Cyclodextrin Polymer Complexation Improves the Tolerability of Parenteral Oestradiol

TL;DR

A new water-based delivery system for oestradiol injections is developed to reduce side effects and improve safety.

Contribution

A novel PEG–β-CD polymer system is introduced for parenteral oestradiol delivery with improved tolerability and solubility.

Findings

The PEG–β-CD polymer significantly increased oestradiol solubility compared to β-cyclodextrin or PEG alone.

The system showed minimal toxicity in cell and larval models and no pro-inflammatory immune responses.

Pharmacokinetic studies in rats showed stable serum oestradiol levels comparable to commercial esters.

Abstract

Background: Menopause is characterised by a decline in oestrogen levels, leading to physical and psychological symptoms that significantly affect quality of life. Current parenteral oestradiol ester therapies, while effective, are often associated with side effects due to their oil-based formulations, including injection-site reactions and immune responses. Methods: In this study, we developed a water-soluble, polyethylene glycol cross-linked β-cyclodextrin (PEG–β-CD) polymer-based system for parenteral oestradiol delivery and evaluated its biocompatibility, solubility enhancement, immune compatibility, and pharmacokinetics. Results: Cytotoxicity assays using NIH-3T3 fibroblasts and RAW 264.7 macrophages showed minimal toxicity up to 10% (w/w). Phase-solubility studies demonstrated a significant increase in oestradiol solubility with the PEG–β-CD polymer, surpassing that of β-cyclodextrin or PEG alone. Dynamic light scattering and FTIR analyses confirmed successful complex formation, with submicron particles averaging 271 nm and physical incorporation of oestradiol into the polymer matrix. Macrophage activation assays and RT-qPCR analyses indicated an absence of immunogenic responses or pro-inflammatory cytokine induction. In vivo toxicity testing in Galleria mellonella larvae confirmed safety, while pharmacokinetic studies in Wistar rats revealed rapid initial absorption followed by stable, low-level serum concentrations comparable to those of commercially used oestradiol esters. Conclusions: These findings indicate that the PEG–β-CD polymer–oestradiol complex provides a safe, water-based alternative to traditional oil-based injections, with the potential to reduce side effects and improve patient compliance in postmenopausal hormone therapy.

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