Abstract
Sulpiride (SPR) is a selective antagonist of central dopamine receptors but has limited clinical use due to its poor pharmacokinetics. The aim of this study was to investigate how metal ligation to SPR may improve its solubility, intestinal permeability and prolong its half-life. The synthesis and characterisation of ternary metal complexes [Ru(p -cymene)(L)(SPR)]PF6 (L1 = (R)-(+)-2-amino-3-phenyl-1-propanol, L2 = ethanolamine, L3 = (S)-(+)-2-amino-1-propanol, L4 = 3-amino-1-propanol, L5 = (S)-(+)-2-pyrrolidinemethanol) are described in this work. The stability constant of the [Ru(p -cymene)(SPR)] complex was determined using Job’s method. The obtained value revealed higher stability of the metal complex in the physiological pH than in an acidic environment such as the stomach. The ternary metal complexes were characterised by elemental analysis, Fourier transform infrared spectroscopy (FT-IR), 1H and 13C nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermal analyses, Ultraviolet-Visible (UV-Vis). Solubility studies showed higher aqueous solubility for complexed SPR than the free drug. Dissolution profiles of SPR from the metal complexes exhibited slower dissolution rate of the drug. Permeation studies through the pig’s intestine revealed enhanced membrane permeation of the complexed drug. In vitro methyl thiazolyl tetrazolium (MTT) assay showed no noticeable toxic effects of the ternary metal complexes on Caco-2 cell line.
Highlights
Www.nature.com/scientificreports were orally administered to rats to achieve sustained drug release
Aqueous solubility improvement of a drug through metal complexation has been previously demonstrated by Ross and Riley who observed an increase in the aqueous solubility of lomefloxacin in the presence of calcium, magnesium, aluminium and iron ions[18]
This study focuses on the investigation of ruthenium (Ru) metal as a possible drug carrier with the ability to enhance the intestinal permeability and to retard the release of the drug bonded to it
Summary
Www.nature.com/scientificreports were orally administered to rats to achieve sustained drug release. A further study in this area was conducted by Breda and co-workers on aluminium (III) complexes of ciprofloxacin and norfloxacin Bioactives in both complexes exhibited higher aqueous solubility than the respective free drugs in the pH range 2–920. Ruthenium metal complexes have shown great potential for use as therapeutic compounds[24] Such metal complexes have many benefits, including improved water solubility, improved bioavailability, and increased lipophilicity for better absorption through the cell membrane[25]. Sulpiride (SPR) is a substituted benzamide derivative antipsychotic agent that belongs to class IV in the Biopharmaceutical Classification System (BCS), and has poor aqueous solubility and limited intestinal permeability[29,30] This drug is slowly and poorly absorbed in the gastrointestinal tract after oral administration, resulting in a bioavailability of approximately 30%, coupled with a relatively short half-life of 6 to 8 hours[31]. SPR remains an effective antipsychotic, the need to develop strategies to improve its pharmacokinetics[33,34]
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