The combination drugs debate: unstable and unpatentable

For an alternative view on combination drugs, go to www.pharmtech.com/overcome

Combination products have been researched and administered for many years, some successfully and others not. I believe that the combination of several active ingredients into one pill, whilst providing a more efficacious remedy, comes with its own set of risks, largely relating to stability. Regulatory and patent challenges also exist when considering the combination of approved and off patent ingredients. In this article, I will specifically discuss one case of a combination product — the polypill; a therapeutic that combines either five or six active ingredients, which was proposed some 6 years ago as a cardiovascular disease preventative.

(David Gould/Getty Images)

The idea of a combination therapeutic is not so new. During the 16th Century the notion was already the subject of much amusement:

"I was in the company where one, I know not who, of my fraternity brought us intelligence of a new sort of pill made up of a hundred and odd ingredients: it made us very merry, and was a singular consolation, for what rock could withstand so great a battery." Michel de Montaigne, French essayist (1533–1592).

What is the polypill?

Polypill, a name that was coined by consumer press, has attracted much media attention in recent months, largely because it has been hyped as a miracle drug for the prevention of heart attacks. Proposed in 2003 by Ward & Law in the British Medical Journal (BMJ), the putative polypill contains a statin, an angiotensin converting enzyme (ACE) inhibitor, a beta blocker, a diuretic, aspirin and folic acid.¹

In the same issue, BMJ's Editor wrote an opinion piece titled, "The most important BMJ for 50 years " This attracted considerable attention in 2003 and 2004, but almost zero activity beyond claims that it would reduce cardiovascular disease by 80%. Later that year, the Editor of BMJ suggested that the polypill would be available in 2 years.² This was somewhat optimistic, particularly in light of an article published in UK newspaper The Independent (7 July 2003) titled, "The one problem with the polypill is that it doesn't exist", in which it was revealed that Professor Ward had tried to interest drug companies and various medical organizations with no success, because such a product would not be patentable.

Combination controversy

In support of The Independent's view, various authorities have further dampened enthusiasm, claiming that commercial considerations stand in the way of the "discovery" being introduced overnight; with all ingredients being off patent, companies might be deterred from investing in development work. Conversely, it has been claimed that the cost to manufacture this pill may only be a few pence, which surely contradicts any commercial arguments.³

Much of the controversy surrounding this therapy, however, has revolved around various medical claims and counterclaims regarding the nature of the clinical trials that are required to prove this treatment's efficacy. Most recently, The Indian Polycap Study (TIPS),⁴ which tested the efficacy of the agent in healthy adults, was criticized because it simply measured the lowering of blood pressure and high density lipoprotein (HDL). This was no great revelation given that these are the prime actions of the individual ingredients.

Setting aside the medical controversy (which often seems to rely on intuition or meta-analysis rather than hard data), some significant points have been ignored in the recent debate.

The author says...

The 2009 version of the original polypill⁴ is minus an ingredient — folic acid. However, given the conclusions of a recent Lancet study indicating that low dose aspirin should not be used in prophylaxis for patients who have not had a heart attack or stroke,⁵ one might ask the question: should aspirin also be dropped?

There are, however, some fundamental problems regarding the chemistry and formulation of the polypill as it is currently proposed.

Formulation instability

The current, five active ingredient containing polypill, combines a number of drug substances that would present serious formulation challenges. Aspirin is very unstable, decomposing rapidly to salicylic acid and acetic acid. The release of acetic acid in particular may react with the other active substances to form acetyl derivatives. To obtain a stable product, careful optimization of the formula, particularly its pH, is required. The pH required for aspirin stability does, however, differ from that required for the optimum stability of some of the other components of the polypill.

For example, the ACE inhibitor ramipril is another unstable molecule — it quickly breaks down to ramipril diacid and a diketopiperazine derivative.⁶ Although there are many patented methods of stabilizing ramipril in formulations, mainly using buffering excipients, such as magnesium oxide or calcium carbonate, the internal pH required for stabilizing ramipril is several pH units away from the optimal pH for aspirin stability.

Statins, such as simvastatin, present formulators with an additional problem because they are susceptible to oxidation. Consequently, formulations of these compounds often require the addition of antioxidants, such as butylated hydroxyanisole (BHA) and ascorbic acid/citric acid.

Even the combination of an ACE inhibitor and a statin is problematic; a patent for a stable tablet requires a triple layer tablet where the simvastatin granulate is formulated for stability, the ramipril granulate is formulated separately and then the two granulates are compressed with a third layer separating them.⁷

Therefore, formulating the polypill presents a significant challenge; the formulator will need to optimize the pH for three different pH sensitive compounds plus one that is susceptible to oxidation.

