The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.

Sealed-heating of salicylic acid (SA) and polyethylene glycol (PEG)/γ-cyclodextrin (CD)-polypseudorotaxane induced a novel complex formation wherein SA was inhabited in the intermolecular spaces formed by the γ-CD/polypseudorotaxane columns. Incorporation of SA into the PEG/γ-CD-polypseudorotaxane structure was clarified by powder X-ray diffraction measurements and 13 C-solid-state NMR spectroscopy. Different water vapor adsorption and desorption behaviors between the novel complex and PEG/ γ-CD-polypseudorotaxane confirmed the incorporation of SA molecules into the intermolecular spaces in the complex.Cyclodextrins (CDs), which are host molecules, are known to include various kinds of guest molecules in their cavities. 1 Inclusion complex formations with active pharmaceutical ingredients (APIs) have been widely studied because inclusion complex formations improve physicochemical properties such as solubility, dissolution rate, bioavailability, and stability of APIs. Guest molecules were reported to be able to exist both in the cavities of CDs and in the intermolecular spaces formed by CDs. 2 Indeed, Harata et al. described that in the evaporated sample of p-nitrophenol/dimethyl-β-CD, p-nitrophenol existed in the interstitial sites of the molecular arrangement of dimethyl-β-CD molecules. 2 In the case of m-nitrophenol or m-bromophenol, the guest molecules were located not only in the cavity of R-CD but also in the intermolecular spaces of R-CD columns. 2 However, there have been few publications that have discussed the existence of guest molecules outside the CD cavities.Recently, a large number of studies on the inclusion complexes of CDs with polymers, named CD-polypseudorotaxanes, have been published. 3,4 CD-polypseudorotaxanes have received a great deal of interest because of their unique structural, electrical, and mechanical properties. Their applications in the pharmaceutical field, however, have been extremely limited because the CD cavities are filled with polymers and no more space in the cavity remains for the inclusion of drugs.Herein we report a novel complex prepared by utilizing the sealed-heating technique, in which both the guest and host molecules are only heated in an enclosed space. 5 In this novel complex, it was found that salicylic acid (SA) molecules were inhabited in the intermolecular spaces formed by polyethylene glycol 2000 (PEG)/γ-CD-polypseudorotaxane columns. A novel inclusion complex was prepared in two steps. In step 1, conventional PEG/γ-CD-polypseudorotaxane was prepared by the coprecipitation method. 3 PEG and γ-CD were suspended in distilled water. The suspension was stirred at 25°C for 2 days and then stored for 1 day at 25°C. The precipitate was filtrated and dried for 1 day at 25°C to obtain PEG/γ-CD-polypseudorotaxane. In step 2, SA and the polypseudorotaxane were sealedheated in order to incorporate SA molecules into the intermolecular spaces of the γ-CD molecules.

RNA-based therapeutics is a promising approach for curing intractable diseases by manipulating various cellular functions. For eliciting RNA (i.e., mRNA and siRNA) functions successfully, the RNA in the extracellular space must be protected and it must be delivered to the cytoplasm. In this study, the development of a self-degradable lipid-like material that functions to accelerate the collapse of lipid nanoparticles (LNPs) and the release of RNA into cytoplasm is reported. The self-degradability is based on a unique reaction "Hydrolysis accelerated by intra-Particle Enrichment of Reactant (HyPER)." In this reaction, a disulfide bond and a phenyl ester are essential structural components: concentrated hydrophobic thiols that are produced by the cleavage of the disulfide bonds in the LNPs drive an intraparticle nucleophilic attack to the phenyl ester linker, which results in further degradation. An oleic acid-scaffold lipid-like material that mounts all of these units (ssPalmO-Phe) shows superior transfection efficiency to nondegradable or conventional materials. The insertion of the aromatic ring is unexpectedly revealed to contribute to the enhancement of endosomal escape. Since the intracellular trafficking is a sequential process that includes cellular uptake, endosomal escape, the release of mRNA, and translation, the improvement in each process synergistically enhances the gene expression.

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In the present study, the molecular state of drug-rich amorphous nanodroplets was evaluated using NMR techniques to reveal the mechanism underlying the crystallization inhibition of drug-rich amorphous nanodroplets by a polymer. Ibuprofen (IBP) with a low glass transition temperature was used for direct characterization of drug-rich amorphous nanodroplets. Highly supersaturated IBP formed IBP-rich amorphous nanodroplets through phase separation from aqueous solution. Increasing the concentration of hypromellose (HPMC) in the aqueous solution contributed to the inhibition of IBP crystallization and maintenance of supersaturation at IBP amorphous solubility. Solution 1H NMR measurements of IBP supersaturated solution containing IBP-rich amorphous nanodroplets clearly showed two kinds of 1H peaks derived from the dissolved IBP in bulk water phase and phase-separated IBP in IBP-rich amorphous nanodroplets. NMR spectral analysis indicated that HPMC did not affect the chemical environment and mobility of the dissolved IBP. However, 1H spin–spin relaxation time measurements clarified that the dissolved IBP in the bulk water phase was exchanged with the IBP-rich amorphous nanodroplets with an exchange lifetime of more than 10 ms. Moreover, the 1H peaks of HPMC partially disappeared due to the formation of IBP-rich amorphous nanodroplets, suggesting that a part of HPMC distributed into the IBP-rich amorphous nanodroplets from the bulk water phase. The incorporation of HPMC significantly changed the chemical environment of the phase-separated IBP in the IBP-rich amorphous nanodroplets and strongly suppressed molecular mobility. The resulting molecular mobility suppression effectively inhibited IBP crystallization from the IBP-rich amorphous nanodroplets. Thus, direct investigation of drug-rich amorphous nanodroplets using NMR can be a promising approach for selecting appropriate pharmaceutical excipients to suppress drug crystallization in supersaturated drug solutions.