Drug repositioning is a high-priority and feasible strategy 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 is limited by the drug's poor bioavailability. Therefore, the molecular encapsulation of disulfiram with cyclodextrins is evaluated to enhance the solubility and stability of the drug. The present work describes for the first time the complexation of disulfiram with randomly methylated-β-cyclodextrin. A parallel analytical andin vitrobiological comparison of disulfiram inclusion complexes with hydroxypropyl-β-cyclodextrin, randomly methylated-β-cyclodextrin and sulfobutylether-β-cyclodextrin is conducted. A significant drug solubility enhancement by about 1000-folds and fast dissolution in 1 min is demonstrated. Thein vitrodissolution-permeation studies and proliferation assays demonstrate 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 glioblastoma (IC₅₀ about 7000 nM) cell lines differ by a magnitude. This pre-formulation screening experiment serves as a proof of concept of using cyclodextrin encapsulation as a platform tool for further drug delivery development in repositioning areas.

Background/Objectives: Early diagnosis and oral or, in severe cases, intravenous antibiotics are usually effective for Lyme disease, but some patients have persistent symptoms unresponsive to standards of care, requiring alternative therapies. Disulfiram (DIS), a drug for alcoholism, is under investigation as a potential adjunctive treatment, but its low bioavailability, rapid metabolism, and safety concerns urge the development of improved formulations for clinical translation. Methods: Screening dissolution and permeation studies were investigated for vehicle and excipient selection, following the pharmacopeia perspectives to develop and optimize the low-dose DIS rectal suppository intended for application in post-treatment Lyme disease syndrome (PTLDS). Further characterizations were carried out by differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy. Results: Cyclodextrin (CD) encapsulation was investigated to improve the aqueous solubility of the hydrophobic drug. The dissolution of DIS from fatty base suppository was very slow; it was remarkably improved by the molecular encapsulation of the drug with CDs. The dissolution of DIS from a water-soluble base was more favorable, but incomplete. In the polyethylene glycol (PEG) based suppositories, the addition of CDs already in a physical mixture ensured the dissolution of the drug. The presented drug delivery system relates to a novel preparation for rectal administration comprising a low-dose disulfiram with improved solubility and permeability by the PEG and hydroxypropyl-β-cyclodextrin (HPBCD) synergistic matrix. Conclusions: The rectal dosage form containing the drug and CD in the physical mixture is advantageous, avoiding the hepatic first-pass effect, minimizing dose-limiting toxicity, simplifying production, and fasting the availability of the repositioned drug.

The relationship between the nanoscale free volume of pharmaceutical polymer films and their hydration behavior remains poorly understood. Eight pharmaceutical polymers were screened at three concentration levels within a quality-by-design framework; only two poly(vinyl alcohol) grades (PVA EG-30P and EG-40P), hydroxypropyl cellulose (HPC), and sodium alginate (Na-alginate) formed continuous films. These were characterized by positron annihilation lifetime spectroscopy (PALS), loss on drying (LOD), and swelling analysis. PALS clearly differentiated HPC, Na-alginate, and PVA, whereas the two PVA grades were similar and the concentration had only a minor effect. HPC showed the largest free volume holes (86.7–89.5 ų), and Na-alginate the smallest holes (36.9–39.6 ų) together with the highest LOD (20.2–21.6%). Across the 12 polymer–concentration combinations, the free volume hole volume correlated inversely with LOD (Spearman ρ = −0.85) but not with the equilibrium swelling index, as both HPC and Na-alginate swelled considerably more than PVA. Thus, PALS discriminates film-forming pharmaceutical polymers and reflects their residual water content, but the free volume of the air-dried films does not predict their swelling capacity.