Development of a mini-tablet-in-capsule dosage form for macromolecular drug delivery

Oral delivery of protein and peptide drugs faces immense challenges, partially due to the inherent unfavourable characteristics of the molecules and partially due to the unfavourable gastrointestinal environment. These barriers to oral protein drug delivery include the large molecular size, enzymatic degradation and hydrophilic nature of protein drugs, which lead to their low oral bioavailability (1 – 2%). Protein drugs (i.e. insulin) are therefore primarily administered via the parenteral route (i.e. subcutaneous injections), which lead to a decrease in patient adherence. Advancements in biotechnology have made it possible for improving oral delivery of protein and peptide drugs. One such advancement is the inclusion of safe and effective absorption enhancers in the formulation of oral dosage forms. Previous studies have shown that the inclusion of A. vera gel and whole leaf materials as well as N-trimethyl chitosan chloride (TMC) can increase the intestinal membrane permeability of protein drugs after application to in vitro and ex vivo models.

The purpose of this study was to develop and evaluate a mini-tablet-in-capsule dosage form by means of developing different sized bead formulations (i.e. 0.5 mm, 0.75 mm, 1.0 mm and 1.5 mm in diameter) containing the model compound fluorescein isothiocyanate (FITC)-dextran 4000 (FD4) and compacting these beads into mini-tablets containing different absorption enhancers (A. vera gel, A. vera whole leaf extract and TMC) in the tablet matrix, which were then filled into hard gelatine capsules. The beads were evaluated with regards to morphology and internal structure, size and FD4 content. Mini-tablets produced were evaluated (BP specifications) with regards to disintegration, friability and mass variation. The delivery of FD4 from the mini-tablet dosage forms across excised pig intestinal tissues was evaluated using a modified Sweetana-Grass diffusion apparatus.
All the mini-tablets complied with the specifications for physical evaluation of tablets namely mass variation, harness and friability. The results of the ex vivo transport studies showed that all three absorption enhancers incorporated into the mini-tablets caused increased FD4 transport across the excised pig intestinal tissues. The effect of the size of the beads used to produce the mini-tablets on FD4 transport was clearly visible; and in general the smaller beads (0.5 mm and 0.75 mm in diameter) showed faster initial, and the highest cumulative FD4 transport in comparison to the larger bead sizes (1.0 mm and 1.5 mm in diameter). Mini-tablets containing A. vera gel exhibited the highest increase in transport, followed by mini-tablets containing A. vera whole leaf extracts and TMC, respectively.

This study has shown that absorption enhancers incorporated as part of the matrix in mini- tablet-in-capsule dosage forms can significantly (p < 0.05) increase the transport of a macromolecular model compound across excised pig intestinal tissues in an ex vivo model.

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Development of a mini-tablet-in-capsule dosage form for macromolecular drug delivery
Dissertation accepted in fulfilment of the requirements for the degree Masters of Science in Pharmaceutics at the North-West University,
Supervisor: Prof JH Steenekamp Co-supervisor: Prof JH Hamman
Graduation: May 2020

Key words: FITC-Dextran, Aloe vera, N-trimethyl chitosan chloride, beads, mini-tablets, microcrystalline cellulose,
Kollidon® VA 64 (vinylpyrrolidone-vinyl acetate copolymer), Ac-Di-Sol® (croscarmellose sodium), Avicel® PH 200 (microcrystalline cellulose), Magnesium stearate