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In this study, xanthan gum-facilitated ethyl cellulose microsponges were prepared by the double emulsification technique and subsequently dispersed in a carbopol gel base for controlled delivery of diclofenac sodium to the skin. Scanning electron microscopy revealed the porous, spherical nature of the microsponges. Increase in the drug/polymer ratio (0.4:1, 0.6:1, 0.8:1, m/m) increased their yield (79.1-88.5%), drug entrapment efficiency (50.0-64.1%), and mean particle diameter (181-255 μm). Compared to the microsponges with high drug/polymer ratio (0.8:1, m/m), the flux of entrapped drug through excised rat skin decreased by 19.9% and 17.0%, respectively, for the microsponges prepared at low and intermediate drug/polymer ratios. When an equivalent amount of pure drug (not entrapped into microsponges) was dispersed into the gel base and the flux was compared, the microsponges (drug/polymer ratio 0.8:1, m/m) were found to reduce the flux by 33.3%. Whether the drug was dispersed either in un-entrapped or entrapped form into the gel base, the drug permeation through rat skin followed Higuchi's diffusion kinetic model. The microsponges prepared at the lowest drug/polymer ratio exhibited a comparatively slower drug permeation profile and were hence considered most suitable for controlled drug delivery application. FTIR spectroscopy and DSC analyses indicated the chemically stable, amorphous nature of the drug in these microsponges. The gel containing these optimized microsponges was comparable to that of a commercial gel formulation and did not show serious dermal reactions. Hence, the microsponge system obtained at the lowest drug/polymer ratio could be useful for controlled release of diclofenac sodium to the skin.

A pH-sensitive graft co-polymer of polyacrylamide (PAAm) and sodium alginate (SA) was synthesized by free radical polymerization under a nitrogen atmosphere followed by alkaline hydrolysis. The co-polymer was characterized by Fourier transform infrared (FT-IR) spectroscopy, elemental analysis and thermogravimetric analysis (TGA). Ketoprofen-loaded graft co-polymer beads were prepared by ionotropic gelation/covalent cross-linking. The beads were characterized by swelling studies, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). A pulsatile swelling study indicated that the co-polymer exhibits considerable pH-sensitive behavior. Release of ketoprofen was significantly increased when the pH of the medium was changed from acidic to alkaline. Stomach histopathology of albino rats indicated that the beads were able to retard the release of the drug in the stomach, and gastric side-effects like ulceration, hemorrhage and erosion of gastric mucosa were diminished when the drug was entrapped into PAAm-g-SA-based pH-sensitive hydrogel beads.

The objective of this study is to select a multiple-unit sustained-release formulation and to compare it with both commercial immediate and single unit sustained-release capsules and also to determine whether an in vitro-in vivo correlation exists for single- and multiple- unit formulations. Indomethacin (20-60% w/w)-loaded, multiple-unit polystyrene microparticles were prepared by emulsion-solvent evaporation method from an aqueous system. The in vitro release profiles obtained in phosphate buffer of pH 6.8 for drug-loaded polystyrene microparticles and for commercial sustained-release capsules (Indocap-SR, 75 mg) were compared. As the microparticles with 50% indomethacin load showed a release profile comparable to that of the Indocap-SR release profile, the microparticles with this drug load was considered as optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in human volunteers. In spite of significantly higher C(max), Ka, and Ke, and lower T(max), t1/2a, t1/2e and AUC(0 --> infinity)) values observed with commercial Microcid immediate-release capsules, there was no sign of difference among the listed parameters between optimized microparticles and Indocap-SR capsules. Indeed, the values of retard quotient (Rdelta) calculated from half-value duration analysis did not show any statistical difference, indicating the occurrence of an almost same degree of retardation of drug release from the optimized microparticles and the Indocap-SR capsules. Furthermore, linear relationship obtained between the percentages dissolved and absorbed suggests a means to predict in vivo absorption by measuring in vitro dissolution. The results suggest that the optimized polystyrene microparticles could provide an alternative controlled-release drug delivery system for indomethacin.

