Sulfadiazine permeation in artificial membrana. In vitro prediction and the influence of DSZ:CD:Aas inclusion complexes

DELRIVO A, GRANERO G, LONGHI MR

Rosario

Congreso; 2º Reunión Internacional de Ciencias Farmacéuticas. RICifa 2010; 2012

Introduction Cyclodextrins (CDs) are natural cyclic oligosaccharides that are formed through enzymatic degradation of starch. CD complexation of a poorly soluble lipophile will improve its aqueous solubility but the complex itself is, in general, unable to permeate biological membranes per se. Consequently, CDs can both enhance and hamper drug permeation through biological membranes (1). Some investigations carried out in our laboratory have shown the feasibility of complex formation between sulfadiazine (SDZ), CD and aminoacids (AAs) and have demonstrated that complexation improved the aqueous solubility of the drug (2, 3). On the basis of these previous considerations, the purpose of the present study was to investigate the potential advantages of the combined use of βCD and AAs, with the aim of better exploiting their favorable carrier properties and evaluating their possible synergistic effects on absorption behavior of SDZ, which was measured with an in vitro method using an artificial membrane (4). Materials and methods SDZ was obtained from Parafarm, βCD was a gift from Ferromet S.A., Lipoid 75 was a gift from DROMEX SA. The studies of permeability through the artificial membrane were conducted using Franz horizontal diffusion cells. Aliquots of 1 ml were taken at specified times from the receptor compartments, which were replaced with same volume of buffer maintained at the same temperature (37°C). The samples were analyzed by UV-VIS spectrophotometry. With the obtained data, we proceeded to graph the amount of SDZ (mg/cm2) accumulated per unit area (exposed surface of the artificial membrane, 0.502 cm2) vs. time (s). Then, the apparent permeability coefficient (Papp) was calculated. Results The Papp value of SDZ was considered statistically different respecting to Papp values obtained for the different binary and ternary complexes. It was corroborated by the application of T test (p <0.05). In addition, according with the limit established by the proposed in vitro method, SDZ permeability was considered low. When analyzing the complexes, different results were obtained, however, all of them increased the permeability of SDZ respecting to when it is free. Then was evaluated the effect of βCD amount in the binary system regarding the Papp values [molar ratios (SDZ:βCD): 1:0.5 / 1:1 / 1:2]. It could be seen that the formation of stable complexes between SDZ and βCD, caused a decrease in the concentration of the free drug, thereby reducing the permeability of it through the membrane, over a period from 0 to 60 minutes. However, after this period, the drug Papp values of complexes were higher respecting to free SDZ. Conclusions The results suggest that the use of suitable combinations of SDZ, CDs and AAs could be exploited to develop appropriate SDZ oral pharmaceutical forms capable of simultaneously improve the permeability of the drug and, consequently, improve its bioavailability. Acknowledgments We thank Ferromet S.A (agent of Roquette in Argentina) for its donation of β-cyclodextrin References 1) Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes. Journal of Pharmacy and Pharmacology 2011; 63:1119-35. 2) Delrivo, A., Zoppi, A., & Longhi, M. R.. Interaction of sulfadiazine with cyclodextrins in aqueous solution and solid state. Carbohydrate Polymers 2012, 87(3):1980-88. 3) Study of the influence of ternary systems on the aqueous solubility of Sulfadiazine. Preparation and characterization in solid state. Delrivo A; Longhi MR. RICIFA 2010 4) DESARROLLO DE UN MODELO IN VITRO PARA PREDECIR LA ABSORCIÓN ORAL DE FÁRMACOS EN HUMANOS. Delrivo A, Granero G., Longhi M. SAFE 2011 HAY QUE SIMPLIFICAR LA REVISTA *Corresponding author. Tel + 54 351 4334163, fax +54 351 4334127; e-mail: mrlcor@fcq.unc.edu.ar