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. 2021 Sep 29;13(10):1586.
doi: 10.3390/pharmaceutics13101586.

Preparation and Pharmacokinetic Characterization of an Anti-Virulence Compound Nanosuspensions

Nan Wang  1 , Feng Qi  1 , Xiaolong He  2 , Honglan Shi  2 , David W Anderson  3 , Hao Li  1 , Hongmin Sun  4
Affiliations

Preparation and Pharmacokinetic Characterization of an Anti-Virulence Compound Nanosuspensions

Nan Wang et al. Pharmaceutics. .

Abstract

Antibiotic resistance has become a worldwide public health threat due to the rapid evolution and spread of antibiotic-resistant bacteria. CCG-211790 is a novel anti-virulence compound that does not kill bacteria but could ameliorate human diseases by inhibiting expression of virulence factors, thereby applying less selection pressure for antibiotic resistance. However, its potential clinical use is restricted because of its poor aqueous solubility, resulting in formulation challenges. Nanosuspension technology is an effective way to circumvent this problem. Nanosuspensions of CCG-211790 with two different particle sizes, NanoA (315 ± 6 nm) and NanoB (915 ± 24 nm), were prepared using an antisolvent precipitation-ultrasonication method with Tween 80 as the stabilizer. Particle and pharmacokinetics (PK) of CCG-211790 nanosuspensions were characterized. Both NanoA and NanoB demonstrated remarkable increases in dissolution rate compared with the bulk compound. The PK parameters of NanoA were comparable to those of CCG-211790 solution formulation in intravenous or oral administration, suggesting that CCG-211790 nanosuspensions with smaller particle size improved oral bioavailability and drug exposure compared to traditional formulations of drug candidates.

Keywords: anti-virulence; biofilm; nanosuspension; pharmacokinetic; wound infection.

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Conflict of interest statement

D.W.A. and H.L. are currently employed by Ivogen Inc., which is a subsidiary of Nanova, Inc. H.S. (Hongmin Sun) is a consultant of Nanova Inc., Ivogen Inc., and owns stocks in Nanova, Inc. F.Q. is currently employed by BeiGene Ltd. X.H. is currently employed by Frontage Laboratories, Inc. The companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The authors would like to declare the following patents associated with this research for methods and compositions for treating bacterial infection: H.S. (Hongmin Sun) is a co-inventor on patents US 8501722, US 9504688, Japan 6293736, and European 2844258; H.S. (Hongmin Sun) and DWA are co-inventors on patent US 9814719; H.S. (Hongmin Sun), D.W.A., and F.Q. are co-inventors on patent US 10441588. Ivogen Inc. is developing products related to these patents. This does not alter the authors’ adherence to all the journal’s policies on sharing data and materials.

Figures

Figure 1
Figure 1
Hydrodynamic particle sizes of the representative batch of NanoA and NanoB suspension after the preparation obtained by DLS.
Figure 2
Figure 2
SEM images of NanoA (A,B), NanoB (C,D), and CCG-211790 bulk powder (E,F).
Figure 3
Figure 3
In Vitro dissolution profiles of CCG-211790 bulk powder and NanoA and NanoB suspensions in 0.5% SDS solution (n = 3). There were statistically significant differences between the dissolution rates of NanoA and NanoB and the dissolution rate of CCG-211790 bulk powder (p < 0.05), while there was no statistical difference between NanoA and NanoB (p > 0.05).
Figure 4
Figure 4
Plasma concentration–time curve for pilot study of CCG-211790 powder suspension (n = 2) and a DMSO/saline solution (n = 2) either following oral administration or intravenous administration in Sprague–Dawley rats at a dose of 5 mg/kg or 2.5 mg/kg, respectively.
Figure 5
Figure 5
Plasma concentration–time curve of PEG/PG solution and NanoA and NanoB suspensions after intravenous administration in Sprague–Dawley rats at a dose of 2.5 mg/kg (n = 6).
Figure 6
Figure 6
Plasma concentration–time curve of the coconut oil solution (n = 6) and NanoA and NanoB suspensions (n = 6) after oral administration in Sprague–Dawley rats at a dose of 5 mg/kg.
Figure 7
Figure 7
Schematic of the diffusion layer proposed by Noyes and Whitney and further modified by Nernst and Brunner. Particle size reduction leads to increased surface area A and decreased hydrodynamic layer thickness hD, therefore increasing dissolution rate dC/dt.
See this image and copyright information in PMC

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