Fixed-Dose Combinations

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Developing fixed-dose combinations (FDCs) is one of the many reformulation strategies used in product lifecycle management. It has the potential to offer quicker commercial returns compared to developing a new chemical entity. For pharmaceutical companies seeking to maximize the value of their drug products, FDCs can provide a means of obtaining supplementary patent protection and differentiating against cheaper generic-drug formulations. These formulations have shown success in the treatment of cardiovascular diseases, diabetes, HIV/AIDS, tuberculosis, and malaria.

Drivers for FDCs
“FDCs can be used either to combine different actives in one single dosage form or to achieve a precise release profile of a specific active-for example, by combining an immediate-release with an extended-release formulation,” explains Stefania Barzanti, marketing manager at IMA Active division. According to her, the success of FDCs is driven by two concurrent needs. “On one side, there is the need for welfare systems to contain healthcare costs; and on the other side, the need for pharmaceutical companies to optimize product lifecycle and exploit the potential of their existing product portfolio,” she says. FDCs are more cost-effective than individual drugs administered separately. They are known for their ability to reduce the pill burden. It is presumed that the simplification of therapy and its convenience lead to better overall patient compliance. The other main advantage of FDCs is the enhanced efficacy and lower incidence of side effects as a result of the synergistic combination of potentially lower doses of the different actives.

Developing an FDC, however, requires careful assessment of the potential advantages against the possible disadvantages, such as the difficulty or inflexibility of dose titration. “It is true that the flexibility in dosing options is reduced with FDCs, and it becomes more difficult to have fine tuning of the medication prescription to the needs of a specific patient,” Barzanti notes. “That’s why careful evaluation of the pros and cons of developing an FDC should drive the choice between the different solutions on the basis of a patient-centric approach that considers lifestyle needs and the medical condition.”

Drug developers are required to justify the pharmacological and medical rationale behind each FDC for the intended therapeutic indication. According to the European Medicines Agency, the rationale should consider the posology and dosing frequency of the different components included in the FDC (1).

Formulation and manufacturing challenges
“In terms of formulation, the first challenge is to bring together the different pharmacokinetic and target-release profiles,” says Barzanti. “This task, of course, becomes more complex with a higher number of active drugs.” The actives in the FDC must be assessed for physical and chemical compatibility, along with their excipients, to ensure that the different components do not generate new impurities or raise unfavorable drug–drug interactions.

“From the manufacturing point of view, however, one of the most common challenges is represented by the combination of two chemically incompatible actives that have to be kept separated but included into a single dosage form,” observes Barzanti. She explains that this issue is particularly crucial for layered tablets, where sometimes an intermediate placebo layer has to be created to avoid any interaction. “During tableting, constant checks and frequent replacement of the scraper blade are also important to avoid mixing of the different powders comprising the various layers.”

Another particularly relevant issue is represented by the control of the dosage of each drug, according to Barzanti. “In a layered tablet, the single layers can be sampled and checked individually on a statistic base, but it is not possible to check them separately in the final complete unit dose,” she says. “During the past four to five years, we have seen a growing interest for hard gelatin capsules, specifically for FDC products. On a capsule filler, different ingredients can be easily combined inside the same capsule shell by simply adding a dosing unit. Besides powder, different product forms can also be dosed, including pellets and minitablets, small tablets or capsules, softgels or liquids, and semi-solids. There are technologies available for in-line check of each single unit produced by the machine.”

In some cases, FDCs can result in higher manufacturing costs because a more complex dosage form is being produced. Barzanti points out that the total cost to develop an FDC should include the subsequent manufacturing phases up to the final packaging. “But in any case, the final cost reduction from the increased patient compliance and better use of medicines makes FDCs beneficial when considering the cost aspect from a global standpoint,” she says.

“I see FDCs as one of many opportunities present on the market to innovate oral solid-dosage forms together with the growing interest for multiparticulate formulations and new drug-delivery solutions,” Barzanti continues. “The overall aim is to make better use of existing product portfolios through optimization of pharmacokinetics, improved bioavailability, and enhanced therapeutic effect, as well as minimization of side effects. FDCs can be especially useful to support long-term concurrent therapies in patients affected by chronic diseases that are related to each other. I believe the current aging population is a driver for growth for this type of oral solid-dosage form.”

Reference
1. EMA/CHMP/281825/2015, Guideline on Clinical Development of Fixed Combination Medicinal Products (London, April 2015).

Article DetailsPharmaceutical Technology
Vol. 39, No. 12
Pages: 30–31

Citation: When referring to this article, please cite it as A. Siew, “Fixed-Dose Combinations,” Pharmaceutical Technology, 39 (12) 30–31 (2015).