Safety of glucocorticoids can be improved by lower yet still effective dosages of liposomal steroid formulations in murine antigen-induced arthritis: Comparison of prednisolone with budesonide

• Published in: International journal of pharmaceutics 2011-09, Vol.416 (2), p.493-498
• Main Authors: Hofkens, Wouter, van den Hoven, Jolanda M., Pesman, Gerard J., Nabbe, Karin C., Sweep, Fred C., Storm, Gert, van den Berg, Wim B., van Lent, Peter L.
• Format: Article
• Language: English
• Subjects: Animals; Antigens - toxicity; arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - pathology; Biological and medical sciences; Budesonide - administration & dosage; Budesonide - pharmacology; Budesonide - toxicity; corticosterone; Corticosterone - blood; dose response; Dose-Response Relationship, Drug; encapsulation; General pharmacology; Glucocorticoid; Glucocorticoids - administration & dosage; Glucocorticoids - pharmacology; Glucocorticoids - toxicity; HPA axis; inflammation; Liposomes; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; prednisolone; Prednisolone - administration & dosage; Prednisolone - analogs & derivatives; Prednisolone - pharmacology; Prednisolone - toxicity; Rheumatoid arthritis; Side effects; Synovial Membrane - drug effects; Synovial Membrane - pathology
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.02.062

The goal of this study was to compare the effects of liposomal and free glucocorticoid formulations on joint inflammation and activity of the hypothalamic-pituitary-adrenal (HPA) axis during experimental antigen-induced arthritis (AIA). A dose of 10 mg/kg liposomal prednisolone phosphate (PLP) gave a suppression of the HPA-axis, as measured by plasma corticosterone levels in mice with AIA and in naïve mice. In a subsequent dose-response study, we found that a single dose of 1 mg/kg liposomal prednisolone phosphate (PLP) was still equally effective in suppressing joint inflammation as 4 repeated once-daily injections of 10 mg/kg free PLP. Moreover, the 1 mg/kg liposomal PLP dose gave 22% less suppression of corticosterone levels than 10 mg/kg of liposomal PLP at day 14 of the AIA. In order to further optimize liposomal glucocorticoids, we compared liposomal PLP with liposomal budesonide phosphate (BUP) (1 mg/kg). At 1 day after treatment, liposomal BUP gave a significantly stronger suppression of joint swelling than liposomal PLP (lip. BUP 98% vs. lip. PLP 79%). Both formulations also gave a strong and lasting suppression of synovial infiltration in equal amounts. However, at day 21 after AIA, liposomal PLP still significantly suppressed corticosterone levels, whereas this suppression was not longer statistically significant for liposomal BUP. Conclusion: Liposomal delivery improves the safety of glucocorticoids by allowing for lower effective dosing. The safety of liposomal glucocorticoid may be further improved by encapsulating BUP rather than PLP.