Methylene blue is finally available in a safe, stable format without heavy-metal contamination, all thanks to a four-year R&D commitment from Provence Technologies.

Methylene Blue is a well-known molecule, primarily used as a dye and used since the 19th century in formulated drugs (for urinary disinfection, or in association with chloroquine for malaria treatment). Because of its chemical nature (phenothiazine derivative) and because of its industrial synthetic route (involving various heavy metal oxidising agents), the quality of standard methylene blue is very poor – so poor that EP limits had to be revised and the acceptance limits of heavy metals were increased to allow some sources to be labelled as EP-compliant but only for restricted uses. Even so, there is an ongoing worldwide shortage of EP-grade methylene blue.

Although the current market quality does not meet the essential Ph.Eur requirements, new important pharmaceutical and medical applications are emerging. For example, according to ongoing clinical trials, methylene blue is being tested as anti-HCV, for treatment of Alzheimer’s disease and very recently for malaria. Therefore, a true pharma grade is obligatory with full compliance with heavy metals limits, especially for chronic and intensive treatments.

No contamination

It is fundamental that patients do not suffer from inconsistent drug supply or with a product contaminated with heavy metals because an appropriate grade of methylene blue is not available. Provence Technologies understood this situation and invested a lot of effort to solve this double problem. Provence Technologies is a custom synthesis and development company created in 1998 in Marseilles, France by its CEO Dr Michel Féraud. Provence Technologies invested four years of intense R&D to obtain the world’s first USP and EP-compliant grade of methylene blue (methylthioninium chloride Ph.Eur). Production, under cGMP conditions, is in an FDA & AFSSAPS approved plant.

Methylene blue from Provence Technologies is fully compliant with the strictest monograph requirements. Provence Technologies produces methylene blue with a robust and reliable industrial process and so can assure supplies for the world market needs. Indeed, methylene blue from Provence Technologies proved itself fully EP-compliant, with a heavy metal content on average 50 times lower than Ph. Eur limits.

‘Purification of ordinary technical grade methylene blue is not an option because there are too many quality variations with up to 50% inorganic residues in some technical grades,’ commented CEO Michel Féraud. Many have tried and failed, so we at Provence Technologies sought and found a new chemical pathway to synthesise our heavy-metal-free methylene blue, so we can guaranty high and stable quality. The entire process has been designed to avoid any source of metal coming into contact with our API.’

Exciting potential

The potential market for methylene blue is tremendous, with the variety of potential applications in which it could be used as an API (and not only as an excipient) increasing regularly, and the medical field discovering its enormous potential in terms of drug power. In the light of the potential of this newly available API grade, Provence Technologies has created its own subsidiary, ProvePharm, to maximise the value of the invention. ProvePharm aims to provide classical and advanced dose forms, fully ICH-compliant development, plus the writing and submitting of NDA and MAA for customers wanting to market methylene blue-formulated drug products using a true API manufactured by an FDA and AFSSAPS-approved GMP-compliant plant.

To manage ProvePharm, Philippe Reulet (former Sanofi Research world director) and Jeff Kaufman (formerly R&D manager at Sterling Health Europe and Nicholas International) have joined ProvePharm as business development director and regulatory affairs and R&D director, respectively.

‘We are very proud at Provence Technologies that we have succeeded in making methylene blue a safe API, whereas previously, a dye contaminated with heavy-metals was used as a drug,’ said Jeff Kaufman. ‘This invention thus opens the doors to new applications that could not be investigated before because of the original poor quality of the drug substance.’

After several years of intense efforts, Provence Technologies, which used to dream in blue, is now thinking blue.