Starch acetate as a film forming excipient in controlled drug delivery

The present investigation highlighted the prospect of using starch acetate as an excipient for coating multi-particulate beads for controlled drug delivery. Starch acetate with high degree of substitution (dS) was synthesized from native com starch using the aqueous paste disintegration method followed by acetylation in pyridine. The dS value as determined by the saponification-titration method was about 2.9. The synthesized polymer was compared with the raw material, starch, by Fourier transform infrared (FTIR), X-ray and molecular mass analysis. The reaction showed high yield and was found to be almost complete The rheologic and interfacial properties of starch acetate solution in chloroform were performed. The solution appeared to be a pseudoplastic system, especially at higher concentrations (1.5-5.0 %). The surface tension of the solution (28.36-33.31 dyne/cm) was relatively unaffected by polymer concentration (0.5- 5%) at 20 °C. Free films obtained from starch acetate solution in the presence of 17 different plasticizers were characterized. Triacetin and triethyl citrate were the best among all common plasticizers tested in terms of physical appearance, mechanical strength and glass transition temperature of the films. Permeation of tritiated water through the films with triacetin was dependent on the extent of plasticization. It increased from 3.15x10"^ to 4.15x10"^ cm^/s when triacetin concentration was increased from 50 to 80%. Scanning electron microscopic (SEM) photographs revealed clear differences between smooth plasticized and rough unplasticized films. Prepared starch acetate was utilized to coat beads containing the model drug.

The model drug, dyphylline was compatible with the core, Nu-pareil® inert beads, the binder, Opadry® and the anticaking agent, talc through thermal, FTIR and content analyses. Dmg loading was performed in a fluid bed coater with a bottom spray system. Drug-loaded beads were coated using starch acetate solution containing triacetin in the fluid bed coater. Seven formulation and process variables were screened by a Plackett- Burman statistical design. Coating weight gain, plasticizer concentration and curing temperature had greater influence than other factors on the in vitro drug release in a USP type-II dissolution apparatus over 12 h.

A further optimization procedure was carried out using response surface methodology (RSM). A three factor, three level Box-Behnken design was employed for this purpose The three factors studied, coating weight gain (X). Plasticizer concentration (X2) and curing temperature (X3), were found to correlate (R^2=99.61) with cumulative percent drug released after 12 h (Y5) by the regression equation, Y5 = 89.83 - 11.98X1 + 2.82X2 - 4.31X1^2 + 1 .90X1X2. Contour and response surface plots explained the interaction effects. Optimization was done by maximizing drug release over 12 h and placing constraints at dissolution time points of 0.5, 1, 4 and 8 hours. The optimized formulation (Xi=10%,X ^2=55%, X3=45 °C) showed a first-order release and was close to the predicted model in terms of the two commonly used fit factors, f1 and f2 values.

A properly trained artificial neural network (ANN) was utilized as an alternative for optimization. A set of designed data were used as the input. Very low system error and more than 99% of train and test R^2 values indicated the strength of the procedure. The observed optimized data were in close agreement with the expected values with f1 and f2 values of 0.67 and 97.18, respectively. This showed that if properly utilized, ANN can compete with the popular experimental designs used in pharmaceutical study.

Thermal, X-ray and infrared analyses suggested absence of any significant interaction of the drug with the excipients used in the optimized formulation. SEM photographs showed a continuous film over the bead covering the drug layer.

Surface roughness of starch acetate coated beads at different coating level was used to determine the completion of coating. Minimum roughness was found at 3% coating level. The optimized bead also had low values of roughness parameters.

The drug release pattern from the optimized formulation was unaffected by acidic environment or a-amylase An in vivo study in male Sprague-Dawley rats showed more sustained plasma dyphylline level as compared to drug powder, used as the control. The mean Cmax, Tmax andAUC for the formulation were calculated to be 5.70+0.56 μg/ml 4 h and 47.08+5.15 μg.h/ml, respectively, compared to 11.10±0.20 μg/ml, ≤1 h and 64.40±I0.63μg.h/ml for the control (n=6). The mean residence time of the drug increased significantly (p<0.05) for the controlled release product (6.2 versus 4.4 h).

These results show that starch acetate with dS 2.9 may serve as a valuable addition to the list of polymeric excipients for controlled drug delivery of small organic molecules such as dyphylline.