Polypill promises?

Tablets containing a combination of several drugs, known as ’polypills’, hit the headlines recently after Indian research suggested they could be just as effective as taking each medication separately. However, although several companies are developing these combination treatments, perfecting their formulation could prove a significant hurdle. 

The Indian results suggested that patients who took a specially-made capsule containing several different cardiac medications could benefit just as much as those who take the medications separately.¹ Their findings suggest that a convenient ’polypill’ could reduce the incidence of heart disease, because people are more likely to take the combination tablet regularly than multiple medications. But there are doubts as to whether such a product could be made sufficiently stable to be marketed, even in capsule form.

The researchers used a capsule made by the Indian generics manufacturer Cadila. Called Polycap, it contained five cardiovascular medicines, namely the anti-clotting agent aspirin, cholesterol-lowering drug simvastatin, and blood-pressure-lowering drugs ramipril, atenolol and hydrochlorthiazide.

In a trial involving 2053 subjects at risk of cardiovascular disease, those taking Polycap improved almost as much as those taking the medicines separately. Giving the medications all at once apparently did not produce any adverse reactions due to interactions.

The researchers say the polypill could theoretically reduce heart attacks and strokes in apparently healthy people by 50 or 60 per cent. 

Another Indian company, Dr Reddy’s, has also developed a fixed-dose combination pill for cardiovascular disease, containing aspirin, simvastatin, hydrochlorothiazide and lisinopril. It is currently being trialled in seven countries. Madrid-based Centro Nacional de Investigaciones Cardiovasculares is also developing a polypill combining aspirin, a statin and an ACE inhibitor in collaboration with Spanish pharmaceutical company Ferrer-Internacional.

But there are practical problems in making such products and getting approval from regulators. According to Malcolm Ross of Switzerland-based formulation specialists Generapharm, multiple-component capsules are unlikely to be stable unless significant time and money is spent developing the formulation.

’Ramipril is extremely unstable if not stored at the right pH, but unfortunately that is exactly the pH at which aspirin breaks down into salicylic acid and acetic acid,’ he told Chemistry World. ’The effect would be to acetylate all the other components, possibly destroying their therapeutic effects.’ Similarly, he said, hydrochlorthiazide is acidic and would hydrolyse other components, while simvastatin readily oxidises unless stabilised.

’Formulating a five-component pill or capsule with a shelf life long enough to satisfy a regulatory authority like the FDA would be a very expensive exercise,’ says Ross. Regulatory authorities rarely accept any medicine with more than two active ingredients, he said, partly because it becomes very difficult to analyse the finished product both for actives and for impurities. ’I am not saying it cannot be done, but it would take even a top generics company five years of devoted effort,’ he said.

Peter Mitchell