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EVALUATION OF ENHANCER EFFECT ON THE IN-VITRO RELEASE OF BETAMETHASONE-17-VALERATE GELS

Taner enyiit, zgen zer


Ege University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 35100, Bornova-zmir, Turkey
*E-mail address: taner.senyigit@ege.edu.tr

INTRODUCTION
Topical corticosteroids are first-line drugs in the therapy of acute exacerbations of atopic dermatitis and contact dermatitis. Betamethasone-17-Valerate (BMV) is the gold standart of these agents and serves as reference in clinical studies for new glucocorticosteroids [1]. Chitosan, a natural poly-(aminosaccharide), is non-toxic and easily bioabsorbable and currently in use for the release of several drugs [2]. The most widely used approach to drug permeation-enhancement across the stratum corneum barrier is the use of chemical penetration enhancers. Enhancers are compounds which can increase the permeability of the stratum corneum by either increasing drug diffusivity and/or by increasing drug partition [3]. The aim of this study was to evaluate the enhancement effect of three different types of enhancers (Oleic acid, D-limonene and 2-pyrrolidone) on the in vitro release of BMV gels. Propylene glycol was chosen as co-enhancer in this study.

RESULTS AND DISCUSSION


The kinetical parameters of BMV obtained from the release of formulations through cellulose acetate membrane were shown in Table 1. The effect of enhancers on the flux of BMV from chitosan gels was also shown in Figure 1. Table 1 Kinetical parameters of BMV
Enhancers Control Oleic Acid D-limonene 2-pyrrolidone Released BMV for 6h (mg/cm2) 0,0174 0,0011 0,0215 0,0007 0,0216 0,0008 0,0175 0,0003 Flux (mg/cm2/h) 0,0024 0,0001 0,0027 0,0001 0,0028 0,0003 0,0027 0,0003 ERflux 1,0 1,13 1,17 1,13 Lag time (h) 0,0030 0,0001 0,0060 0,0003 0,0063 0,0005 0,0035 0,0002

0,0035 0,003

Flux of BMV

0,0025 0,002 0,0015 0,001 0,0005 0


Control Oleic Acid

MATERIALS AND METHODS


Materials BMV was kindly gifted from GlaxoSmithKline. Weight Chitosan, D-limonene and 2-pyrrolidone from Sigma and Oleic acid was obtained from glycol was purchased from Riedel-de-Haene. All were of analytical grade. Preparation of Chitosan Gels In our previous study [4], high molecular weight chitosan gel formulation showed lower drug release and good textural properties. Therefore, we decided to use different types of enhancers to increase the release rate of this formulation. High molecular weight chitosan 1.5 % (w/w) was dissolved in 1.5 % (v/v) acetic acid solution. BMV was dissolved in propylene glycol and added to chitosan solution with continuous stirring until uniformity. Enhancers were added to formulations at different concentrations (Oleic acid 1 %, D- limonene 2 % and 2-pyrrolidone 5 %). High Molecular were purchased Fluka. Propylene other chemicals

Enhancers

D-limonene

2-pyrrolidone

Figure 1 Effect of enhancers on the flux of BMV from chitosan gels When all kinetical parameters evaluated together, no significant correlation was established among the enhancers. ER value was found higher than control in all cases. D-limonene provided the best enhancement activity between the enhancers studied (Table 1, Figure 1). By the way, when the amount of drug at the end of six hours was investigated, D-limonene and Oleic acid exhibited higher drug release when compared with 2-pyrrolidone (Table 1). It was reported that propylene glycol has showed synergic effect with many enhancers such as Oleic acid and D-limonene [5]. So, the results of this study could be due to the synergic effect between D-limonene, Oleic acid and propylene glycol. In addition, Dlimonene increased the thermodynamic activity of BMV and the released amount of BMV has been increased. However, 2pyrrolidone showed same drug release and lag time with control formulation (Table 1).

In Vitro Release Studies


The release of BMV from formulations was determined with dialysis tubes through cellulose acetate membrane (Sartorius, pore size: 0,2m, Germany) which was placed in continuously stirred (600 rpm) ethyl alcohol-distilled water (1:1) mixture at 370,5C. After serial sampling at specified time intervals, the amount of BMV was determined spectrophotometrically at 240 nm. The cumulative amount of BMV released through the cellulose acetate membrane was plotted as a function of time. The slope of the linear portion of the plot was calculated as the steady state flux (mg/cm2/h). Determination of Enhancement Efficacy The permeation enhancing activities enhancement ratios of flux (ERflux). were expressed as

CONCLUSION
On the basis of above observations, it can be concluded that Dlimonene and Oleic acid could be suitable enhancers in the presence of propylene glycol for high molecular weight chitosan gels of BMV.
ACKNOWLEDGEMENTS
The authors are grateful to the Novartis Drug Company for its financial support of this study.

REFERENCES
[1] R. Sivaramakrishnan, C. Nakamura, W. Mehnert, H.C. Korting, K.D. Kramer, M. Schafer-Korting, J. Cont. Rel. 97 493-502 (2004). [2] K.C. Gupta, M.N.V. Ravi Kumar, Biomaterials 21 1115-1119 (2000). [3] P.A. Cornwell, B.W. Barry, J.A. Bouwstra, G.S. Gooris, Int. J. Pharm. 127 9-26 (1996). [4] T. enyiit, .zer, 8th International Conference of the European Chitin Society, 8-11 September, Antalya-Turkey p. 152 (2007) [5] I. Z. Schroeder, P. Franke, U.F. Schaefer, C.M. Lehr, J. Cont. Rel. 118 196-203 (2007).

ERflux=

BMV flux with enhancer in gel BMV flux with no enhancer