Cocrystallization of Amantadine Hydrochloride with Resveratrol: The First Drug–Nutraceutical Cocrystal Displaying Synergistic Antiviral Activity

Abstract

In order to highlight the advantages of the nutraceutical resveratrol (RVA) in perfecting the in vitro/in vivo properties of amantadine hydrochloride (ATHC), to realize advantageous complementarities between the two components and thus fill gaps in a drug–nutraceutical cocrystal with synergistically antiviral efficacy, a cocrystallization strategy of bidirectional coupling optimization has been developed. In this strategy, ATHC’s advantage of high water solubility is used to enhance RVA’s dissolubility and bioavailability, thereby activating its auxiliary antiviral effect, and meanwhile the excessive solubility of ATHC is properly reduced. The perfected antiviral activity of RVA, in return, contributes cooperativity with ATHC in antiviral efficacy, achieving a synergistic effect for the cocrystal. Using this strategy, the first antiviral drug–nutraceutical cocrystal, ATHC-RVA has been prepared and structurally characterized. The in vitro/in vivo property evaluations conducted both by theoretical and experimental methods reveal 152 and 9.64 times improvements, respectively, in the solubility and bioavailability of RVA, and the risk of toxic effects caused by the excessive solubility of ATHC is reduced through a slower release. Especially, the antiviral synergy of ATHC and RVA is significantly increased with CI < 1, exhibiting a potential to overcome drug resistance. All these benefits open a new pathway for the development of synergistic antiviral pharmaceutical cocrystals through cocrystallization techniques.

The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus

“…In each run, serial dilutions of the SARS-CoV-2 RNA reference standard (GBW(E)091089, National Institute of Metrology, China) were carried out in parallel to determine the viral RNA copies per μg RNA. IC 50 values were calculated using the GraphPad Prism 6 software using reported methods (Version 6.01, GraphPad Software, Inc., San Diego, CA, 2012) [36] , [37] , [38] . All experiments were performed at biosafety level-3 (BSL-3) in the Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences.…”

The First Cocrystallization of Milrinone with Nutraceuticals: The Adjusting Effects of Hydrophilicity/Hydrophobicity in Cavities on the In Vitro/In Vivo Properties of the Cocrystals

“…As a fundamental factor that affects the systemic absorption and even therapeutic effect of drugs, solubility is one of the major challenges for developers in drug development. 50 To evaluate the improvement ability in solubility for MLN after cocrystallization with the two phenolic acid nutrients, the solubility assays of 1 and 2 are performed in different pH buffers of 1.2, 4.0, and 6.8 and compared with those of MLN per se, and the outcomes are given in Figure 8.…”

Drug-nutrient cocrystallization-driven strategy towards self-assembly of milrinone and ferulic acid provides an exemplification in perfecting in vitro/vivo characteristics of anti-heart failure drugs

“…49 As we all know, lg P is a considerable parameter for evaluating permeability, which has an important influence on the permeability of cocrystals. 48 Since the lg P value of 1.51 for FEA 22 is remarkably higher than that of MLN (0.33), 33 the hydrophobicity and transmembrane abilities of the cocrystal can be effectively improved by getting the utmost out of FEA's superior permeability. Besides these, when FEA molecule as a cocrystal coformer is introduced into MLN crystal lattice through the self-assembly of stable heterosynthons between the carboxyl group of the former and lactam of the latter, it can reduce the number of free hydrogen-bonding polar sites, and thus increasing the ability of the cocrystal as a whole to pass through the non-polar membrane, and benefiting to the enhancement of its permeability.…”

“…As a significant parameter for evaluating drug dissolution performance from the kinetic viewpoint, IDR is more related to drug release in vivo than solubility. 48 Therefore, IDR tests of plain MLN and the cocrystal have been completed, and the corresponding outcomes are given in Fig. S3 (ESI †), with the calculated IDR values tabulated in Table 3.…”