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Development of stable affinity-based subcutaneous peptide formulations

Egbu, Raphael; (2021) Development of stable affinity-based subcutaneous peptide formulations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Polypeptides are an important class of drugs used in the clinic for a number of disease states. However, the development of subcutaneous peptide formulations still poses challenges such as aggregation (fibrillation) and short half-life. By utilising formulation approaches, this study aimed to circumvent both aforementioned challenges in a Glucagon-like peptide-1 agonist (GLP-1) termed G48. Kinetic assays revealed that the fibrillation of G48 is pH dependent. At acidic pH (pH 3.7) the peptide displayed off-pathway fibrillation, forming largely amorphous aggregates, whereas above neutral pH (7.4 and 8.5), the peptide showed typical nucleation-dependent fibrillation, leading to highly ordered structures. In all cases the β-sheet rich fibrillar structures were completely suppressed by judicious use of non-ionic surfactants capable of occupying the air-water interfaces. Exploiting the inherent overall negative charge of G48, a hyperbranched polycation (pKH) was synthesised and found to have moderate affinity for G48 (KD = 10 ⁻⁵ M). Following this, two affinity-based formulations were designed: (i) a binary complex composed of pKH and G48 and (ii) a ternary complex composed of pKH, G48 and a polyanion (OG). In vitro release studies revealed that in comparison to the control, which showed complete G48 release within 7 h, the binary and ternary systems slowed release markedly, resulting in ~20 and 40 % G48 release after 168 h. In vitro cytotoxicity studies carried out with human dermal fibroblasts revealed the formulations were non-toxic (PrestoBlue, 100 µg/mL, 32 h). No visual signs of toxicity or weight loss were observed during in vivo studies in which CD-1 mice were subcutaneously administered with the binary or ternary complex formulations containing a G48 dose of 1mg/mL/kg.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of stable affinity-based subcutaneous peptide formulations
Event: UCL
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/10119121
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