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. 2023 Feb 9;12(2):424.
doi: 10.3390/antiox12020424.

3D-Printed, Liquid-Filled Capsules of Concentrated and Stabilized Polyphenol Epigallocatechin Gallate, Developed in a Clinical Trial

Philippe-Henri Secretan  1 , Victoire Vieillard  2 , Olivier Thirion  2 , Maxime Annereau  1   3 , Hassane Sadou Yayé  4 , Alain Astier  2 , Muriel Paul  2   5 , Thibaud Damy  6 , Bernard Do  1   2
Affiliations

3D-Printed, Liquid-Filled Capsules of Concentrated and Stabilized Polyphenol Epigallocatechin Gallate, Developed in a Clinical Trial

Philippe-Henri Secretan et al. Antioxidants (Basel). .

Abstract

In vitro studies have shown that epigallocatechin gallate (EGCG), the most potent antioxidant of the green tea polyphenol catechins, is able to effectively prevent the formation of amyloid plaques and induce their clearance. However, its high chemical reactivity promotes high chemical instability, which represents a major obstacle for the development of pharmaceutical forms containing solubilized EGCG, an essential condition for a better systemic passage via the oral route. After discovering that EGCG forms a deep eutectic with choline chloride, we exploited this property to formulate and patent liquid-filled capsules containing 200-800 mg of soluble EGCG in easy-to-administer sizes. The gelatin envelopes used are of the conventional type and their filling has been achieved using 3D printing technology. Not only did the EGCG-choline complex allow the formulation of hydrophilic solutions with a high concentration of active substance but it also contributed significantly to its chemical stability, since after at least 18 months of storage at 25 °C/60% RH and one year at 40 °C/75% RH, the capsules show unchanged hardness, chromatographic profiles and antioxidant activity compared to T0. Preclinical studies in monkeys showed that bioavailability was increased by a factor of 10 compared to marketed capsules comprising EGCG powder. This pharmaceutical development was conducted in the context of upcoming clinical trials to evaluate EGCG alone or in combination when treating transthyretin and light-chain cardiac amyloidosis.

Keywords: bioavailability; epigallocatechin gallate; eutectic solution; formulation; oral solution; stability.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a): appearance of the fill before division into capsules. (b): capsule comprising 400 of EGCG. (c): typical containers for one month’s treatment.
Figure 2
Figure 2
(a): ESI-MS spectrum of an EGCG–choline chloride solution; (b): ESI-MS2 spectrum of the [(EGCG + Choline + HCOOH) − H]− product ion (m/z = 607.1).
Figure 3
Figure 3
Release profiles of EGCG as a function of the pH.
Figure 4
Figure 4
(a) Chromatographic profile of the formulation at time 0. (b) Chromatographic profile of the formulation after 18 months under standard conditions. (c) Chromatographic profile of the formulation after 6 months under accelerated conditions.
Figure 5
Figure 5
Evolution of EGCG (assay, % with respect to time 0) as a function of time and storage conditions.
Figure 6
Figure 6
Antioxidant activity expressed in the Trolox equivalent of green tea extract powder of capsules prepared extemporaneously and of capsules stored at 40 °C.
Figure 7
Figure 7
(a) Plasmatic concentrations of EGCG as a function of time; (b) box plots of the total area under curve.
See this image and copyright information in PMC

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