**5. Conclusions**

During the last two decades, skin has been shown to be a suitable delivery site for drugs that are formulated dermally. Researchers have been trying to overcome gastrointestinal side effects by dermal and transdermal delivery of NSAIDs. Dermal administration of

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**Biologics** 

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**Biologics** 

48 Rheumatoid Arthritis – Treatment

Williams, AC. & Barry, BW. (2004). Penetration enhancers. *Adv Drug Deliv Rev*, Vol. 56, pp.

**3** 

*Japan* 

**The Role of Tocilizumab in the Treatment** 

The characteristic pathophysiology in rheumatoid arthritis (RA) is the destruction of bone and cartilage due to persistent synovitis of unknown etiology. Pro-inflammatory cytokines, including tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1), and interleukin-6 (IL-6), are overproduced in inflamed synovial membranes, and are critically involved in the spread and persistence of the inflammation. IL-6, which was identified as a B-cell stimulatory factor in 1986, is a multifunctional cytokine (Hirano, 2010), and a key mediator in the pathological processes of RA, especially in the activation of immune cells and osteoclasts (Cronstein, 2007). For RA drug therapy, therefore, inhibition of IL-6 signaling is suitable for shutting down both inflammation and bone destruction. Tocilizumab (TCZ) is a humanized monoclonal antibody (human IgG1 κ subclass) against IL-6 receptor (IL-6R). The data from the recent clinical studies on TCZ suggests that TCZ has several advantages over other anti-

Human IL-6 binds to human IL-6 R with a dissociation constant (Kd) of 5.5 nM, and this low affinity complex subsequently recruits a gp130 molecule to form a high-affinity complex (IL-6/IL-6R/gp130 ternary complex) with a Kd of 50 pM (Hibi et al, 1990). TCZ binds selectively and competitively to both soluble IL-6R (sIL-6R) and membrane bound IL-6R (mIL-6R) with a Kd of 0.71 nM and 2.54 nM, respectively (Japan Pharmacists Education Center, 2008; Mihara et al., 2005). TCZ suppressed the binding of IL-6 (10 ng/mL) to sIL-6R in a dose dependent manner at of a concentration between 0.002 and 4 µg/mL and completely inhibited at concentrations of > 4 µg/mL. Moreover, TCZ was able to dissociate IL-6/sIL-6R preformed complex which was made by mixing IL-6 (200 ng/mL) and sIL-6R (40 ng/mL). The percentage binding of IL-6 to sIL-6R fell in a TCZ concentration-dependent manner, and was less than 10% of the binding seen in the presence of TCZ at concentrations of > 1 µg/mL. On the other hand, the binding of TCZ to sIL-6R rose in a concentrationdependent manner and reached a plateau at 0.1 µg/mL (Mihara et al., 2005). *In vitro*, 100 µg/mL of TCZ completely inhibited cell growth of IL-6 dependent KT-3 cells in the presence of up to 0.32 ng/mL IL-6. Cell growth inhibition by TCZ was dose-dependently decreased

**1. Introduction** 

rheumatic drugs (Bergman et al., 2010).

**2. Pharmacological properties** 

**2.1 Pharmacodynamics** 

 **of Rheumatoid Arthritis** 

*2Graduate School of Medicine, Tohoku University* 

Yasuhiko Hirabayashi1,2 *1Hikarigaoka Spellman Hospital,* 
