(-)-Epigallocatechin-3-gallate (EGCG) exhibits a low oral bioavailability due to several factors. The aim of this work was to develop a solid oral dosage form containing EGCG with potentially improved oral bioavailability. The chemical degradation during the gastro-intestinal passage and within the dosage form is one of the factors leading to the poor bioavailability. As a consequence, finding the appropriate release window and pattern as well as investigating the physical and chemical compatibility of EGCG with excipients is crucial for the formulation development.
First of all, the autoxidative degradation of EGCG in aqueous solution was investigated and showed that the degradation occurs at pH ≥ 5 and follows a biphasic degradation pattern with a first fast degradation phase which is pH- and concentration-dependent. The second phase is pH- and concentration-independent and slower with a constant degradation rate. This degradation pattern could be attributed to the formation of EGCG self-aggregates. This knowledge helps to adjust the release window and release pattern of EGCG according to its chemical stability in solution and thus to increase its oral bioavailability.
The most common commercial dosage forms for EGCG are capsule formulations. Consequently, hard capsule formulations out of gelatin, HPMC and HPMC with gellan gum were investigated. All capsule materials interacted with EGCG and resulted in a phase-separation and chemical instability. The former one lead during the dissolution studies of EGCG out of HPMC-capsules to capsule shell solidification and sustained incomplete release.
This work gives an overview of factors influencing the chemical instability of EGCG upon 6 months storage stability studies at 40°C/ 75% RH and allows pre-estimation of its occurrence.
Additionally, the possibility to stabilize EGCG within tablets over 6 months storage by the use of ascorbic acid, sodium ascorbate and a mixture of both was investigated. A pro-oxidant effect could be observed predominantly. A deliquescence of ascorbic acid and its salt occurred which was not induced by EGCG in form of Teavigo® powder but by the other tableting excipients. The degradation of EGCG correlated with the results of the deliquescence studies of ascorbic acid, sodium ascorbate and their binary mixture as well as the stabilizer amount. Radicals of ascorbate were formed due to the deliquescence, as well as the difference in pH-optima of both antioxidants. The formed radicals exhibited, dependent on the amount of moisture uptake and microenvironmental pH of the formulation, a pro- or antioxidant effect on EGCG in tablets. Nevertheless, it was shown that sodium ascorbate is capable of enhancing EGCG stability in dosage forms as long as the excipients do not induce a too high degradation of ascorbate.
In the end, EGCG immediate release tablets could be successfully formulated with a high EGCG loading, faster release than the reference formulations and stability over 6 months of storage at 40°C/ 75% RH.
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