Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer

Abstract

Objectives To develop and manufacture both immediate and sustained release vaginal tablets containing the anticancer drug disulfiram, which has the potential to be used as a non‐invasive treatment for cervical cancer. Methods Disulfiram‐loaded vaginal tablets were manufactured at pilot scale using the direct compression method. These tablets were tested in accordance with the European Pharmacopeia testing of solid dosage form guidelines. They were also tested using a biorelevant dissolution method as well as a dual‐chambered release model designed to better mimic the dynamic nature of the vaginal vault. Key findings We have developed both immediate and sustained release vaginal tablets, which when manufactured at pilot scale are within the limits set by the European Pharmacopeia for the testing of solid dosage forms. Furthermore, these tablets are capable of releasing disulfiram in vitro using the dual‐chambered release model at levels 25 000 times and 35 000 times greater than its IC50 concentration for the HeLa cervical cancer cell line. Conclusions The successful pilot manufacture and testing of both the immediate and sustained release disulfiram‐loaded vaginal tablets warrant further investigation, using an in‐vivo model, to assess their potential for use as a non‐invasive treatment option for cervical cancer.

Cytotoxic Effect of Disulfiram/Copper On Human Cervical Cancer Cell Lines and LGR5-Positive Cancer Stem-Like Cells

“…Previous studies developed a vaginal tablet of DS to be used in HeLa and Ca-Ski cells for the localised treatment of cervical cancer [28,42]. This study showed animal experiments provided a basis for systemic application of DS.…”

Vaginal drug delivery for the localised treatment of cervical cancer

“…Baffoe et al describe the manufacture and testing of both immediate and sustained release vaginal tablets containing 130 mg of the drug disulfiram [ 73 ]. Disulfiram has been used safely in the clinic for many years to treat alcoholism and has shown potential anti-tumour activity as it can induce apoptosis in some cell lines and reduce cell growth in certain tumours [ 74 ].…”

“…Baffoe et al demonstrate that disufiram has a dose-dependent inhibition of the HeLa cervical cancer cell line with an IC 50 value of 124.3 nM, which is significantly more therapeutic than cisplatin with an IC 50 value of 2.2 μM against the same cell line. Furthermore, they show, using a bio-relevant dissolution model, that their immediate and sustained release tablets can release disulfiram at 25,000 to 35,000 times its IC 50 concentration [ 73 ]. A multicentre observational study in 256 patients with histologically proven CIN I demonstrated a 75.5% regression rate (the CIN was completely eradicated) to a negative histology after twice-weekly administration of bovine-colostrum containing vaginal tablets (Ginedie®) for 6 months [ 84 ].…”

A Bilayer Vaginal Tablet for the Localized Delivery of Disulfiram and 5-Fluorouracil to the Cervix

“…Disulfiram (DSF), a drug currently used in the treatment of chronic alcoholism, has been shown to possess anti-tumor activity [21]. DSF can induce apoptosis in some cell lines and reduce cell growth in certain tumours including prostate cancer, breast cancer, lung cancer, leukaemia and cervical adenocarcinoma [21][22][23]. Furthermore, its chemical structure has a high affinity towards copper, which is essential for the tumour angiogenesis processes, and contributes to making DSF selective to cancerous cells, thus sparing healthy cells [24].…”