A carbohydrate polymer is a critical variable in the formulation of drug nanocrystals: a case study of idebenone

ABSTRACT

Objective: Stabilizers, especially carbohydrate polymers, have been shown to be necessary for the stabilization of drug nanocrystals. However, the impacts of select stabilizers on the in vitro and in vivo efficacy of therapeutics have rarely been reported. The aim of this study was to evaluate the importance of stabilizers in the formulation of drug nanocrystals.

Research design and methods: Idebenone nanocrystals (IDBNC) stabilized by various stabilizers were formulated using a milling method. The in vitro dissolution profiles in water and in situ absoprtion were compared. Finally, an in vivo pharmacokinetic study was performed.

Results: The IDBNC profiles were found to have acceptable sizes and similar morphology and crystallinity. The dissolution profiles of IDBNC stabilized by different stabilizers were notably different, indicating the critical influence of stabilizers on the release rate of IDB. The Soluplus-stabilized IDBNC (IDBNC_{400 nm}/Soluplus) achieved better absorption than HPMC stabilized IDBNC (IDBNC_{400 nm}/HPMC). The pharmacokinetic study demonstrated that Soluplus-stabilized IDBNC had preferable kinetics, with an AUC_0–24h of IDBNC_{400 nm}/Soluplus (3.08-fold relative to IDB suspension), compared to IDBNC_{400 nm}/HPMC (1.88-fold).

Conclusions: Choice of stabilizer plays an important role in the formulation of IDBNC. We anticipate that the role of stabilizers in the pharmacokinetic disposition of IDBNC has significant implications for a wide range of other drug crystal formulations.

KEYWORDS:

• Idebenone
• nanocrystals
• stabilizer
• dissolution
• oral bioavailability

Author contributions

M Ma was involved in the preparation and in vivo evaluation of the IDBNC, and also involved in the drafting of this manuscript. G Zhang was involved in the characterization and in vitro evaluation of the formulations. W Li was involved in drawing of graphs and analysis of data. M Li was involved in pharmaceutical analysis. Q Fu was involved in the conception and design and guidance of this study. Z He was involved in the guidance of this study. All authors agree to be accountable for all aspects of the work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Additional information

Funding

This work was financially supported by the National Science and Technology Major Project (No. 2017ZX09101001), by the National Nature Science Foundation of China (No. 81502993), by Nature Science Foundation of Liaoning Province (No. 20170540842), Basic Research Projects of Universities of Liaoning Provincial Department of Education (2017LQN02), and the Science and Technology Innovation Projects for Young and Middle-aged Talents of Shenyang (RC180261).