Preparation and characterization of simvastatin/DMβCD complex and its pharmacokinetics in rats

Abstract

Simvastatin is poorly bioavailable because it is practically insoluble in water and shows dissolution rate-limited absorption. Solubilizing effects of several β-cyclodextrin (βCD) derivatives such as HPβCD, SBEβCD and DMβCD on simvastatin in aqueous solution were investigated using the phase solubility technique. The solubility diagram of simvastatin with each βCD derivative could be classified as AL-type, indicating soluble complex formation of 1:1 stoichiometry. Among the above βCD derivatives DMβCD was found to be the ideal complexing agent for improving drug solubility. The simvastatin complex with DMβCD was prepared using the co-evaporation method and was then characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and in vitro dissolution. Dissolution and pharmacokinetic studies indicated that the simvastatin/DMβCD complex exhibited an increased dissolution rate, rapid absorption, and improved bioavailability in rats compared to free drug. Maximum plasma concentration (cmax) and the time to reach it (tmax) were 21.86 μg mL-1 and 1.4 h for the drug complex, 8.25 μg mL-1 and 3.0 h for free drug, respectively. Main pharmacokinetic parameters such as tmax, cmax were significantly different (p < 0.01) between the simvastatin complex and free drug. Bioavailability of the simvastatin complex relative to free drug was up to 167.0 %.

Aurisin A Complexed with 2,6-Di-O-methyl-β-cyclodextrin Enhances Aqueous Solubility, Thermal Stability, and Antiproliferative Activity against Lung Cancer Cells

“…As shown in Figure 5 , the characteristic endothermic/exothermic peaks of the free compounds were as follows: (i) AA at 93.0, 213.9, 229.7, and 284.1 °C and (ii) DMβCD at 51.8 °C. The endothermic peaks found at 213.9 and 229.7 °C corresponded to the melting point of AA, as previously reported [ 1 ], whereas the broad endothermic peak of DMβCD detected at 51.8 °C indicates the release of water molecules from the DMβCD’s hydrophobic inner cavity [ 29 ]. In the thermogram of the freeze-dried AA/DMβCD inclusion complex, the characteristic thermal peaks of AA and DMβCD totally disappeared, coinciding with the appearance of a new endothermic peak at 72.0 °C and an exothermic peak at 198.7 °C, similar to other reports [ 15 , 16 , 23 , 26 , 30 ].…”

Preparation of Solid Dispersions of Simvastatin and Soluplus Using a Single-Step Organic Solvent-Free Supercritical Fluid Process for the Drug Solubility and Dissolution Rate Enhancement

“…The characteristic absorption peaks of SIM were observed at 3548 cm −1 (free O–H stretching vibration), 2929 cm −1 (aromatic C-H stretching vibration), 1723 and 1695 cm −1 (stretching vibration of C=O for ester and lactone) [ 44 ]. In the case of SOL, the absorption peaks including a broad band at 3476 cm −1 (O-H stretching), 2924 cm −1 (aromatic C-H stretching), 1732–1625 cm −1 (C=O stretching), and 1478 cm −1 (C-O-C stretching) were observed in their ATR-FTIR spectrum [ 35 , 45 ].…”

<p>Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile</p>

“…PDI >1 indicates low uniformity, and vice versa. 4 The formulated co-crystals had low PDI (0.142-0.182), which suggested the uniformity of particle size. The FTIR spectra of the formulated co-crystals showed new peaks.…”

“…Pure SIM exhibited a sharp endothermic peak in the DSC curve at 138.8°C, which denoted its melting point. 4,14 The…”

“…The hydroxy acid form of SIM is pharmacologically active, thanks to the chemical and enzymatic actions on the prodrug. 4 SIM reduces high glucose levels and mitigates vascular events in people with type-2 diabetes mellitus. 5 Use of drugs that have poor solubility in water leads to problems with respect to dissolution and bioavailability.…”