**4. Conclusions**

In conclusion, this article provided a novel concept of two-step control of the release rate of pH-sensitive drugs. Additionally, the results of the drug in vitro release profiles proved that both the dissolution-rate controlling step created by the sub-layer containing CA and the diffusion-rate

controlling step developed by the ADEC coating showed significant effects on the release rate of LXP. In addition, the amount of the acid modifier in the optimal formulation, which accounted for only approximately 3% of the total preparation weight, was dramatically decreased compared with other formulations containing acidic modifiers. The in vivo studies revealed that this novel two-step control system could achieve a more stable and sustained release plasma concentration of LXP compared with the immediate release tablet.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/11/6/260/s1, Figure S1: pH solubility profiles of loxoprofen at 25 ◦C. Figure S2: Contour plots showing the effects of (**A**) *X*1 and *X*2, (**B**) *X*2 and *X*3, and (**C**) *X*1 and *X*3 on the response *Y1*. Figure S3: Contour plots showing the effects of (**A**) *X*1 and *X*2, (**B**) *X*2 and *X*3, and (**C**) *X*1 and *X*3 on the response *Y*2.

**Author Contributions:** Conceptualization, D.W. and L.L.; methodology, D.W., M.Z., J.Z.; and L.L.; formal analysis, L.L.; investigation, D.W.; writing—original draft preparation, D.W. and M.Z, writing—review and editing, D.W. and M.Z.

**Funding:** This research no external funding.

**Acknowledgments:** We are thankful to Colorcon Coating School® for technical and excipient supports.

**Conflicts of Interest:** The authors declare no conflicts of interest.
