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Formulating fixed-dose combination drugs proves more complex than simply adding one ingredient to another.
Fixed-dose combination (FDC) drugs offer a number of benefits to drug manufacturers, patients, and caregivers. These medicines contain two or more active ingredients in a defined composition or fixed ratio. The greater focus on patient centricity and improving patient medication adherence has led to a growing interest in FDC formulations.
In the past five years, approximately 43 fixed-dose combinations were approved in the United States, according to Anil Kane, global head of scientific and technical affairs at Thermo Fisher Scientific. The majority were treatments for cardiovascular, metabolic disorder (including diabetes), and infectious diseases (including HIV). Most are solid, orally delivered drugs.
FDC medicines, because they contain multiple APIs, provide advantages for patients and opportunities for manufacturers. From a patient perspective, according to Torkel Gren, senior director and science and technology officer at Recipharm AB, FDC products can be consumed quickly and easily because fewer tablets need to be taken. “By altering and controlling API release rates through the combination of multiple drug products into a single carrier, treatment is ultimately more efficient and straight-forward for patients,” he says. “To this end, FDCs have helped to improve patient compliance and by extension the overall treatment of diseases,” Gren adds. FDCs also have the potential to offer patients increased efficacy and synergistic effects that may enable the need for lower doses, according to Kane.
For manufacturers, Gren notes that formulating FDCs has enabled the introduction of new products with improved properties and with significantly lower development costs. “Reformulating and combining drugs that have been proven to be safe and effective into FDCs represents an essential strategy for drug development companies to realize maximal commercial potential returns in a faster way than developing new molecular entities, which can be a lengthy, expensive, and high-risk endeavour,” agrees Kane.
Lifecycle management, Kane observes, is in fact one of the major strategies used in the pharmaceutical industry in response to several significant trends, including patent expiry of major blockbuster drugs in the coming 5–10 years, stiffer competition in the market due to the presence of generic players, and a drought in the pharmaceutical R&D pipeline. Combination drugs also offer an opportunity for intellectual property and exclusivity.
Developing an FDC formulation that offers these benefits and challenges can be difficult, however. Because many active ingredients are incompatible-meaning they are less stable in the presence of each other-selecting excipients and processes that reduce the degradation rate of the active ingredients and afford the optimal composition and process parameters increases in difficulty as the number of active ingredients increases, Gren notes. In fact, the main challenge to fixed-dose combination development usually involves product formulation and manufacturing strategy to address stability, dose differential, and analytical method development issues, according to Kane.
The APIs in an FDC must be physically and chemically compatible with one another and all of the excipients used in the formulation and not generate any new impurities or raise any new drug-drug interactions. “The physicochemical properties and stability of each of the APIs in an FDC will define the formulation approaches to maintain stability during the shelf life of the combined drug product. As an example, the hygroscopicity of one active drug substance can influence the stability of the other drug in a combination product unless they are completely separated by way of multiple techniques,” explains Kane.
Dosage size is another challenge experienced during pharmaceutical development, according to Gren. For example, if several high-dosage drugs are combined, the resulting target may be too large to be consumed by the patient. Differentials in individual drug doses are another issue. “The particle size distribution of a low-dose drug and the distribution of a second high-dose drug can impact the content uniformity of the former and the flow and processability of the latter in a single two-layer tablet,” Kane observes.
From an analytical chemistry standpoint, it may be challenging to develop an analytical method that can quantitate all of the active ingredients and their degradation products, according to Gren. New analytical methodologies are often required to be developed for these innovative formulation strategies to accurately assess the product potency of multiple ingredients, as well as potential degradation products and their quality parameters, Kane agrees. “One alternative,” says Gren, “is to apply several analytical methods. However, the employment of multiple analytical methods will increase quality control costs and subsequently impact the cost of goods,” he notes.
Finally, Kane observes that the packaging of a fixed-dose combination product may need to be re-considered based on the criticality of the multiple actives and their stability profiles in combination.
The best way to overcome these challenges, Kane asserts, is for formulators to fully evaluate/understand the individual drugs that need to be combined in FDC products with respect the API characteristics, forced degradation and stability profiles, site of absorption and pharmacokinetics, potential for drug-drug interactions and chemical compatibility, and the individual doses required to have an optimal therapeutic effect. “A thorough pre-formulation assessment of the combination and generation of critical data is the key to a successful formulation development strategy,” he concludes.
Clarity around the stability of the APIs to be formulated into an FDC product can be gained through retrieved literature data and experimental work, notes Gren. “Gathering information and knowledge around the specific patient population and other market conditions, combined with an understanding of stability issues, will allow for a clear development strategy to be outlined and implemented,” he states.
Where the APIs in FDCs are known to be incompatible in the presence of each other, formulation in a single pill can be achieved using a number of different options. Kane identifies multilayer tablets, compression-coated tablets, multi-particulates in capsules, and combinations of coated and uncoated beads and pellets of one active placed with a powder of another active as common technologies.
A suitable way to manage incompatibilities is by separating the different active ingredients with multilayer tablets or by including one of the drug substances in the coating and another at the core of the tablet, Gren notes. Formulation of different actives into separate pellets that can then be mixed into a capsule or tablet can make it easier to vary the doses of each API, he adds. For modified-release formulations, the pellets are typically coated.
It is important to note, however, that although pellet technology has broad applications in oral FDCs, it is not a universal tool. “While some drug substances can be readily combined in a conventional tablet without any problems occurring, liquid or semi-solid formulations are often required for some indications and administration routes,” Gren comments.
In general, therefore, the strategy for developing FDCs is entirely dependent on the individual active ingredients in the combination, their dose, stability profile, target release profile, sight of release, and other factors, Kane asserts.
Looking to the future, 3D printing has recently been introduced as a manufacturing method for pharmaceutical products and may enable contract development and manufacturing organizations to effectively customize combination drugs for individual patients, according to Gren. He notes that it could also potentially facilitate the separation of different drug substances to reduce incompatibility issues.
The first approval of a product manufactured using 3D printing (Aprecia Pharmaceuticals’ Spritam) was granted by FDA in 2015. “There are, however, several quality assurance and regulatory issues that need to be solved before this technology can be employed across the industry on a larger scale,” Gren says.
Vol. 44, No. 3â¨
When referring to this article, please cite it as C. Challener, “Characterizing APIs is Essential for Combo Drug Formulations," Pharmaceutical Technology 44 (3) 2020.