In China, NSCLC has the highest incidence rate among all malignant tumor types. Gemcitabine hydrochloride, an effective drug for treatment of the disease, has long been under global patent monopoly and the price of finished drug product is very expensive. Breaking technical barrier to produce our own version of the drug has since long been a challenging task for Chinese pharmaceutical companies. The award winning “innovative synthetic process for the key intermediate of the new oncology drug gemcitabine” (Patent No. ZL03151156.2) developed by Jiangsu Hansoh Pharmaceutical Group Co., Ltd. employs the company’s experience in chiral synthesis and successfully overcomes industry challenges including low stereoselectivity in core process, low yield and purity of the key intermediate ribulose (4b), and difficulty in mass production of pharmaceutical grade products.
In the preparation process, polymerized (R) -2, 3-O-glyceraldehyde-acetonide reacts directly with halogenated ethyl difluoro acetate to obtain trans-product 2b with high selectivity. The method solves the problem of low selectivity of trans-product and increases the ratio of main product to by-product from 3:1 to 14:1. Also it adopts vacuum distillation in the purification process to replace column chromatography which is both time-consuming and difficult to apply in mass production. The yield rises from 32% to 51%, and the purity of the key intermediate ribulose (4b) goes up from 95% to 99%, both greatly improved. Besides, since the reaction does not require column chromatography or flammable, explosive and highly corrosive raw materials, production cost and complexity of the process are reduced, indicating a bright prospect for practical application.
With the enforcement of this patent, Hansoh successfully breaks the patent barrier set by originator drug manufacturer; very few pharmaceuticals have managed to do this. Taking advantage of patent protection, the company has strengthened its position and competitiveness in the market of gemcitabine. Gemcitabine hydrochloride for injection (Zefei), the product manufactured using the patented process, is only half as expensive as the imported drug. Since launch, it has created significant economic and social benefits. It has been used in over 900 hospitals and accumulatively treated over 300,000 patients, with sales reaching RMB3.42 bn with tax payment of RMB500 mm, saving medicine costs of RMB3.2 bn for patients. The API, due to its good quality and lower price, is exported to European and US markets and accumulated foreign earned income exceeds USD 100 mm. In 2011, the exports exceeded 1,000kg, accounting for 1/4 of total consumption worldwide.
Comment: This patent is an example of Hansoh’s cooperation with universities and institutes. Technical breakthroughs solved problems such as high cost and difficulty in mass production. It is particularly commendable that based on the patent the company has submitted several applications for relevant and improvement patents, establishing all-around protections for its innovations, and thus paving the way for long-term and effective maintenance of its technological advantages and market competitiveness of the product.