Posted by „The most fruitful basis for the discovery of a new drug is to start with an old drug.”
(Sir James Black, Nobel-laurate)
Drug repositioning is a drug discovery strategy in which an existing drug is utilized as a therapeutic agent for a different disease. Since all information regarding the safety, pharmacokinetics, and formulation of existing drugs is already available, the cost and time required for drug development is reduced. In recent years, many pharmaceutical companies are developing new drugs with the discovery of novel biological targets by applying the drug repositioning strategy in drug discovery and development program. This strategy is highly efficient, time saving, low-cost and low risk of failure. It maximizes the therapeutic value of a drug and consequently increases the success rate. (1)
Table 1. examples of FDA approved repurposed APIs
| API | Original purpose | Repurposed use |
| Amantadine | Parkinson’s disease | Influenza A |
| Acetylsalicylic acid | Inflammation, pain | Antiplatelet |
| Cyclosporine | Rheumatoid arthritis | Transplant rejection, proriasis |
| Minoxidil | Hypertension | Alopecia |
The role of cyclodextrins (CDs) in drug repositioning has earlier been subject of several papers (Ref. 2,3,4,) and this unique option of drug development using suitable CDs, is still of high priority option of modern drug development.
A recent paper by Benkő et al (5) deals with the CD-assisted repositioning of Disulfiram an old API, originally used to support the treatment of chronic alcoholism, producing an acute sensitivity to ethanol by inhibiting the enzyme aldehyde-dehydrogenase.
Drug repositioning is a feasible strategy even in the field of oncology research, where the unmet medical needs are continuously unbalanced. Disulfiram is a potential non-chemotherapeutic, adjuvant anticancer agent. However, the clinical translation of this drug is limited by the its poor aqueous solubility and bioavailability. Therefore, the molecular encapsulation of Disulfiram with CDs was evaluated aiming at the enhancement of the solubility and stability of the drug. The paper described the first time the complexation of disulfiram with randomly methylated-β-cyclodextrin. A parallel analytical and in vitro biological comparison of disulfiram inclusion complexes with hydroxypropyl-β-CD, randomly methylated-β-CD and sulfobutylether-β-CD was conducted. A significant drug solubility enhancement by about 1000-fold and fast dissolution within 1 min were demonstrated. The in vitro dissolution-permeation studies and cell proliferation assays demonstrated the solubility-dependent efficacy of the drug. Throughout the different cancer cell lines‘ characteristics and disulfiram unspecific antitumoral activity, the inhibitory efficacy of the cyclodextrin-encapsulated drug on melanoma (IC50 about 100 nM) and on poorly treatable glioblastoma (IC50 about 7000 nM) cell lines differ by a magnitude.
This pre-formulation screening experiment serves as a proof of concept of using CD encapsulation as a promising platform tool for further drug delivery development in drug repurposing areas. The rational excipient selection method should be the primary goal during repositioned drug development, to balance the benefits and achieve industrial scale-up, completing the healthcare assistance from bench to bedside. From this perspective, as reported in this paper, RAMEB can be a promising enabling excipient in the repositioning of Disulfiram. The inclusion complex could serve for drug development to fulfil the unmet need, such as adjuvant local melanoma therapy, also by overcoming the poor oral bioavailability of the drug.
References
1. Drug Repurposing – Hypothesis, Molecular Aspects and Therapeutic Applications Edited by Farid A. Badria. IntechOpen (2020)
2. Anurag Lodagekar et al . Formulation and evaluation of cyclodextrin complexes for improved anticancer activity of repurposed drug Niclosamide : Carbohydrate Polymers 212, 252-259 (2024)
3. Josefina Priotti,et al. Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer. AAPS PharmSciTech 212, 252-259 ( 2018)
4. Zhiqiang Wang, et al . Cyclodextrin complexation studies as the first step for repurposing of Chlorpromazine International Journal of Pharmaceutics 584, 119391 (2020)
5. Beáta-Maria Benkő, et al. Cyclodextrin encapsulation enabling the anticancer repositioning of disulfiram: Preparation, analytical and in vitro biological characterization of the inclusion complees International Journal of Pharmaceutics, 657, 124187 (2024)