Novel pH-sensitive hydrogel beads were prepared using a hydrolyzed poly(acrylamide-g-xanthan) (PAAm-g-XG) copolymer from a complete aqueous environment and evaluated for targeting ketoprofen to the intestine. The PAAm-g-XG copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The copolymer was characterized by FTIR spectroscopy, (1)H NMR spectroscopy, elemental analysis and thermogravimetric analysis. Pulsatile swelling study indicated that the copolymer exhibits considerable pH-sensitive behavior unlike pristine xanthan gum. Ketoprofen-loaded pH-sensitive beads were prepared by ionotropic gelation with Al(3 + ) ions. Release of drug from all the copolymeric beads was much lesser than that from pristine xanthan beads. Moreover, a maximum of 20% ketoprofen was released from the copolymeric beads in pH 1.2-5.5 during a period of 3 h, while a major portion of the drug was released in pH 6.8-7.4 gradually over a longer period. Pharmacodynamic activity and stomach histopathology of albino rats indicated that the beads were able to retard the drug release in stomach, and gastric side effects such as ulceration, hemorrhage and erosion of gastric mucosa were diminished when the drug was entrapped into PAAm-g-XG-based pH-sensitive beads.

The major aims of the present study were (1) to select a multiple-unit formulation that matched the in vitro dissolution profile of single-unit sustained-release commercial capsules, (2) to compare the sustaining/controlling efficacy of the selected multiple-unit formulation with that of the single-unit commercial conventional tablet and sustained-release capsules, and (3) to determine whether an in vitro-in vivo correlation exists for single- and multiple-unit formulations. Ibuprofen (20%-60% wt/wt)-loaded multiple-unit polystyrene microparticles were prepared by an emulsion-solvent evaporation method from an aqueous system. The in vitro release profiles obtained in phosphate buffer of pH 6.8 for drug-loaded polystyrene microparticles and for commercial sustained-release capsules (Fenlong-SR, 400 mg) were compared. Since the microparticles with 30% ibuprofen load showed a release profile comparable to that of the Fenlong-SR release profile, the microparticles with this drug load were considered to be the optimized/selected formulation and, therefore, were subjected to stability study and in vivo study in human volunteers. A single-dose oral bioavailability study revealed significant differences in C(max), T(max), t(1/2a), t(1/2e), K(a), K(e), and AUC between the conventional tablet and optimized or Fenlong-SR capsule dosage forms. However, all the parameters, with the exception of K(a) along with relative bioavailability (F) and retard quotient (R(Delta)), obtained from the optimized ibuprofen-loaded microparticles were lower than that obtained from the commercial Fenlong-SR formulation. Furthermore, linear relationship obtained between the percentages dissolved and absorbed suggests a means to predict in vivo absorption by measuring in vitro dissolution.

The antiinflammatory agent diclofenac sodium (Dc) exhibited remarkable antibacterial effects both in vitro and in vivo. Fifteen different bacteria sensitive to Dc as well as to a number of common antibiotics were tested for synergistic effects in vitro. Disc diffusion test with Dc and aminoglycosides assessed by stringent computation showed clear-cut synergism. Synergism between Dc and streptomycin (Sm) was found to be statistically significant (p < or = 0.01) when compared with their individual effects. By the checkerboard assessment procedure, the fractional inhibitory concentration (FIC) index of this combination was found to be 0.49, confirming synergism. The mouse protective capacity of this combination was then evaluated in vivo against S. typhimurium as the virulent infecting bacterium, and the size of bacterial load determined from infected autopsied animals. Statistical analysis by Student's 't' test suggested this drug combination is highly synergistic; synergism was also noted between Dc and other aminoglycosides.

Indomethacin-loaded polystyrene microparticles were prepared by emulsion-solvent evaporation method from an aqueous system. The effect of different parameters like concentration of aqueous phase emulsion stabilizer, volume of the organic disperse phase and initial drug loading on drug content and release of drug were investigated. Keeping the drug-polymer ratio constant, variation in the concentration of emulsion stabilizer and volume of the organic disperse phase did not produce any significant change either in the actual drug content or in the drug release. The initial drug loading, however, greatly influenced the drug release which, as revealed by different analyses, was due to the presence of drug in different physical forms in the microparticles. Physical characterization using thin layer chromatography and infrared spectroscopy apparently revealed the absence of drug degradation and sizeable interaction between the drug and the polymer. Regardless of lack of interaction, thermodynamic properties such as solubility of the drug in the polymer and fraction of the drug present in crystalline form were determined by using differential scanning calorimetry and was further substantiated with scanning electron micrography and X-ray diffraction analysis.