Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations

Background: Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness. Objective: The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl β- cyclodextrin (HPβCD). It has slow and erratic absorption after oral administration. Methods: This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet. Results: In-vitro study (100 % drug release in 15 minutes), and in-vivo study of an AL-type (linear type) phase solubility diagram indicated a complex of AMS-HP-β-CD with the constant complex formation of 13245 M−1 at 37°C. The complex formation was confirmed by DSC, IR, and X-ray diffraction. The extent of absorption of the complex was determined in rats and was compared with that of pure drug and the market product. The peak plasma concentration of pure drug was 30.05 ± 1.3 ng/ml (Cmax) at 60 ± 3 min, whereas with the market product the value was 54.85 ± 1.2 ng/ml at 40 ± 1 min and with AMS-HPβCD inclusion complex the value was 79.01 ± 1.5 ng/ml. The AUCtot of the pure drug was 2980.34±3.6, the market product was 7238.73±2.9 and of the inclusion complex was 11871.1±2.8. Conclusion: Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%.

Preparation and in vitro Evaluation of Inclusion Complexes of Nelfinavir with Chemically Modified ?-cyclodextrins

Nelfinavir is a poorly water-soluble antiretroviral drug with relatively low bioavailability. In the present study, the practically insoluble drug, nelfinavir (NFV) and its inclusion complexes with hydroxypropyl-?-cyclodextrin (HP-?-CD) were investigated to improve the aqueous solubility and the dissolution rate of the drug, thus enhancing its bioavailability. The phase solubility diagram with HP-?-CD was classified as AL-type at all temperatures investigated, indicating the formation of higher order complexes. The apparent complexation constants (K1:1) calculated from phase solubility diagram were 145.49, 188.45 and 255.54 M-1 at 25, 37 and 45 ± 0.5°C, respectively. Aqueous solubility and dissolution studies indicated that the dissolution rates were remarkably increased; this could be mainly attributed to the improved solubility and dissolution associated with inclusion complex between drug and HP- ? -CD. Absence of endothermic and characteristic diffraction peaks corresponding to NFV was observed for the inclusion complex in DSC and PXRD. FT-IR study indicated that the presence of intermolecular hydrogen bonds between NFV and HP-?-CD in inclusion complex, resulting in the formation of amorphous form. DOI: http://dx.doi.org/10.3329/dujps.v11i2.14558 Dhaka Univ. J. Pharm. Sci. 11(2): 107-116, 2012 (December)

Molecular solubilization of fullerene C60 in water by γ-cyclodextrin thioethers

Various hydrophilic γ-cyclodextrin (CD) thioethers, containing neutral or ionic side arms were found to form molecular disperse solutions of C60 in water reaching concentrations of 15 mg/L. Equilibrium state was approached after seven days without the use of organic cosolvents. The 1:2 stoichiometry of the C60/γ-CD thioether complexes was demonstrated by a parabolic phase-solubility diagram. In contrast, native γ-CD forms nanoparticles with C60. Particle sizes of C60 were determined by dynamic light scattering.

The Influence of Cyclodextrin and pH on the Solubility of Ketoprofen

Cyclodextrin complexation and pH adjustments have been reported as useful tools to increase the solubility of drug. The aim of this study was to investigate the influence of both cyclodextrin and pH on the overall solubility of ketoprofen. β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) were used for the preparation of inclusion complex by shaking method in aqueous solution at pH 2, 5, 7 and 10. It was found that the solubility of ketoprofen significantly increased with increasing pH and cyclodextrin concentration, showing AL type phase solubility diagram. However, the apparent stability constant of complex (KC) was found to decrease with increasing pH due to the decreased affinity of ionized drug to cyclodextrin cavity. The ionization of ketoprofen increased when the pH was raised, corresponding with its higher zeta potential. The result indicated that the solubility of ketoprofen could be improved by using a combined approach of pH adjustments and complexation with cyclodextrin. Moreover, the unionized drug that was formed by pH adjustments interacted with cyclodextrin more strongly than the ionized drug.