Towards an improved understanding of drug excipient interactions to enable rapid optimization of nanosuspension formulations.

Autor: Ferrar JA; Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Sellers BD; Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Chan C; Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Leung DH; Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: leung.dennis@gene.com.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2020 Mar 30; Vol. 578, pp. 119094. Date of Electronic Publication: 2020 Jan 29.
DOI: 10.1016/j.ijpharm.2020.119094
Abstrakt: Suspensions of drug nanoparticles known as nanosuspensions have emerged as a successful enabling formulation approach for poorly soluble drug candidates. These nanoparticles typically require stabilization with specific polymer or surfactant excipients to prevent aggregation from occurring. This study demonstrates the necessity of formulating drug nanosuspensions with amphiphilic excipients possessing long hydrophobic alkyl or polymer block chains to produce stable nanoparticles. 28 different excipients and excipient combinations at various loadings were screened across the 3 drug compounds and their effectiveness, as characterized by the lowest excipient loading needed to stabilize a monodisperse drug suspension, is quantified as a function of various excipient parameters such as molecular weight, HLB value, CMC, H-bond donors and acceptors, and the length of the hydrophobic alkyl chains and polymer blocks within their molecular structure. Traditional characterization parameters (molecular weight, HLB value, and CMC) fail to predict excipient effectiveness. The conformational flexibility and length of the hydrophobic regions of amphiphilic excipients appears to be critical for effectiveness. This hypothesis was supported by molecular modeling studies to better understand the interactions between the excipients with the drug nanoparticle surface.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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