Abstract
Plumbagin, a bioactive naphthoquinone, has demonstrated potent antitumor potential. However, plumbagin is a sparingly water-soluble compound; therefore, clinical translation requires and will be facilitated by the development of a new pharmaceutical formulation. We have generated an oil-in-water nanoemulsion formulation of plumbagin using a low-energy spontaneous emulsification process with propylene glycol caprylate (Capryol 90) as an oil phase and Labrasol/Kolliphor RH40 as surfactant and cosurfactant excipients. Formulation studies using Capryol 90/Labrasol/Kolliphor RH40 components, based on pseudoternary diagram and analysis of particle size distribution and polydispersity determined by dynamic light scattering (DLS), identified an optimized composition of excipients for nanoparticle formulation. The nanoemulsion loaded with plumbagin as an active pharmaceutical ingredient had an average hydrodynamic diameter of 30.9 nm with narrow polydispersity. The nanoemulsion exhibited long-term stability, as well as good retention of particle size in simulated physiological environments. Furthermore, plumbagin-loaded nanoemulsion showed an augmented cytotoxicity against prostate cancer cells PTEN-P2 in comparison to free drug. In conclusion, we generated a formulation of plumbagin with high loading drug capacity, robust stability, and scalable production. Novel Capryol 90-based nanoemulsion formulation of plumbagin demonstrated antiproliferative activity against prostate cancer cells, warranting thus further pharmaceutical development.
Highlights
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone,Figure 1) is a naturally occurring 1,4-naphthoquinone found in Plumbaginaceae and other plant families [1]
In order to select the optimal constituents of a nanoemulsion formulation for plumbagin, we first measured the solubility of plumbagin in various lipid-based excipients
Excipients based on medium chain glycerides such as Labrasol, Labrafac, and Capmul MCM, or on propylene glycol esters such as Capryol 90, have a remarkably high capacity to solubilize plumbagin. Plumbagin concentrations in these excipients are higher than 80 mg/ml, reaching 125mg/ml in Labrasol, compared to 50-60 mg/ml range in glyceryl trioleate, Peceol, Span 80, or Span 85
Summary
Figure 1) is a naturally occurring 1,4-naphthoquinone found in Plumbaginaceae and other plant families [1]. A key finding from our group showed that plumbagin significantly improved the efficacy of androgen deprivation therapy (ADT) in hormone-responsive models of prostate cancer, leading to tumor regression and extended survival when used in combination with ADT [10, 11]. These preclinical studies established the framework for the first-inhuman clinical trial of the combination of plumbagin and ADT in prostate cancer patients (NCT03137758). Nanoemulsion formulations have critical advantages for oral drug delivery, including high encapsulation capacity and high surface-to-volume ratio, as well as favorable physicochemical properties facilitating their stability. High loading capacity for plumbagin, long-term stability, retention of particle size in simulated physiological environments, and increased sensitivity to the antiproliferative activity of plumbagin in prostate cancer cells indicate that Capryol 90-based nanoemulsion formulations of plumbagin are suitable for further development
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