Miloud Rahmouni

Enzymatic degradation of cross-linked high amylose starch tablets and its effect on in vitro release of sodium diclofenac.

The influence of several physicochemical parameters on enzymatic hydrolysis and the in vitro release of sodium diclofenac (SDic) from cross-linked high amylose starch (Contramid) (CLA) tablets was evaluated. These parameters included pH, ionic strength of the medium, enzyme concentration, compression force and incorporation of gel-forming polymers such as hydroxypropyl methylcellulose (HPMC), poly(ethylene oxide) (PEO) and poly(vinyl alcohol) into the tablet. Pure CLA tablets were incubated in phosphate buffer (pH 6.8) containing alpha-amylase and the extent of enzymatic erosion was determined by gravimetry. Release of SDic from CLA tablets, in the presence of alpha-amylase, was measured using a USP type III dissolution apparatus. For low alpha-amylase concentrations (<2250 IU/l), the drug release was mainly diffusion-controlled. At higher alpha-amylase concentrations (>4500 IU/l) both diffusion and erosion contributed to the release of SDic. The hydrolysis kinetics of CLA tablets by alpha-amylase was biphasic. During the first phase (2-4 h), the hydrolysis rate was hyperbolically related to the alpha-amylase concentration but was practically alpha-amylase concentration-independent during the second phase. Enzymatic erosion and drug release kinetics appear to be relatively independent of ionic strength, pre-incubation time in simulated gastric fluid, and compression force of the tablets (6-34 kN). Incorporation of HPMC or PEO into the tablet resulted in a significant decrease of both tablet erosion and drug release rates.

Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethylcellulose used in the preparation of controlled release tablets.

Cross‐linked amylose starch (CLA), hydroxypropylmethylcellulose (HPMC), and HPMC/CLA matrices were prepared by direct compression. HPMC was used to slow down the enzymatic degradation of CLA matrices. CLA was either granulated alone and mixed with HPMC or cogranulated with the latter. Compaction characteristics of the powder, hydration and mechanical properties of the resulting matrices, as well as the release profiles of three model drugs were investigated. The results showed that wet granulation of CLA in the presence of 10% HPMC improved significantly the flow properties of the powder without compromising its compactibility. Both CLA and HPMC deformed mainly by plastic flow (yield pressures are 75 and 124 MPa, respectively), but CLA exhibited a stronger elastic component (elastic recoveries are 18.4 and 11.5%, respectively). The values of yield pressure increased linearly with the concentration of HPMC. The addition of HPMC to CLA slightly decreased the resistance to consolidation but the crushing force of the final compacts was found to be proportional to the HPMC concentration. Mechanical studies on swollen matrices revealed that CLA formed a stronger gel than HPMC or CLA/HPMC mixture, and swelling and erosion of the tablets increased with HPMC content and incubation time. The in vitro release kinetics of three model drugs (pseudeoephedrine sulfate, sodium diclofenac, and prednisone) showed a clear effect of drug solubility and presence of α‐amylase in the dissolution medium on the release rate. The addition of HPMC to CLA protected the tablets against α‐amylase hydrolysis and reduced the release rate of prednisone and sodium diclofenac. The release of pseudoephedrine sulfate was fast and independent of HPMC and occurred mainly by diffusion.