Multilayer Tablets: Key Challenges and Trends - Pharmaceutical Technology

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Multilayer Tablets: Key Challenges and Trends
Experts in solid dosage discuss the formulation and manufacture of multilayer tablets.

Pharmaceutical Technology
Volume 36, Issue 3, pp. s22-s33

PharmTech: Can you give examples of successful, rational FDCs?

Gupta (Imperial College London): Currently there are numerous examples of success stories with FDCs. An FDC of antituberculosis medications, compared with the corresponding free-drug combinations, was associated with significantly higher treatment rates and significantly lower adverse effects. Similarly, among those with HIV, the use of an FDC of anti-HIV drugs has shown greater rates of remission. In comparison to these examples, the success stories with the use of FDC in the field of cardiovascular medicine are not that dramatic. However, there is a rapidly growing body of data, suggesting that the usefulness of FDCs in cardiovascular and metabolic medicine is likely to be no different than that seen in other fields of medicine.

In cardiovascular medicine, the main utility of FDCs is mediated through improved compliance, which in turn may increase the treatment efficacy and decrease the outcomes. This hypothesis is partially supported by findings of our meta-analyses: the use of FDCs (compared with the use of corresponding free-drug combination) was associated with a greater (albeit statistically insignificant) reduction. Elsewhere, a few observational studies have shown that the improved adherence with medications is likely to be associated with greater cardiovascular benefits.

Another potential advantage with the use of FDC is a possible reduction in adverse effects. In our meta-analysis, compared with the corresponding free-drug combination given separately, allocation to FDC was associated with lower adverse event rates. The use of a low-dose FDC of two drugs as an initial therapy (in several situations) may have significantly lower adverse events and a better tolerability, than either of the medication alone. A classic example of this is an FDC combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium-channel blocker (CCB) is likely to be associated with lower incidence of ankle swelling, compared with the same dose of CCB alone.

Udupa/Sreedhar (Manipal University): Fixed-dose combinations are especially useful when treating diseases like human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria, and tuberculosis where more than one drug is usually recommended. There are also certain other conditions and diseases, such as cancer, cardiovascular diseases, diabetes, neuropsychiatry and pain where FDCs may offer benefits. Some successful and rational FDCs include:

  • Antiretroviral combinations: abacavir + lamivudine, tenofovir disoproxil fumarate + emtricitabine and efavirenz + tenofovir + emtricitabine.
  • Antimalarial combinations: artesunate + amodiaquine, artemether + lumefantrine and amodiaquine + sulphadoxine + pyrimethamine.
  • Antitubercular combinations: Rifampicin + Isoniazid + Pyrazinamide.
  • Hypertensive combinations that provide better blood pressure control: Amlodepine + Atenolol, Amlodepine + Losatan and Irbesartan + Hydrochlorthiazide.
  • Antidiabetic combinations that provide better glycaemic control: Glibenclamide + Metformin, Glipizide + Metformin and Pioglitazone + Metformin.

PharmTech: How do you think the benefits and disadvantages of FDCs shape up against one another? Should the industry pay more attention to potential FDCs or would the time be better spent on other areas of innovation?

Gupta (Imperial College London): This is an interesting question, but there is no readily available answer. In my opinion, each new FDC formulation should be based on a thorough understanding of disease mechanism, as well as the mechanism of action, pharmacokinetics and pharmacodynamics of each constituent component—separately and in combination.

There are a few FDCs that are more frequently prescribed over the other because of the prevalence of the clinical situations that they are most effective in. However, given the numerous clinical prescribing situations, I believe all FDCs will have their own niche in treatment settings. Having said that, I believe that there are only a finite number of possible FDCs and with the rapid introduction of new FDCs, the market will probably be saturated in the next few years or so. For long-term sustainability, the pharma industry should spend a significant amount of time on other areas of innovation, including the development of new drugs and effective drug delivery mechanisms.

Udupa/Sreedhar (Manipal University): Benefits and disadvantages should be looked at simultaneously and not individually when evaluating an FDC. If there is considerable evidence that the proposed FDC has more benefits than disadvantages, then it's a definite 'go' situation.

The pharma industry should definitely explore the potential benefits FDCs offer over their individual component products. It is difficult for small- to medium-scale companies to bear R&D costs and even larger companies are finding it risky to develop new drugs and so most pharma companies are now in search of new business models. One of these options is to develop FDCs of existing individual components that are co-prescribed in order to help preserve patents.

When developing FDCs, however, companies must consider the safety and efficacy of the active components in combination, the benefits of simultaneous use of active ingredients and possible interaction between the components. Fixed-ratio combination products are usually considered for marketing approval by regulatory authorities only when the dosage of each ingredient meets the requirements of a defined population group and when the combination has a proven advantage over single compounds administered separately in its therapeutic effects, safety, or compliance.

References

1. A.K. Gupta, S. Arshad and N.R. Poulter, Hypertension, 55(2), 399–407 (2010).

2. K. Jamerson et al., N Engl J Med., 359, 2417–2428 (2008).

3. ADVANCE, "ADVANCE Trial — Blood pressure lowering arm results". http://www.advance-trial.com/

4. R.D. Feldman et al., presentation at Scientific Sessions 2007 of the American Heart Association (Orlando, 2007).


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