The regulatory aspect

Another challenge lies in regulatory requirements. To register the product it must have a stable formulation, and be proven to be compliant with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) regulations, which require the development of stability indicating methods. In addition to the six active compounds and their degradation products, any HPLC method with UV detection will also need to consider the excipients, such as BHA and ascorbic acid. As the complexity of an analytical method increases proportionally with the number of compounds being assayed, it is clear that even the development of a non-stability assay will be a major challenge.

The challenge of formulation complexity coupled with the complicated analytical procedures required to formulate the polypill mean that considerable resources will be required to conduct uniformity of final blends, content uniformity and dissolution testing, all of which are necessary as part of the submission for marketing authorization.

The stability specifications will also require considerable effort and justification; initial requirements by regulatory authorities will be to set the impurity levels according to those already approved for the monotherapies. It is unlikely that the polypill can achieve the same level of stability of the individual therapies and may demand further toxicology. One could hope that the regulatory authorities might look upon the product as something so beneficial and so simple, as the press would have us believe, that they would waive these requirements! This, however, is unlikely.

The patent status

On the issue of patents, it has been suggested that companies will not sponsor the development of the polypill because it cannot be patent protected. I am, however, dubious about this claim. The pharmaceutical industry is most adept at finding patentable claims in some of the simplest formulations, and is capable of protecting them quite vigorously. Even if a company loses a patent claim in court, a pharmaceutical company can still manage to eke out several years' patent prolongation with uninterrupted competition. In the case of the polypill, the serious formulation challenges and considerable scientific development would undoubtedly provide protection that would allow any investment to be recouped.

The possibility of patenting the combination as a medical claim may have been destroyed by the early publications of Professor Ward himself. Formulation patents (cf. the European Patent Application EP1924266A for a COX-2 inhibitor, a statin, an ACE inhibitor and an ARB) are feasible ways round this.

Even without patent protection there would, however, be protection in Europe under the data protection rule giving 10 years' exclusivity before generic competition could encroach on profits. In the US, it might be anticipated that 5 year exclusivity would be obtained and, as a potential over-the-counter (OTC) product, a branded approach would preserve market share after that period.

Commercial potential

Two major hurdles must be overcome before the commercialization of the polypill can be considered. On the one hand there are the pure development costs related to the complexity of the analytical methodology and the formulation. In addition, it is probable that formulating the product will require more than just throwing the active ingredients together with a few excipients, mix and dispense. Thus it is likely that this product will cost considerably more than the media's predicted 'few pence' (incidentally, even at generic prices the costs of the APIs alone will take it to that level without any finished dosage form manufacturing or packaging costs).

On the other hand, product exclusivity and/or patent protection would allow the successful company to sell the product at sufficiently high costs thus allowing them to recoup any initial costs. Cost-effectiveness must, however, be carefully considered before this product can be confidently developed and presented to healthcare providers. With this in mind, in an article titled "The polypill: at what price would it become cost effective " determined that the cost of the polypill should be no more than €302 or €410/year in certain populations, for it to be cost effective.⁸ Although the authors conceded that the polypill could be a highly effective intervention, they felt that the cost of the medication could "be its caveat for implementation in the primary prevention of cardiovascular disease."

Polypill: coming to a provider near you?

To summarise, what may seem a simple and attractive idea when reported in the popular press, the manufacture and commercialization of the polypill might be far too complicated and expensive, which could explain why the pharmaceutical industry has been less than enthusiastic about adopting this product. Possibly a simpler idea was the one published by Franco et al.⁹ where they proposed "The polymeal: a more natural, safer, and probably tastier (than the polypill) strategy to reduce cardiovascular disease by more than 75%". This evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. In this remarkable study, the authors concluded: "The polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population." Maybe it's that simple!

Malcolm Ross is President at Generapharm — Training and Consultancy, Basel (Switzerland).

For an alternative view on combination drugs, go to www.pharmtech.com/overcome

References

1. N.J. Ward and M.R. Law, BMJ, 326(7404), 1419 (2003).

2. R. Smith, BMJ, 330(7481), 8 (2005).

3. Preventing chronic diseases — a vital investment (WHO Global Report, WHO, 2005).

4. The Indian Polycap Study (TIPS), The Lancet, 373(9672), 1341–1351 (April 2009).

5. Antithrombotic Trials (ATT) Collaboration, The Lancet, 373(9678), 1849–1860 (May 2009).

6. World Patent WO 2006/050533 A2.

7. US Patent US 2004/0137054 A1.

8. O.H.Franco et al., Journal of Epidemiology and Community Health, 60, 213–217 (2006).

9. O.H. Franco et al., BMJ, 329, 1447 (2004).