Sacubitril-valsartan cocrystal revisited: role of polymer excipients in the formulation

ABSTRACT

Objectives: This study investigated the impact of polymer excipients on a typical cocrystal for sacubitril (SAC) and valsartan (VAL), aiming to guide optional formulation design and maximize oral bioavailability.

Methods: Poly vinyl pyrrolidone (PVP) and hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) were selected. The dissolution/permeation system was used to predict both the kinetics of drug supersaturation and the simple permeation. The intermolecular interaction was analyzed by ¹H NMR spectroscopy and molecular dynamics simulation. Pharmacokinetic study was performed to assess the impact of polymer excipients in vivo.

Results: Our study found that unappreciated excipients in the formulation, especially some polymers, might compete with the intermolecular hydrogen bonding among the cocrystals components and provide unexpected affinity, and thus leverage the therapeutic benefits. HPMC as a coating excipient used in the Entresto® tablet hampered the supersaturation of API, which led to the poor oral absorption of cocrystals. Conversely, PVP appeared to promote and maintain drug supersaturation, resulting in improved bioavailability of API.

Conclusion: In conclusion, understanding the interplay between the cocrystal components and polymers is the key to optimizing the excipients to maximize the performance of cocrystal based oral drug formulation.

KEYWORDS:

• Cocrystal
• excipient
• polymer
• solubility
• permeability
• oral absorption

Author contributions

Y Zhang and H Liu were involved in the conception and design. Y Zhang, X Du, and Z He were involved in the analysis and interpretation of the data. H Wang was responsible for software support. Y Zhang was responsible for the drafting of the paper. H Liu was involved in revising it critically for intellectual content. All authors agree to be accountable for all aspects of the work.

Reviewer disclosures

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

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.

Supplementary material

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Additional information

Funding

This paper was not funded.