Blue sky innovation

Methylene blue has a range of pharmacological properties but manufacturers have never produced sufficient high quality grade compounds for widespread clinical trials. Now customers can rely on Provepharm’s stable source of the pure pharma-grade cGMP-compliant compound.

Methylene blue is a compound that has shown considerable promise in a number of medical applications, not least the treatment of malaria, and possibly even Alzheimer’s. However, it has proved elusively difficult to deliver a compound of sufficient quality for use in widespread clinical trials – until now that is. A recent scientific breakthrough means that, for the first time, high quality, pure pharma-grade methylene blue is now available.

The compound methylene blue was first discovered over 100 years ago. Initially used as a dye substance, a use it retains today, methylene blue also has pharmacological properties, and for over 50 years was used for a range of medical purposes: as a topical antiseptic, an oral antiseptic for urinary infections, even in combination with other drugs to combat malaria.

Heavy metals
Unfortunately, as researchers began to look more closely at the molecule, they discovered that the industrial synthetic manufacturing process involving various heavy metal oxidising agents meant that the quality of standard methylene blue was very poor.

Consequently, European Pharmacopoeia (EP) limits were revised to accommodate the new findings and allow restricted uses. While methylene blue continued to be used as an effective treatment for methemoglobinemia, the levels of impurities curtailed its use in other areas.

‘Many companies attempted to produce a better quality methylene blue, but were unable to even after several years of trying,’ says Jeff Kaufman, R&D director at pharmaceutical company Provepharm. ‘However, through some very clever chemistry, Provepharm’s parent company Provence Technologies has been able to manufacture this material without any contact with metals at all throughout the whole process. It required an innovative synthetic approach, different from anything that has been tried in the past, and we were able to produce a material that is clean.’

The result was the world’s first US Pharmacopoeia (USP) and EP-compliant grade of methylene blue (methylthioninium chloride Ph.Eur). The breakthrough is well timed as interest in existing and future applications with methylene blue as the active pharmaceutical ingredient is increasing.

‘About ten clinical trials are published on methylene blue every month, so people are looking at it again in different ways,’ notes Kaufman. ‘There are visualisation uses, where it is injected into the body to stain it blue chromoendoscopy, to identify dysplasia or pre-cancerous lesions, and in lymph node dissections it can be used to identify lymphatic drainage. Clinical trials for other applications include its use as an anti-adherent.’

Methylene blue is even being looked at again as an antimalarial. Unlike most other molecules on the market it has no resistance problem. There is also some talk of the compound being effective in the treatment of Alzheimer’s disease due to its exceptional capacity to chelate metals.

Pharma quality
To date, most trials have had to use contaminated poor quality methylene blue. Now, however, Provepharm has moved to regular large-scale semi-industrial production and at the end of 2009 will have full-scale production at two GMP (US FDA and European) independent manufacturing sites.

‘We will be soliciting the EP, the USP, the Brazilian Pharmacopoeia and others to tighten up their specifications, and we will be updating the pharmacopoeia with respect to specifications and methods of analysis; we are doing a complete update on the product,’ says Kaufman. ‘We are doing a full tox package, and will be updating the toxicology file to remove any doubts that may remain with respect to the toxicological profile – it is an extremely safe material. The US DMF and European DMF will be available at the end of 2008 on the current scale of production. At the beginning of 2009 we will be making an application for CEP.’

Kaufman has a message for all those companies and researchers currently using methylene blue. ‘The improved quality methylene blue means that people can stop using unqualified materials,’ he says. ‘Or at the very least they should test their materials according to the new EP methods.’