Molecular Encapsulation of Thalidomide with Sulfobutyl Ether-7 β-Cyclodextrin for Immediate Release Property: Enhanced In Vivo Antitumor and Antiangiogenesis Efficacy in Mice

Abstract

Thalidomide's reported ability to inhibit tumor angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. Since thalidomide exhibits low oral bioavailability due to limitations in solubility, inclusion complexation using sulfobutyl ether-7 beta-cyclodextrin was used to improve the delivery of thalidomide. Our main goals were to increase the solubility, bioavailability as well as chemical stability of thalidomide through complexation with anionic beta-cyclodextrin, to characterize the complex in solid state using differential scanning calorimetry, X-ray powder diffractometry, and to explore thalidomide's antitumorigenic and antiangiogenesis potential when administered orally as free and in combination with cyclodextrin to experimental animals. The aqueous solubility and aqueous alkaline stability of thalidomide was markedly increased by the SBE7betaCD complexation. Thalidomide administered orally in combination with SBE7betaCD, led to a significant delay in tumor formation as a result of improved cellular drug absorption, distribution through solubilization in experimental animals. The improved pharmacological efficacy of the thalidomide-cyclodextrin complex compared to free thalidomide in mouse melanoma model suggest that such a delivery system may be useful for the improved therapeutics of thalidomide, in vivo.

Preparation, Characterization, and In Vitro Intestinal Permeability Evaluation of Thalidomide–Hydroxypropyl-β-Cyclodextrin Complexes

“…This enhancement has been attributed to the formation of stable complexes in the solid state, improving the hydrophilicity of the molecule and reducing its crystallinity, as indicated by DSC, XRD, and SEM studies. The in vitro dissolution results obtained with the free drug in this study were slightly different from those obtained by Kale and co-workers (13). This variability was attributed to the use of different thalidomide samples and experimental conditions.…”

“…The low solubility and poor dissolution of the drug in the gastrointestinal tract lead to an erratic and incomplete absorption (6,8). In order to circumvent instability and solubility issues, different pharmaceutical strategies have been employed which include: isolation of pure enantiomers (9), association with polymeric carriers (10), incorporation into nanoemulsions (11), and complexation with cyclodextrins (12)(13)(14)(15)(16).…”

Role of Angiogenesis and Microenvironment in Melanoma Progression

“…However, the minor effects founded on peripheral tumour manifestations, has led to the conclusion that Thalidomide might be part of the treatment strategy for these patients. On the basis of these promising but non optimal results and since Thalidomide exhibits low oral bioavailability due to limitations in solubility, some experimental modification of oral preparation have been tested to improve the delivery of Thalidomide and its therapeutical activity (Kale et al, 2008). Its complexation with sulfobutyl ether-7 beta-cyclodextrin has demonstrated to increase stability, oral bioavailability, drug absorption, and distribution through solubilization of Thalidomide in experimental animals.…”

Sulfobutyl Ether7 β-Cyclodextrin (SBE7 β-CD) Carbamazepine Complex: Preparation, Characterization, Molecular Modeling, and Evaluation of In Vivo Anti-epileptic Activity

“…Thus, SBE 7 β-CD can be considered to be very safe for oral administration. SBE 7 β-CD inclusion complexes of some hydrophobic drugs such as chlorpromazine, valdecoxib, and thalidomide have already been evaluated, and SBE 7 β-CD inclusion complexes were able to improve the oral bioavailability and/or therapeutic efficacy of these drugs (11)(12)(13).…”