Controlled release of a local anesthetic from fatty acid dimer based polyanhydride

Abstract

Prolonged reversible nerve blockade has broad applications in a number of clinical areas involving acute or chronic pain. The desired periods of reversible nerve blockade could vary from as little as one day to as long as one week. Implantation of a biodegradable controlled release local anesthetic device adjacent to nerves could potentially be a valuable dosage form. Therefore, controlled release devices based on polyanhydride polymers were prepared which would release the local anesthetic bupivacaine hydrochloride with varying rates. The parameters affecting the release of drug were studied in order to optimize the formulation. The studies were conducted with rectangular devices consisting of bupivacaine HCl dispersed homogeneously in the polymer at a loading of 10% w/w. Devices fabricated from three different copolymers, synthesized from fatty acid dimer and sebacic acid, were studied to determine the effect of comonomer on the release kinetics of the drug. Release studies were conducted at pH 7.4, 37°C, and the release profiles were analysed to determine the mechanism of release. The release of bupivacaine HCl could be best described by first order release kinetics from all the three copolymers and the release rate constant, k r , was directly proportional to the hydrophilicity of the polymer. The first order release rate constants were linearly proportional to both, the erosion rate and drug release rate ( r 2 = 0.999). Release profiles from all the three copolymers could also be described by an equation derived for a surface eroding cylindrical device. The erosion rate, B in cm/day, was obtained by fitting the release profile to the equation using a nonlinear regression method. The results showed that the drug release is controlled by erosion for the three copolymers, P(FAD-SA) 30:70, 20:80, and 10:90 and the release rates were 0.0004, 0.00066 and 0.0012 g/cm 2/day, respectively. In addition, release profiles expressed as m t / m ∞ (fractional agent release profile) versus t/ t ∞ fitted the theoretical equation for all the three copolymers. These results suggest that polyanhydrides undergo pure surface erosion at pH 7.4 and therefore the device geometry and erosion rate determine the release kinetics. Thus, knowing the erosion rate of the fatty acid dimer based polyanhydride, would help in achieving the appropriate drug release kinetics by manipulating the geometry of the device.