The in-vitro and in-vivo characterization of PLGA:L-PLA microspheres containing dexamethasone sodium phosphate.

Dexamethasone sodium phosphate (DSP) is a widely used corticosteroid in the treatment of brain oedema associated with brain tumours. DSP has many side effects that limit its usage at an effective concentration. The objective of this study was to minimize these side effects by encapsulating DSP using biodegradable synthetic polymers, to extend the release time from microspheres and to evaluate the effectiveness in the treatment of brain oedema. Microspheres containing 5% DSP were formulated by the solvent evaporation method by using a 1:1 mixture of two synthetic polymers, poly(lactic-co-glycolic acid) and L-polylactic acid (PLGA and L-PLA). The surface morphologies and particle size distribution of the microspheres were investigated. The in-vitro release studies were performed in pH 7.4 phosphate buffer solution. For determining the effectiveness of microspheres in the treatment of brain oedema, Sprague-Dawley rats weighing 200-250g were used as an animal model. Brain oedema was generated by the cold lesion method, and the effectiveness of the microspheres in treatment of oedema was investigated by the wet-dry weight method, lipid peroxidation ratios and histological evaluations. The average particle size of the microspheres was 13.04 +/- 2.05 microm, and the in-vitro release time of the microspheres was 8 h for 100/release. The degree of oedema was significantly different from the control group for the wet-dry weight method and lipid peroxidation ratio (p < 0.05). Similarly, histological evaluation of the tissues shoved that degree of oedema was significantly decreased with respect to the control group. All these results showed that implantation of microspheres was significantly more effective with respect to the systemic administration of DSP.

The effect of recombinant human erythropoietin on serum selenium levels in hemodialysis patients.

Succesful results in the treatment of anemia, one of the main complications of chronic renal failure, can be achieved by the use of recombinant human erythropoietin (RhEPO), which is available almost fifteen years in clinics. On the other hand, as both chronic renal failure and maintenance hemodialysis reduce the levels of trace elements, this study was designed to evaluate the interaction potential of RhEPO with serum concentrations of selenium (Se) during four months. Thirty one adult hemodialysis outpatients participated in the study. Ten of them, not on any drug therapy to interact with RhEPO, recruited as "Control Group", and the remainder, on RhEPO therapy, as "RhEPO Group". Blood was drawn from the Control Group at the beginning of the study, and from the RhEPO Group at every month for four months. Serum erythropoietin leveLs were measured by a radioimmunoassay method and Se status by a spectrofluorometric method. It was found that Se levels were not affected by RhEPO treatment during 3 months of therapy, while an increase was seen on the fourth month. The observation indicates that the increase in serum Se levels would be significant in longer than three-month RhEPO treatment.

Preparation and properties of a stable intravenous lorazepam emulsion.

Lorazepam is normally administered as a solution in organic solvents such as propylene glycol. This type of formulation is undesirable. This study describes the development of a parenteral emulsion formulation for lorazepam. The stability of lorazepam in the emulsion was examined. Ten per cent corn oil emulsions stabilized with egg lecithin, Pluronic F68 and Pluronic F88 were used. The incorporation of lorazepam does not appear to destabilize the emulsion, and lorazepam itself appears to be stable for at least 1 year in this liquid formulation. Haemolysis caused by emulsion formulations containing lorazepam and different emulsifiers was evaluated using human and rabbit blood to assess their safety as parenteral drug carriers. The results show that the emulsions did not have any significant haemolytic activity whereas organic solvents and solutions of lorazepam in organic solvents caused substantial haemolysis.

Phenytoin sodium microcapsules: bench scale formulation, process characterization and release kinetics.

The objective of this investigation was to formulate and prepare sustained-action microcapsules of phenytoin sodium (diphenyl hydantoin sodium salt). Using ethylcellulose and methyl acrylic acid copolymers (Eudragit S-100 and L-100) as coating materials, microcapsules of phenytoin sodium were formulated by an organic phase separation and a granule coating method. The phase diagrams were used to study the phase separation in an ethylcellulose-petroleum ether-toluene system, and the effect of temperature and amount of petroleum ether on the ethylcellulose left in the organic solvent mixture was investigated. The phase diagrams showed that increase in temperature did not significantly affect the ethylcellulose residue, and 60 ml of nonsolvent was found adequate for microencapsulation. In vitro release of the formulated microcapsules and the commercially available preparations was performed in CO2-free distilled water using the USP XXIII rotating basket method, and the profiles were evaluated by Higuchi kinetics. Geometric mean diameters of the microparticles prepared by two different methods showed differences due to different core:wall ratios. A 4 x 5 factorial design was utilized and multiple regression was applied to the dependent variables (ethylcellulose content, percent dissolved) against the independent variables (amount of nonsolvent, temperature, core:wall ratio); the optimum phenytoin sodium-to-ethylcellulose ratio was 1:2.3. Utilizing second-order polynomial equations, response-surface graphs and contour plots pointed out the time necessary for 40%, 55%, and 70% release of phenytoin sodium. The desired release profiles were obtained with formulations E-5, ES-2 and ESL-2.

Properties of human albumin microparticles prepared by a chilled cross-linking technique.

