Evaluation of antibiotic and antibiotic/analgesic hydrogels with potential utility as topical therapy

BREDA S ANDREA; MANZO, RUBEN; OLIVERA M

Cordoba

Congreso; 1º Reunión Internacional de Ciencias Farmacéuticas-RICiFa; 2010

Topical therapy is a convenient way to administer drugs, optimizing concentration in the target site and/or minimizing systemic exposition. Hydrogels are an important class of biomaterials. Since their ability to uptake exudates, sustained release of drugs and convenient biocompatibility, rheological and bioadhesive properties, these systems are potentially suitable for therapeutic uses. A fundamental understanding of mechanical properties, drug release and underlying molecular mechanisms is crucial for determining whether these biomaterials. Goal: develop a ciprofloxacin (or enrofloxacin)-loaded hydrogel and a ciprofloxacin/lidocaine-loaded hydrogel, with antibiotic and antibiotic/analgesic sustained release properties with potential utility in human and/or veterinary topical therapy. Materials and Methods: Series of carbomer-ciprofloxacin (or enrofloxacin) and carbomer-ciprofloxacin-lidocaine hydrogels were prepared by neutralizing a 0.5-1% dispersions of carbomer with variable amounts of NaOH solution, followed by addition of constant concentration of aqueous dispersions of the drugs (ciprofloxacin and enrofloxacin 0,3%, lidocain 0,67%). The hydrogels were sterilized (autoclave) and subjected to visual observation, weight changes, pH determination, rheology measurements and kinetic release studies in simulated biological fluids. Experiments were carried out at temperatures simulating conditions of ambient (25ºC), eye (32ºC), skin (35ºC) and mucosa (37ºC). Stability was assessed at 23ºC y 40% HR during 6 months by HPLC methodology. Irritation and refreshing potential (using silver sulfadiazine cream as a reference) were assessed by Draize1 and modified Tail Flick tests. Results: The pH values ranged 6.80-7.01. Differences in NaOH produced small modifications of pH, suggesting high buffer capacity, related to the overlapping of acid-base equilibrium of drugs and carbomer. Although pH increases with temperature (p<0.05), owing to ionic pairs dissociation2,3, the systems maintain within the physiologically recommended pH range for topical administration. The hydrogels obtained at 0.5% of carbomer showed the best subjective and rheologic characteristics (plastic flow, yield stress=90 Pa/seg, independent of temperature) to be applied to skin and mucous tissues. No physical or chemical modifications neither of the drugs nor the formulations were observed after sterilization and storage period, suggesting they are stable and can be obtained as sterile products. In addition, no irritation signs emerged after application to skin (primary irritation index=0). Longer reaction times to the heat were observed after application of hydrogels to healthy skin compared to reference, suggesting an immediate refreshing effect due to water evaporation. Release profiles fitted to Higuchi release kinetics, with sustained release up to 24 h in presence of biological fluids. Bactericidal and minimal analgesic concentrations were achieved in the first 30 and 10 min, respectively. Enrofloxacin released 1.96 folds faster than ciprofloxacin probably due to the steric hindering produced by ethyl portion of enrofloxacin. An increase in release rate with temperature (p<0.05) was also observed, matching pH observations. When lidocaine was incorporated, a reduction in ciprofloxacin release rate was observed. Although statistically significant, differences observed are too small to have a clinical impact. Conclusions: The obtained systems have a smart release behavior. They are stable and can be obtained as sterile products. Their antibiotic and antibiotic/analgesic properties suggest they could be potential candidates for the topical prophylaxis and/or treatment of susceptible infections such as wounds burns and endometritis equine. Uterous biocompatibility and efficacy studies are in progress.    Acknowledgments: This work was supported by SECyT-UNC, FONCyT and Ministerio de Salud de la Nación Argentina, Breda S thanks for the CONICET fellowship.   References (1)          Draize J, Woodard G, Calvery H. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 1944; 83: 377?390. (2)          Vilches A, Jimenez A, Alovero F, Olivera M, Allemandi D, Manzo R. Release kinetics and up-take of model fluoroquinolones from carbomer hydrogels. Int J Pharm 2002; 246: 17-24. (3)          Jimenez A, Allemandi D, Manzo R. Mechanism of lidocaine release from carbomer-lidocaine hydrogels. J Pharm Sci 2002; 91: 267-72.