In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract. I. Comparison of pH-responsive drug release and associated kinetics.

Multiple unit dosage forms for oral delivery of bioactive agents offer many advantages over single unit products (e.g., site-specific delivery, predictable gastrointestinal transit time and less localized adverse effects). In view of such benefits, this paper investigates the crosslinking of sodium alginate, low methoxylated pectin and their novel binary mixture with calcium ions through ionotropic gelation to pelletize the model drug, diclofenac sodium, using "environmentally benign" solvents and processing techniques. Crosslinked pellets of the above polymers in 2% (w/v) aqueous calcium chloride solution were prepared and evaluated for their structural and release behavior. The average size of the different pellets was 1.3 mm and drug entrapment capacity was optimized by reducing the calcium chloride solution pH to 1.6. Three types of pellet formulations were subjected to dissolution studies using the USP 23 Apparatus 2 and 3 over a pH range simulating the human gastrointestinal tract. Negligible drug release occurred in pH 1-4. However, rate of drug release in pH 6.6 ranged from rapid to slow (i. e., 100% drug release in 4 to 10 h, respectively) but always in a controlled manner. Weight change/erosion studies and swelling measurements were used to provide experimental correlation of kinetic model analysis for each of the three pellet systems. From model fitting studies and statistical treatment, the modified Hopfenberg equation {Mt/M infinity =1-[1-k1(t-tL,min)]n} best described the release kinetics for calcium-pectinate pellets. The model assumes heterogeneous erosion with kinetic constant k1=k0/C0r0, in which k0 is the erosion rate constant, C0 is the uniform initial concentration of drug in the matrix, r0 is the initial radius and tL, min is the lag time. The n values of 1, 2 and 3 apply to a slab, cylinder and sphere, respectively. In addition, the exponential models, namely the Power Law (Mt/M infinity =k1tn) and its derivative containing the lag time [Mt/M infinity =k1(t-tL,min)n], employed in the statistical treatment of data provided n values of approximately 0.8-1 in the case of the calcium-alginate and calcium-alginate-pectinate release kinetics. It is concluded that the proper selection of rate-controlling polymers and their interactive potential for crosslinking is important, and will determine the overall size and shape of pellets, the duration and pattern of dissolution profiles, pH sensitivity, drug loading capacity and mechanism of drug release.