Liquid–liquid phase separation drug aggregate: Merit for oral delivery of amorphous solid dispersions

Zhao, Peixu; Wen, Hao; Shu, Yecheng; Li, Mo; Sun, Yichi; Sui, Xiaofan; Liu, Bingyang; Tian, Baocheng; Liu, Yanhua; Fu, Qiang

doi:10.1016/j.jconrel.2022.11.033

Cited by 22 publications

(5 citation statements)

References 90 publications

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“…Most new drug candidates show poor water solubility, and their low oral bioavailability may hamper the development of orally administrated formulations. , An amorphous solid dispersion (ASD), in which an amorphous drug is dispersed into a polymer matrix, is widely used as an effective technique to improve the oral absorption of poorly water-soluble drugs . Amorphous drugs have a higher free energy than their crystalline counterparts. , Thus, when the ASD is dispersed into water, the amorphous drug dissolves beyond its crystalline solubility, forming a supersaturated drug .…”

Section: Introductionmentioning

confidence: 99%

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid–Liquid Phase Separation

Yoshikawa,

Ueda,

Hakata

et al. 2024

Mol. Pharmaceutics

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Drug-rich droplets formed through liquid−liquid phase separation (LLPS) have the potential to enhance the oral absorption of drugs. This can be attributed to the diffusion of these droplets into the unstirred water layer (UWL) of the gastrointestinal tract and their reservoir effects on maintaining drug supersaturation. However, a quantitative understanding of the effect of drug-rich droplets on intestinal drug absorption is still lacking. In this study, the enhancement of intestinal drug absorption through the formation of drug-rich droplets was quantitatively evaluated on a mechanistic basis. To obtain fenofibrate (FFB)-rich droplets, an amorphous solid dispersion (ASD) of FFB/ hypromellose (HPMC) was dispersed in an aqueous medium. Physicochemical characterization confirmed the presence of nanosized FFB-rich droplets in the supercooled liquid state within the FFB/HPMC ASD dispersion. An in situ single-pass intestinal perfusion (SPIP) assay in rats demonstrated that increased quantities of FFB-rich nanodroplets enhanced the intestinal absorption of FFB. The effective diffusion of FFB-rich nanodroplets through UWL would partially contribute to the improved FFB absorption. Additionally, confocal laser scanning microscopy (CLSM) of cross sections of the rat intestine after the administration of fluorescently labeled FFB-rich nanodroplets showed that these nanodroplets were directly taken up by small intestinal epithelial cells. Therefore, the direct uptake of drug-rich nanodroplets by the small intestine is a potential mechanism for improving FFB absorption in the intestine. To quantitatively evaluate the impact of FFB-rich droplets on the FFB absorption enhancement, we determined the apparent permeabilities of the FFB-rich nanodroplets and dissolved FFB based on the SPIP results. The apparent permeability of the FFB-rich nanodroplets was 110−130 times lower than that of dissolved FFB. However, when the FFB-rich nanodroplet concentration was several hundred times higher than that of dissolved FFB, the FFB-rich nanodroplets contributed significantly to FFB absorption improvement. The present study highlights that drug-rich nanodroplets play a direct role in enhancing drug absorption in the gastrointestinal tract, indicating their potential for further improvement of oral absorption from ASD formulations.

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Section: Introductionmentioning

confidence: 99%

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid–Liquid Phase Separation

Yoshikawa,

Ueda,

Hakata

et al. 2024

Mol. Pharmaceutics

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“…17,18 In a pharmaceutical context, the phenomenon of LLPS has emerged as an important factor influencing the effectiveness of drug delivery in the case of substances with poor water solubility. [19][20][21] It has also been suggested that directly targeting and exploiting the intracellular LLPS can serve as a novel way to treat disease and to precisely deliver therapeutical agents which otherwise lack specific binding sites. 22,23 Thus, a complete understanding of the forces that drive condensation and coacervation is necessary not only for synthetic polymer materials but also for potential therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

The effect of monomer polarizability on the stability and salt partitioning in model coacervates

Riggleman¹

2023

Soft Matter

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“…2 Crystallization usually proceeds by nucleation and subsequent growth, and the role of solvent is a critical factor, since it determines the thermodynamic competition between solvation and species association, as well as the kinetics usually affected by the rate of solvent exchange rate. 3 Liquid−liquid phase separation (LLPS) during molecular self-assembly have been found and applied in biomedicine, 4 separation science, drug delivery, 5 and aerosol particles 6 fields, which has attracted great attentions of researchers and has been extensively investigated. LLPS refers to the phenomenon wherein droplets of the newly formed second liquid phase appear in the solution during the process of molecular assembly.…”

Section: Introductionmentioning

confidence: 99%

“…Liquid–liquid phase separation (LLPS) during molecular self-assembly have been found and applied in biomedicine, separation science, drug delivery, and aerosol particles fields, which has attracted great attentions of researchers and has been extensively investigated. LLPS refers to the phenomenon wherein droplets of the newly formed second liquid phase appear in the solution during the process of molecular assembly .…”

Section: Introductionmentioning

confidence: 99%

Regulating of Liquid–Liquid Phase Separation and Molecular Self-Assembly through Selective Solvation

Huang,

Wang,

Wang

et al. 2023

Ind. Eng. Chem. Res.

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Effectively regulating the liquid–liquid phase separation (LLPS) phenomenon in the process of molecular self-assembly is critical for controlling the qualities of the final products. However, the underlying mechanisms of LLPS that greatly affect the transition from molecules to crystals have not been fully addressed. Here, target solvents with properties of solvation or selective solvation suppression were theoretically screened to regulate the emergence and elimination of LLPS. Quantitative analysis of molecular electrostatic potential surfaces (MESP) was first applied to screen the antisolvent with solvation suppressing effect. Selective solvation suppressing was revealed, and the evolution mechanism of self-assembly in the nucleation pathways with or without LLPS was explored by experiments. It was found that clusters with unique properties of core–shell structure with dispersion transition layer may be the key to the occurrence of LLPS. This further provides new insights for understanding LLPS, which is a typical case for nonclassical nucleation theory.

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Liquid–liquid phase separation drug aggregate: Merit for oral delivery of amorphous solid dispersions

Cited by 22 publications

References 90 publications

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid–Liquid Phase Separation

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid–Liquid Phase Separation

The effect of monomer polarizability on the stability and salt partitioning in model coacervates

Regulating of Liquid–Liquid Phase Separation and Molecular Self-Assembly through Selective Solvation

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