinds of pharmaceutical chemicals within a tablet.
In this study, using mesoporous silica for the solubility enhancement of poorly water-soluble drug was investigated. Although the incorporating drug into mesoporous silica is generally performed through the solvent method, the new melting method was proposed in the present study. Fenofibrate, a poorly water-soluble drug, was incorporated into mesoporous silica by solvent method and melting method. The obtained samples were observed by SEM and their physicochemical properties were evaluated by PXRD and DSC measurement. The dissolution and supersaturated property were also investigated. The results from SEM, PXRD and DSC measurement showed that drug could be loaded into pore via the melting method as well as by the solvent method. The drug loaded quantity depended on the pore volume. Drug up to 33% could be incorporated into mesoporous silica and existed in amorphous state. When drug was overloaded or difficulty in incorporation into pore was found, recrystallization of drug occurred at the outer surface of mesoporous silica. From the dissolution test, samples prepared by solvent method and melting method gave the supersaturated drug concentration which sample from melting method showed superior dissolution to the one from solvent method. From this study, drug was efficiently incorporated into mesoporous silica by the melting method which is a simple and solvent-free process, and the aqueous solubility enhancement of poorly water-soluble drug was achieved.
The interaction between FSM-16 and flurbiprofen (FBP) in the mesopores of FSM-16 was investigated by using three types of FSM-16 with different pore diameters, i.e., FSM-16(Oc), FSM-16(Do) and FSM-16(Doc) (pore diameters 16.0, 21.6, 45.0 Å, respectively). Solid dispersions of 30% FBP–70% FSM-16 were prepared by solvent evaporation and sealed-heating of the physical mixture at 100 °C for 6 h. Changes in the molecular state of FBP were investigated using powder X-ray diffractometry, thermal analysis and FT-IR spectroscopy. The changes in pore diameter and specific surface area of FSM-16 systems were investigated by small angle X-ray scattering and nitrogen gas adsorption. Powder X-ray diffractometry and thermal analysis revealed that FBP was adsorbed onto the mesopores of FSM-16(Do) and FSM-16(Doc), leading to an amorphous state, while no change was observed for FSM-16(Oc). Fourier-transformed IR spectroscopy showed a hydrogen bond interaction between the carbonyl groups of FBP and the silanol groups of FSM-16. The pore diameter and specific surface area of FSM-16 in solid dispersions decreased due to the adsorption of FBP. Improved dissolution of FBP from solid dispersions prepared by the evaporation and the sealed-heating methods was observed in comparison with FBP crystals.
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.
