(T0930-12-82) Dexamethasone-Loaded Colon-Targeting UniORV^® with Improved Anti-inflammatory Effects and Reduced Risks of Systemic Side Effects

Purpose: Dexamethasone (DEX) has been used for the treatment of inflammatory bowel diseases (IBD). However, excessive systemic exposure of corticosteroids is often associated with severe side effects, including hypertension, hyperlipidemia, hyperglycemia, and immune suppression. To achieve safe and effective treatment of IBD using DEX, appropriate formulation system for colon delivery would be desirable. UniORV^® is a new platform for polymer based amorphous solid dispersion prepared with an apparatus for manufacturing seamless capsules [1]. The drug release property could be controlled by optimization of the polymer type and addition of other ingredients in the formulation prepared with UniORV^® approach. The aim of the present study is to deliver orally-dosed DEX to the colon, the disease site of IBD, employing colon-targeting UniORV^® (cUO).

Methods: DEX-loaded cUO (cUO/DEX) was prepared by dropwise spheroidizing technique according to previous report with slight modifications [1]. For the colon delivery of DEX, chitosan (CS) and sodium alginate (ALG) were included in the composition of cUO/DEX. The cUO/DEX was physicochemically characterized in terms of appearance and release behavior in pH1.2 and pH6.8 with or without rat cecum homogenates (4 w/v%). To evaluate systemic exposure after oral administration of DEX samples (5 mg-DEX/kg, p.o.), pharmacokinetic study in rats were conducted. The anti-inflammatory effects of DEX samples (5, 25, and 100 µg-DEX/kg/day, p.o. for 3 days) were evaluated using a rat model of IBD induced by 2,4,6-trinitrobenzenesulfonic acid. Blood glucose levels were measured after repeated oral administration of DEX samples to assess safety concerns caused by excessive systemic exposure.

Results: The cUO/DEX was found to be spherical particles with an average size of approximately 200 µm. In pH1.2 and 6.8 solutions, cUO/DEX showed significant suppression of DEX dissolution compared with crystalline DEX due to the controlled release properties derived from CS and ALG. In pH6.8 solution with rat cecum homogenates, the dissolution of DEX from cUO was accelarated in the presence of chitosan-degrading enzymes, possibly contributing the site specific release of DEX at the colon. After oral administration of DEX samples (5 mg-DEX/kg) to rats (Fig. 1), crystalline DEX showed the maximum plasma concentration (C_max) and bioavailability (BA) of 1.9 µg/mL and 44%, respectively. In contrast, orally-dosed cUO/DEX exhibited suppressed systemic exposure of DEX as evidenced by C_max and BA of 0.3 µg/mL and 13%, respectively, suggesting reduced absorption of DEX from upper gastrointestinal tract. In the rat model of IBD, cUO/DEX (100 µg-DEX/kg) could inhibit the inflammatory symptoms like thickening colon wall and neutrophilia at the disease site. Although repeated oral administration of crystalline DEX elicited hyperglycemia, there was no significant elevation of blood glucose level in cUO/DEX group at pharmacologically effective dose, suggesting wide safety margin with enhance anti-inflammatory effects by the application of cUO approach.

Conclusion: Strategic colon delivery of DEX using cUO approach might be a promising approach for the effective and safe treatment of IBD.

References: [1] Iyama, Y. et al., Int. J. Pharm., 570, 118630 (2019)

Acknowledgements: The authors declare no conflicts of interest.

Fig. 1 Pharmacokinetic study after oral administration of DEX samples (5 mg-DEX/kg, p.o.) in rats. ▼, cUO/DEX and ◯, crystalline DEX. Each bar represents mean±SE of 4 independent experiments.