Lurasidone Hydrochloride

Stress exposure is a key risk factor for the developmentof depressive-like conditions. However, despite the higher incidence of Major Depressive Disorder in the female population, classical stress-based experimental paradigms have primarily focused on males. In the present study, we used the well-established chronic mild stress (CMS) paradigm to investigate the development of anhedonia, a cardinal symptom of affective disorders, in the female animals and we also studied the potential effect of the antipsychotic drug lurasidone in normalizing the alterations brought about by stress exposure. We found that three weeks of CMS exposure produced a significant reduction of sucrose intake in 50% of the animals (vulnerable, CMS-V), whereas the others were resilient (CMS-R). The development of an anhedonic phenotype in CMS-V was associated with a significant elevation of different immune markers, such as Complement C3 and C4, and inflammatory cytokines, including INFß and Il1ß in dorsal and ventral hippocampus. Interestingly, sub-chronic treatment with the antipsychotic drug lurasidone was able to revert the anhedonic phenotype while normalizing most of the molecular alterations found in rats vulnerable to CMS exposure. This study extends the ability of lurasidone to normalize the anhedonic phenotype in CMS rats also to females. Moreover, we provide novel evidence on lurasidone's potential effectiveness in treating mental disorders characterized by immune-inflammatory dysfunction.

Coamorphous drug delivery systems have received increasing interest owing to their potential to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs. However, the crystallization risk is one of major limitations in their application. It has been widely recognized that the coformer plays a vital role in physical stability of coamorphous formulation. Unfortunately, the screen of optimal coformer still adopts a trial-and-error method, which is time-consuming and expensive. Herein, a supramolecular synthon approach based on the interaction between functional groups, was exploited to design coamorphous systems (CMs) consisting of lurasidone hydrochloride (LH) and three coformers, saccharin (SAC), L-tryptophan (TRP), and L-cysteine hydrochloride (CYS). X-ray powder diffraction suggested the order of physical stability of the coamorphous systems was ranked as LH-CYS CM > LH-TRP CM > LH-SAC CM. The charge-assisted hydrogen bond between LH and coformer was confirmed by infrared spectroscopy and solid-state ¹³C NMR. Moreover, structural, electronic, and molecular interaction information, especially hydrogen bonding interactions, were quantified by theoretical calculations, including miscibility calculations, molecular dynamics simulations and quantum chemical calculations. It was revealed that LH-CYS CM exhibited the best miscibility, strongest binding energy and strongest H-bond with partially covalent character, demonstrating the significant role of supramolecular synthon in stabilizing coamorphous formulations. Interestingly, LH-TRP CM, not LH-CYS CM, exhibited the lowest molecular mobility among three coamorphous systems, which was inconsistent with their physical stability. But from thermodynamic perspective, the order of configurational entropy and physical stability of coamorphous systems was completely consistent. We shed light on the comprehensive effects of molecular mobility and configurational entropy on physical stability of coamorphous systems. Importantly, the relationship between supramolecular synthon and kinetic/thermodynamic mechanisms was also discussed, and the positive correlation between configurational entropy and intermolecular interactions was proposed in this paper. Our findings demonstrated the great potential of supramolecular synthon in designing coamorphous systems with tailored physical stability, and further provided a deeper insight into the mechanisms of physical stability of coamorphous systems.