Development of Orally Administered γ-Tocotrienol (GT3) Nanoemulsion for Radioprotection.

Grace Ledet,Tarun Mandal,Levon Bostanian,Vidya Kumar,Shukla Biswas,Richard Graves,Sanchita Ghosh,Taylor Parker,Demaurian Mitchner

doi:10.3390/ijms18010028

Abstract

The purpose of this study was two-fold: (1) to formulate γ-tocotrienol (GT3) in a nanoemulsion formulation as a prophylactic orally administered radioprotective agent; and (2) to optimize the storage conditions to preserve the structural integrity of both the formulation and the compound. γ-tocotrienol was incorporated into a nanoemulsion and lyophilized with lactose. Ultra performance liquid chromatography–mass spectroscopy (UPLC–MS) was used to monitor the chemical stability of GT3 over time, the particle size and ζ potential, and scanning electron microscopy (SEM) were used to study the physical stability of the nanoemulsion. Radioprotective and toxicity studies were performed in mice. The liquid formulation exhibited GT3 degradation at all storage temperatures. Lyophilization, in the presence of lactose, significantly reduced GT3 degradation. Both the liquid and lyophilized nanoemulsions had stable particle size and ζ potential when stored at 4 °C. Toxicity studies of the nanoemulsion resulted in no observable toxicity in mice at an oral dose of 600 mg/kg GT3. The nano-formulated GT3 (300 mg/kg) demonstrated enhanced survival efficacy compared to GT3 alone (200 and 400 mg/kg) in CD2F1 mice exposed to total body gamma radiation. The optimal long-term storage of formulated GT3 is as a powder at −20 °C to preserve drug and formulation integrity. Formulation of GT3 as a nanoemulsion for oral delivery as a prophylactic radioprotectant shows promise and warrants further investigation.

Highlights

The development of radioprotective agents which can be used prior to exposure is critical for first responders within a radiation exposure field [4], and, oral administration has clinical relevance as an effective countermeasure for both first responders as well as for at-risk civilian populations in a nuclear accident [9]
The most common methods to prepare dry powder formulations are spray drying and freeze drying. Both of these methods are effective in drying nanoemulsion formulations, the optimum choice depends on the economics of the process and the intended route of administration [13]
The only significant alteration of the nanoemulsion formulation following lyophilization was the polydispersity index, which translates into inhomogeneity in the particle size of the reconstituted lyophilized GT3 NE

Summary

Introduction

The development of radioprotective agents which can be used prior to exposure is critical for first responders within a radiation exposure field [4], and, oral administration has clinical relevance as an effective countermeasure for both first responders as well as for at-risk civilian populations in a nuclear accident [9]. The most common methods to prepare dry powder formulations are spray drying and freeze drying Both of these methods are effective in drying nanoemulsion formulations, the optimum choice depends on the economics of the process and the intended route of administration [13]. Spray drying is faster and suitable for inhalable powder formulations, but the process uses high temperature gas which may be detrimental to some heat sensitive drugs [14]. To preserve the emulsion following the removal of the aqueous phase of the emulsion, whether by freeze drying or by spray drying, a shell material must be incorporated into the formulation prior to drying. The radioprotective efficacy of the GT3 nanoemulsion was compared to that of unformulated GT3 following oral administration 24 h prior to radiation exposure

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