Examination of conditions needed to form albumin microparticles (in the 1-5 microns diam. size range) by glutaraldehyde cross-linking, at low temperature (-15 degrees C), suggested that the particles formed very rapidly over a short time scale and at low concentrations of cross-linking reagent. Detailed analysis showed that the particles increased in size with time of reaction and with an increase in glutaraldehyde concentration. Evaluation of the particle matrix using a dilute trypsin digestion process suggested that the above factors may influence the internal composition since the particles dissolved less rapidly than might be anticipated from a consideration of particle diameter alone.

Factorial design-based optimization of the formulation of isosorbide-5-mononitrate microcapsules.

Sustained action Isosorbide-5-mononitrate (IS-5-MN) microcapsules are prepared in order to overcome the tolerance developed in conventional preparations and to increase patient compliance. For this purpose, factorial design experiments are performed and microcapsules of IS-5-MN are formulated by the organic phase separation method using ethylcellulose with two different viscosities (10 and 45 cp) as coating material. The independent variables in the 2 x 3 x 3 factorial design are core: wall ratio, particle size and pH of the medium. The dependent variable, t50 percent is investigated by the second-order polynomial equation to establish the correlation between independent variables. By using the calculated equations, the response-surface graphs, from which various levels of independent variables could be predicted, are obtained. The in vitro release profiles of the formulated microcapsules and the commercially available preparations are obtained by using the rotating basket method. In vitro release is evaluated by zero-order, first-order, Hixson-Crowell and Higuchi release kinetics. The t50 percent values obtained from the Higuchi equation are used as response in the 2 x 3 x 3 factorial design experiments.

Sustained release isoniazid tablets. I--Formulation and in vitro evaluation.

Isoniazid (INH) has been widely used in the preventive therapy of tuberculosis since the early 1950's. The aim in designing a sustained release tablet form was to attain in fast inactivators sustained blood concentrations similar to those produced by ordinary INH tablets in slow acetylators during chemotherapy. In the present paper, the release of INH incorporated into three different matrix materials, polymethylmethacrylates, polyvinyl chloride and carbomer were studied. The release rate of a unit dose of conventionally formulated INH tablets was used as a basis of comparison. The best sustained effect on the release rate of INH was obtained with 30% carbomer matrix tablets.

Studies on zinc sulphate microcapsules: (III) in vivo evaluation.

Zinc sulphate capsules and syrup were prepared as conventional dosage forms and in vivo experiments were performed for both on the conventional dosage forms as well as on microcapsules. Blood samples were taken from healthy volunteers at 1, 2, 3, 4 and 5 hours and AUC3 and AUC5 were calculated by trapezoidal rule. Relative bioavailability of zinc was calculated and the 5th hour relative bioavailability difference was found to be significant. The results show that zinc sulphate in microcapsule form was able to prolong the action.

Studies on zinc sulphate microcapsules (1): Microencapsulation and in vitro dissolution kinetics.

Microcapsules of zinc sulphate with core: wall ratios of 1:1 and 2:1 were prepared by the coacervation method, using ethylcellulose as the coating material. The prepared microcapsules were separated into batches of 250 and 500 micron in size by sieving. The effects of particle size, the amount of zinc sulphate, and the core: wall ratio on the dissolution kinetics were studied, and evaluated kinetically by the Rosin-Rammler-Sperling-Bennet-Weillbull (RRSBW) distribution.

Studies on zinc sulphate microcapsules (2): Application of factorial design.

In this study a 2(3) factorial design has been applied to the evaluation of dissolution characteristics of zinc sulphate microcapsules. The kinetic model according to the Rosin-Rimmler-Sperling-Bennet-Weillbull (RRSBW) distribution was applied for the parametric representation of the dissolution curves. The effect of three factors; core: wall ratio, amount of zinc sulphate and particle size of the microcapsules, on the dissolution rate of zinc sulphate were studied at two levels. The factorial design method proved to be useful for the examination of microcapsules.

Formulation and release of dihydralazine sulphate from tabletted microcapsules.

One of the principal uses suggested for the microencapsulation of pharmaceuticals has been the preparation of the sustained release dosage form. The finished microcapsules have usually been presented in the form of suspensions or gels, but in order to obtain greater sustained release effect a non-disintegrating tablet would be a better formulation. Dihydralazine sulphate (Nepresol) is a dihydralazine-1,4-phthalazine derivative and used as an antihypertensive drug. This work was planned to prepare sustained action preparations of dihydralazine sulphate by microencapsulation and by tabletted microcapsules. Microcapsules were prepared from the microcapsule fractions using biconvex punches with 0.81 cm diameter fitted into a single punch by hand compressor. Avicel PH 101 and lactose were used as disintegrating materials in tablets having 2 kg hardness. Dissolution from both suspended microcapsules and the tablets was studied using the USP XX basket method. A study of in vitro release for both the free and tabletted microcapsules showed basically the same pattern but the time for the release was extended in the case of the tabletted preparations. Dissolution of dihydralazine sulphate was found to be governed by the core: wall ratio, microcapsule size, and the amount and kind of disintegrating agents. Dissolution kinetics were studied and evaluated.