New source of Tamiflu ingredient could boost production

By Gregory Roumeliotis

- Last updated on GMT

American chemists have found that seeds of the sweetgum fruit
contain significant amounts of shikimic acid, the main starting
material for Tamiflu, in a discovery that could prove vital, as
demand for the drug skyrockets amidst bird flu fears.

Roche is battling to meet demand for Tamiflu by increasing its external contractors and finding new methods to produce shikimic acid, as sales this year for the drug are expected to reach 1.1bn to 1.2bn Swiss francs (€7bn-€7.5bn).

But the shikimic acid used in the manufacturing of Tamiflu is obtained almost exclusively from the pods of the star anise, a fruit that is found mainly in China and whose availability has dwindled due to high demand for the flu drug.

Researchers however have discovered that shikimic acid can also be extracted from the seeds of the sweetgum fruit, which is abundant in North America, in yields of around 1.5 per cent, so just 4Kg of sweetgum seeds are enough for 14 packages of Tamiflu.

Although star anise has been reported to yield 3 to 7 per cent shikimic acid, the methods of extraction are different, and since both fruit have high seed to 'flesh' ratios, using the star anise extraction method on sweetgum seeds might yield similar yields.

Shikimic acid is also found in the leaves and bark of the sweetgum tree, but it is most abundant in the fruit.

The fruit emerges as a green seedpod that later dries into a brown, spiny husk, which releases an abundance of tiny, grain-like seeds.

The extraction of shikimic acid from the seeds is achieved using methanol as a solvent, thus obtaining other cellular material from the seeds as well, including DNA.

"We have an easy way to separate the DNA from the shikimic acid, though I don't want to give this step away until we publish our paper on it - this step is crucial otherwise the shikimic acid is unrecoverable,"​ study leader Thomas Poon from the WM Keck Science Center in California told In-PharmaTechnologist.com​.

"All of this is scaleable, although any seed extraction operation could simply use the existing method for extracting shikimic acid."

Once the separation is completed, the purification of the crude material is done via column chromatography.

The results of Dr Poon's study were presented last month at the national meeting of the American Chemical Society, where Gilead, the company that owns the patent on Tamiflu, attended.

"Roche cannot speculate about the value of this early research and its possible application in the commercial large scale production of shikimic acid that would be required to make any significant difference to the production of Tamiflu,"​ a Roche spokeswoman told In-PharmaTechnologist.com​.

"Roche welcomes any research and collaborations with companies that can significantly enhance our efforts to expand the production of Tamiflu and we welcome being updated on any developments in this area."

The Swiss drugmaker is also interested in fermentation, using special e-coli bacteria which, when overfed glucose, produce shikimic acid.

Martek and Sanofi-Aventis both produce shikimic acid for Roche via fermentation; Martek in South Carolina and Sanofi in France.

To date Roche has accepted pandemic orders for Tamiflu from more than 65 countries worldwide, with several nations ordering enough of the drug to cover 20 percent to 40 per cent of their populations.

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