Diquafosol Tetrasodium Purification Application Case

Introduction

Dry eye is a global issue, with nearly 300 million patients in China alone

In the mobile internet era, the "smartphone-addicted" population continues to grow. This has led to an increasing number of eye diseases, with dry eye (keratoconjunctivitis sicca) being the most common chronic ocular surface disease. It is a multifactorial ophthalmic disease where abnormalities in the quality or quantity of different tear film components lead to reduced tear film stability, triggering different types of dry eye. Dry eye can cause various ocular discomfort symptoms or visual dysfunction. The global prevalence rate is 5%-34%, while in China it is 21%-30%. Currently, there are nearly 300 million dry eye patients in China.

Multiple factors contributing to the continued increase in dry eye patients in China

In recent years, the accelerating pace of life, increasing life pressures, irregular routines, and severe sleep deprivation have become the norm. Combined with increased use of smartphones and computers, and an aging population, these comprehensive factors have led to a continuous rise in the incidence of dry eye in China.

Diquafosol Tetrasodium — A New Drug for Dry Eye Treatment

As a purinergic P2Y2 receptor agonist, clinical data demonstrate that diquafosol tetrasodium stimulates P2Y2 receptors on the ocular surface, stabilizing the tear film and treating dry eye.

Figure 1. Chemical structure of diquafosol tetrasodium

Diquafosol tetrasodium (U2P4) was developed by Santen Pharmaceutical after obtaining a license from Inspire Pharmaceuticals (a subsidiary of Merck). It was approved for marketing in Japan in April 2010 for the treatment of dry eye, under the brand name Diquas®, primarily as an ophthalmic solution containing 3% diquafosol tetrasodium.

In China, it was approved for import in October 2017 under the trade name Liais®, and is currently the only topical secretagogue drug in China that promotes mucin secretion. It improves all layers of the tear film simultaneously, comprehensively enhancing tear film stability. As such, diquafosol tetrasodium eye drops hold broad prospects in dry eye treatment.

In recent years, domestic companies such as Qilu Pharmaceutical, Chengdu Sidi, Guangdong Zhongsheng Pharmaceutical, and ShaPuAiSi have begun developing generic versions of diquafosol tetrasodium eye drops. To date, only Chengdu Sidi and Qilu Pharmaceutical have filed for market approval in the second half of 2020.

Challenges in Diquafosol Tetrasodium Separation and Purification

Although several methods exist for synthesizing diquafosol tetrasodium, more efficient synthetic approaches still require further optimization and improvement. During the manufacturing process, critical impurities significantly impact purification outcomes such as purity and yield, and are difficult to remove. To achieve high yield and high purity of the target compound, strict control of impurity levels is essential.

Purification Results

NanoMicro has developed a medium-pressure liquid chromatography resin ion-exchange purification process that demonstrates excellent purification performance for diquafosol tetrasodium samples. Using a phosphate buffer with gradient elution, results on a 6.6*305mm small column showed: at a loading of 20mg/mL, purity reached 99%, with single impurity <0.5% and a yield of 92.56%. This meets all purification attributes required by customers.

Figure 2. Uni® ion-exchange chromatography media product image

Conclusion

Through repeated validation with a 305mm bed height, a stable purification process has been established that can be directly scaled up and applied to 300~400mm bed heights. Based on a 5-hour batch processing cycle, the DAC450 annual production capacity is 700kg of purified product.

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*This table only shows a portion of NanoMicro's ion-exchange resins. For other resin requirements, please contact us.