Cardiovascular effects of transdermally delivered bupranolol in rabbits: effect of chemical penetration enhancers.

Bupranolol is a promising candidate for transdermal drug delivery system (TDDS) development. The effect of permeation enhancers on the in vivo delivery and beta-blocking effect of reservoir type TDDS was studied in comparison with intravenous BPL in rabbits. The beta-blocking effect was quantified by measuring the inhibition of isoprenaline induced tachycardia in rabbits after BPL administration via transdermal and intravenous routes. The reservoir type TDDS containing a hydroxypropyl cellulose gel and polyethylene membrane was used as a control device. In comparison, the TDDS containing skin penetration enhancers, either 2-pyrrolidone or partially methylated beta cyclodextrin (PMbetaCD) were evaluated. The control device (no enhancer) produced about 52% inhibition of isoprenaline induced tachycardia at 2 h and the effect continued over 24 h application period, however, the devices with 2-pyrolidone or PMbetaCD produced about 85% inhibition of isoprenaline induced tachycardia at 3 h and the same effect continued over 24 h application period. Likewise, the AUC of these devices were significantly higher than that of control device. The intravenous bupranolol showed rapid decline in the pharmacodynamic effect with time indicating its rapid elimination. The in vivo delivery of bupranolol (as estimated by a mass balance study) from the devices made with pyrolidone or PMbetaCD was 3-fold higher than that of control. The results of this study strongly suggest that the penetration enhancers in the TDDS increased the in vivo delivery of BPL, thereby increased the beta-blocking activity of BPL by 50-60% higher than control, enabling the reduction of the TDDS patch size, accordingly.

Preparation and characterization of a customized cellulose acetate butyrate dispersion for controlled drug delivery.

The purpose of the present experiment was to prepare and characterize the aqueous-based pseudolatex system of cellulose acetate butyrate (CAB) for controlled drug delivery. Aqueous pseudolatex systems are advantageous over organic-based coating systems because these systems are devoid of criteria pollutants such as carbon monoxide, nitrogen oxides, nonmethane volatile organic compounds, and sulfur dioxide. Pseudolatex was prepared with CAB and polyvinyl alcohol (stabilizer) by a polymer emulsification technique. The stability of pseudolatex was evaluated. Particle size was measured and rheological experiments were conducted. The glass transition temperature, microscopic free volume, permeation coefficient, and mechanical properties of plasticized pseudolatex films were estimated. Surface roughness of coating on inert Nu-Pareil beads (Ingredient Technology Corp., Mahwah, NJ) was measured as a function of coating weight gain. The CAB Pseudolatex was found to be stabilized by steric forces. From intrinsic viscosity, the thickness of the stabilization layer was estimated. An increase in polymeric particles proportionately decreased the thickness of the stabilization layer. All the essential properties of a coating membrane such as microscopic free-volume fraction, permeability coefficient, mechanical properties, and glass transition temperature were fairly controllable as a function of plasticizer concentration. The pseudolatex dispersion of CAB was stable with negligible sedimentation volume and a particle size of 300 nm. Because CAB is water insoluble and non-ionizable, this pseudolatex can be used for pH-independent coating. The films obtained were strong and flexible for controlled drug delivery applications. Coating with the CAB dispersion reduced the surface roughness of beads but it remained stable as a function of increase in coating weight gain.

Optimization and characterization of controlled release multi-particulate beads formulated with a customized cellulose acetate butyrate dispersion.

The objectives of the present investigation were: (1) to model the effect of process and formulation variables viz., coating weight gain, duration of curing, and plasticizer concentration on in-vitro release profile of verapamil HCl from multi-particulate beads formulated with a novel aqueous-based pseudolatex dispersion; (2) to optimize the formulation by response surface methodology (RSM) and artificial neural network (ANN); and (3) to characterize the optimized product by thermal and X-ray analyses. Inert beads (Nupareil) were loaded with verapamil HCl and subsequently coated with a custom designed aqueous-based pseudolatex dispersion of cellulose acetate butyrate (CAB). Experiments were designed and data was collected according to a three factor, three level face centered central composite design. Data was analyzed for modeling and optimizing the release profile using both RSM and ANN. Model fitted the data and explained 90% of variability in response in the case of RSM and at least 70% in the case of ANN. Release profile was optimized for a zero-order model. Optimized formulations were prepared according to the factor combinations dictated by RSM and ANN. In each case, the observed drug release data of the optimized formulations was close to the predicted release pattern. However, the modeling and optimization abilities of RSM as evaluated by the R-squared values, were found to be higher than that of ANN. X-ray and drug content analysis suggested the absence of any degradation of verapamil HCl and excipients incorporated in the formulation.