Thioridazine microspheres

Figure 7. Scanning electron micrographs of thioridazine microspheres prepared with mole NaOH/mole lactic acid ...

Figure 7. Continued. Scanning electron micrographs of thioridazine microspheres prepared with mole NaOH/mole lactic acid (C) 0.09 and (D) 0.14. Drug loading, 43%. Emulsifier, sodium oleate.

In the preparation of microspheres by solvent evaporation from oil-in-water emulsions, the presence of base (NaOH) was found to enhance the release of thioridazine from polylactide micro-spheres. The amount of drug release as a function of time was dependent on the amount of base added to the aqueous phase of the emulsion. Scanning electron micrographs indicate that this increased drug release may be due to modification of the internal structure of the microspheres by sodium hydroxide during fabrication. 

The release of thioridazine from the microspheres was determined by placing a sample containing the equivalent of 5 mg thioridazine in 1 L of pH 7.4 phosphate buffer (solubility, 23 mg/L). The mixture was maintained at 37°C with stirring at 300 rpm. Aliquots were withdrawn at various time points and assayed by measuring at the X for thioridazine, 265 nm, with a Cary Model 14 spectrophotometer. 

The solvent evaporation microencapsulation process using sodium oleate as the emulsifier produced microspheres in high yields (75-95%), essentially free of agglomeration (1). Drugs with low solubility in water (0.02 mg/ml or less) e.g. thioridazine, were incorporated with 80-99% efficiency. Core loadings up to 60% were attained along with prolonged in vitro release. 

Another contribution to drug release was indicated in a previous paper (5) which reported on the hydrolysis of polyesters catalyzed by encapsulated amine drug such as thioridazine. The microsphere batches prepared for this investigation have identical drug loadings. Therefore, any contribution due to the amine drug should be equal for all the samples being compared. 

The effect of NaOH on drug release was examined with microspheres prepared with thioridazine and two biodegradable polymers. The wall-forming polymers were poly(DL-lactide) and poly(L-lactide). Sodium oleate was used as the emulsifier, with the exception of one set of experiments where the emulsions were stabilized with polyvinyl alcohol. 

The time for 50% release was 8 days for the 50% thioridazine-loaded microspheres prepared without NaOH. It was decreased to 5 days for those prepared with NaOH. The effect of NaOH was more pronounced when the drug loading was increased to 58%, as shown in Figure 4. The time for 50% release was significantly reduced from 7 days (without NaOH) to 1 day (with NaOH). 

To recapitulate, thioridazine release from microspheres was enhanced when NaOH was added to the emulsion prior to the solvent evaporation step. This was observed for both poly(DL-lactide) and poly(L-lactide) and also for two emulsifier systems, sodium oleate and polyvinyl alcohol. It should be pointed out that NaOH is added only to the aqueous phase of the emulsion. It is not incorporated into the microspheres by this process. 

Figure 2. Effect of NaOH on thioridazine release from poly(L-lactide) microspheres. Key (o) no NaOH, 15-100 pm ( ) 0.14 mole NaOH/mole lactic acid, 10-90 pm (A) nonencapsulated drug. Drug loading, 58%. Emulsifier, sodium oleate.

Figure 6. Effect of NaOH posttreatment on thioridazine release from poly(DL-lactide) microspheres. Key (o) before NaOH posttreatment,...

Drug release of thioridazine was enhanced when the microspheres were prepared in the presence of base. The effect was dependent on the amount of NaOH added to the aqueous phase of the emulsion prior to the solvent evaporation step. 

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