(M1330-11-71) Design and Evaluation of Colon-Targeted Dexamethasone Solid Dispersions for Inflammatory Bowel Disease

Purpose: To design and evaluate locally colon-targeted dexamethasone solid dispersions (DEX-SDs) to treat Inflammatory Bowel Disease (IBD). The goal of this approach is to increase the local concentration of dexamethasone in the colon while reducing its systemic exposure, thus improving its therapeutic efficacy while minimizing its adverse effects.

Methods: Two different solid dispersion formulations (SD-1 and SD-2) of dexamethasone (DEX), prepared using different ratios of Hydroxypropyl methylcellulose (HPMC) and Eudragit S100 polymers by the solvent evaporation method. SD-1 contains a mixture of both polymers with a drug to polymer ratio of 5:95 and a polymer to polymer ratio of 40:60. On the other hand, SD-2 contains only Eudragit S100 with the same drug to polymer ratio of 5:95.The SDs-DEX was prepared by solvent evaporation technique with a DEX-to-polymers ratio of 5:95 (w/w %). To assess solubility, pure DEX and DEX-SDs were compared using the shake flask method, while the yield and drug loading efficiency were analyzed using HPLC. FT-IR spectra, Differential scanning calorimetry (DSC) analysis, and Powder diffraction( PXRD) patterns were performed to characterize both the polymers and DEX-SDs. Finally, drug release was conducted through a dissolution test apparatus with simulated gastric fluid composed of 0.1 M hydrochloric acid (HCl) (pH 1.2) and phosphate buffer solution (0.05 M) with pH 6.8. This media is recommended by Food and Drug Administration. The identification of DEX-SDs was performed using a Polarized Light Microscope (PLM). Approximately 1000 µg of each sample was placed on glass slides, covered with glass covers, and viewed under a 10x lens magnification. The microscope images were captured for each sample under the PLM, using Deltapix software.

Results: The solubility of DEX and DEX-SDs was measured at 25 ± 1°C and 37 ± 1°C in PBS (pH = 7.4) and water, as shown in Table 1. The results showed a significant improvement in the solubility of DEX with the use of DEX-SDs. This improvement was attributed to the conversion of DEX to an amorphous form within the polymers, as confirmed by DSC and PXRD results. DEX-SDs were successfully prepared using solvent evaporation method, with relative high yield 86%. In addition, drug loading efficiency was 92.06 ± 1.25% and 95.93 ± 0.45% for SD1 and SD2, respectively. The study used polarized light microscopy to analyze the physical state of the solid dispersion formulations. Birefringence was observed in pure DEX, indicating a crystalline form, while DEX-SDs showed some birefringence suggesting the presence of some crystalline material which was not detected by XRPD. DEX-SDs are mostly amorphous, but some crystals were present as shown in Figure 1. This discrepancy could be due to to the possible contamination of the sample with some crystalline material, such as Eudragit S100. The physical mix formulations exhibited an endothermic event at around 240 °C, indicating the depressed melting of DEX as shown in Figure 2. The DSC thermograms of the physical mixes showed a baseline change at around 170 °C - 180 °C, which corresponds to the expected glass transitions of EU-S100 and HPMC. The physical mixtures of SD-1 and SD-2 were analyzed by DSC using a heat-cool-reheat cycle, and the thermograms showed no signs of DEX recrystallization. Both SD formulations exhibited endothermic events consistent with the Tg of the polymers, and no crystalline DEX was visible in the second heating cycle. This suggests that, within the limits of detection of DSC, there are no signs of crystalline DEX in either formulation, and it is likely that a solid dispersion has been successfully formulated in both formulations. This was further confirmed by Powder X-Ray Diffraction. The PXRD diffraction patterns of HPMC, physical mix formulations, and solid dispersion formulations were analyzed. HPMC, SD-1, and SD-2 showed an amorphous with no visible diffraction patterns. In contrast, physical mix formulations showed specific peaks in the 5θ – 20θ range, indicating crystalline content. These results suggest that SD-1 and SD-2 contain DEX in the molecularly dispersed phase, without any crystalline DEX present. This finding is consistent with the DSC results. DEX was released from the SDs gradually during the first 20 min, then the release was constant and it was noticed that approximately 80% of DEX was released within 30 min in colon simulated media.

Conclusion: In conclusion, the study successfully developed solid dispersion formulations of DEX using EU S100 and HPMC by the solvent evaporation method, resulting in increased solubility and dissolution rate of DEX. The DEX-SDs displayed a dissolution rate exceeding 80% within 30 minutes in a colon simulated media and less than 20% in an acidic medium, indicating their potential effectiveness in treating colonic IBD.

Acknowledgements: This work received financial support from the Zarqa University.

Table 1: The solubility of pure DEX and DEX-SDs at 25°C and 37°C.(Mean ± SD)

Figure 1: Polarized photographs of ; A and B: pure DEX, C: SD1 and D: SD2 (Magnification 10x).

Figure 2: the DSC thermograms of the physical mixes of SD -1 and SD-2.