Apremilast (trade name otezla) is a drug developed by celgene biotechnology company in the United States to treat psoriasis and psoriatic arthritis. As a small molecule inhibitor of phosphodiesterase 4 (PDE4), this product specifically acts on cyclic adenylate monophosphate (cAMP). Inhibition of PDE4 can lead to the increase of cAMP level in cells, It can reduce joint swelling and improve the physiological function of joint parts. At present, the drug has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for psoriatic arthritis, patients with moderate and severe plaque psoriasis and oral ulcer of Behcet's disease. In 2020, the global sales of the drug will be nearly 2 billion US dollars.

【Intellectual property】

       After searching, the earliest compound patent cn1420889 (applied by Searle gene company) was granted in November 1999, 2007 and waived in 2012 due to unpaid annual fee. This product has no compound patent and preparation patent, but Searle gene company later applied for crystal form patent, which involves a, B, C, D, e, F and G. The crystal form patent has been authorized in the United States and Japan, and its protection period ranges from 2028 to 2032.
       Our company has researched and developed a new crystal form II with more stable thermodynamics and applied for patents at home and abroad. Crystal form patents have been authorized in the United States, Europe, Japan, Russia, Australia and other countries. Using crystal form II developed by our company can ensure that generic drugs can be listed in regulatory markets such as the United States and Japan 5-8 years in advance. As a new crystal form, the X-ray diffraction pattern of crystal form II is completely different from various crystal forms reported in the existing literature. The DSC pattern shows a single peak, and the thermal weight loss shows that it does not contain crystal water or crystal solvent. At present, we have found a method to directly convert crystal forms a, B, C, D, e, F and G into crystal form II without dissolution under heating in a certain solvent. This experiment directly proves that crystal form II is more stable than crystal form B in terms of thermodynamic stability. In vitro solubility test showed that crystal form II was basically consistent with crystal form B; The electrostatic effect of crystal form II is significantly weaker than that of crystal form B, which is conducive to the processing of the preparation. The dissolution of self-made tablets of crystal form II and celgene original tablets in five media were compared in vitro. The similarity factor between them was more than 60% and 90% in water.
       The in vivo absorption of the two crystal forms was compared in rats. The results showed that the self-developed crystal form II and the original crystal form B showed great male and female differences, which was consistent with the report of the original FDA application data. The Tmax, Cmax and T1 / 2 of the two crystal forms were almost the same. The exposure of the two crystal forms in male rats was not much different. The exposure of the self-developed crystal form II in female rats was about 1.5 times that of crystal form B. The results of double crossover experiment in beagle dogs showed that there was no difference between the two crystal forms.

【Work progress】

       Considering that alprostat is a long-term or even lifelong drug product, it is very necessary to develop a sustained-release preparation for the convenience of patients. At present, the company has preliminarily completed the small-scale and pilot process research on the formulation of sustained-release agent, and hopes to seek the cooperation and joint development of relevant manufacturers.