engleski

Inclusion complexes of nabumetone with β-cyclodextrin and its selected derivates

Nabumetone (NAB) is a nonsteroidal anti- inflammatory prodrug which is clinically used for reducing pain and inflammation in the treatment of patients with osteoarthritis or rheumatoid arthritis. Its main active metabolite, 6-methoxy-2-naphtylacetic acid acts as a strong inhibitor of cyclo- oxygenase isoenzymes [1]. Since NAB possesses low aqueous solubility [2], it can be classified as a Class 2 drug substance according to The Biopharmaceutics Classification System. Cyclodextrins (CDs) are group of cyclic oligosaccharides containing six (α-CD), seven (β-CD) or eight (γCD) D-glucopyranose units which are α-(1, 4)-linked in a ring formation. Their structure is visualized as a truncated cone with hydrophilic outer surface and hydrophobic central cavity. Their ability of forming water soluble inclusion complexes with lipophilic drug molecules has been intensively studied [3]. Inclusion complexes of NAB with α- CD [4], γ-CD [2], β-CD and its derivatives [4, 5] have already been studied, as was the influence of α-CD and γ-CD on the enhancement of NAB solubility in unbuffered aqueous solution [6]. The aim of this study is to evaluate influence of β-CD and its hydroxypropyl (HPβCD), sulfobutylether (SBEβCD) and randomly methylated (RMβCD) derivatives on intrinsic solubility of NAB in water and in buffered aqueous solutions (simulated gastric fluid, pH 1.0. ; simulated duodenal fluid, pH 4.5 and simulated intestinal fluid, pH 6.8) by means of phase-solubility analysis according to the existing Higuchi-Connors method [7]. In order to evaluate total drug solubility changes in the presence of increasing CD concentration phase-solubility diagrams were constructed. Quantitative determination of NAB was performed by developed UV/Vis spectrophotometric and spectrofluorimetric methods. Complexation of NAB with selected β-CDs was studied by fluorescence spectroscopy since CD- induced variation of native NAB fluorescence was noticed. In order to determine formation constants BenesiHildebrand plots were constructed [7]. REFERENCES [1] T. Hedner, O. Samulesson, P. Währborg, H. Wadenwik, K.-A. Ung, A. Ekbom, Drugs 64 (2004) 2315–2343. [2] N. A. F. Al-Rawashdeh, J. Inclusion Phenom. Macrocyclic Chem. 51 (2005) 27–32. [3] P. Jansook, N. Ogawa, T. Loftsson, Int. J. Pharm. 535 (2018) 272–284. [4] M. Valero, S. M. B. Costa, J. R. Ascenso, M. M. Velázquez, L. J. Rodríguez, J. Inclusion Phenom. Macrocyclic Chem. 35 (1999) 663–677. [5] N. Goyenechea, M. Sánchez, I. Vélaz, C. Martín, C. Martínez- Ohárriz, G. González- Gaitano, Luminescence 16 (2001) 117–127. [6] N. Goyenechea, M. Sánchez, I. Vélaz, C. Martín, C. Martínez-Ohárriz, A. Zornoza, J. Inclusion Phenom. Macrocyclic Chem. 44 (2002) 283–287. [7] K. Connors, Binding Constants, John Wiley & Sons, New York, 1987, 141–281.

cyclodextrins ; nabumetone ; inclusion complexes

nije evidentirano