Delivering fixed-dose combination therapies with hard capsules: part I

In this article, authors Dr Jnanadeva Bhat and Ms Anita Solanki describe how fixed-dose combination therapies can be delivered using hard capsules

The global pharmaceutical manufacturing market was valued at $405.52 billion in 2020 and is projected to increase at a compound annual growth rate of 11.34% between 2021 and 2028.1

Substantial capital investments have also been seen in R&D and digital innovation.2 This emphasis on innovation has made it imperative for pharmaceutical companies to demonstrate competitive advantages in the market, particularly in light of cut-throat rivalry playing out with both branded and generic products.3

Owing to this competitive environment, there is a need for different strategies to deal with the ever-changing market ecosystem. A key focus when it comes to maintaining and building market share is new product development (NPD).4

As a result, companies are grappling to distinguish themselves in this field and demonstrate how successful they can be.

Dr Jnanadeva Bhat, Head of Formulation R&D (Pharma & Nutra)

Product lifecycle management, technology amalgams and patient-centric approaches are the trends that have added to the importance of creating new avenues in product development.

Innovation in NPD can take different routes, such as incorporating novel drug forms (such as a salt or isomers), new therapeutic indications for older molecules or creating new dosage forms with enhanced efficacy.

Combination therapy is another key focus for product development. It consists of two or more drugs with complementary modes of action that can be used when there is a need for multiple drugs to treat a single disease.5

What is a fixed-dose combination?

A drug or fixed-dose combination (FDC) is a dosage form consisting of two or more active ingredients in a particular fixed dose (such as Atenolol + Nifedipine in a capsule).

FDCs are becoming more prevalent as they increasingly become part of product-cycle management strategies to expand the intellectual property rights exposure of older pharmaceutical products.6

In the healthcare industry, multiple drugs are prescribed to treat various diseases and medical conditions, including hypertension, tuberculosis, diabetes, respiratory diseases, cancer and HIV.

Anita Solanki, Lead, White Papers, Formulation R&D (Pharma & Nutra)

The rationales for this are many, as it is better to combine two or more drugs for better efficacy rather than increase the dose of a single drug. On several occasions synergistic drug combinations have shown benefits compared with single drug therapies, including increased efficacy, decreased dosage with equal efficacy and reduced side-effects.

Apart from being synergistic, if drugs with different mechanisms of action for the same therapeutic indication are given, then the overall patient outcome may also improve.7

Drug resistance

Drug combinations are often beneficial when it comes to reducing drug resistance. Drug resistance may arise during single-drug treatment, so there are major advantages to using combination therapy to treat certain diseases (such as tuberculosis or malaria) as it reduces the probability of drug-resistant mutations in pathogens.8–10

Patient centricity

For the reasons outlined above, the combination approach may be the preferred method to treat chronic diseases; but, prescribing multiple drugs separately can be disadvantageous for patient compliance.

Multiple drugs can confuse patients or increase the likelihood of them forgetting to take some, or all, of their prescribed medication. This can lead to issues with the dosing regimen, which can be potentially dangerous.

Synergistic effect with patient compliance

Combination therapy in a single dosage form offers a number of potential advantages. Combining drugs in this way not only reduces the pill burden on patients, it can also reduce medical expenses and improve patient adherence.

Furthermore, in cases of cardiovascular disorders such as hypertension, single dosage forms can include lower doses of each drug than would be necessary to achieve targets with a monotherapy, which may explain their better tolerability compared with higher dose treatment programmes.11

For example, the combination of a calcium antagonist (amlodipine) and an angiotensin converting enzyme (ACE) inhibitor (ramipril) in patients with hypertension resulted in a significantly lower incidence of peripheral oedema compared with an amlodipine-only therapy and was associated with a significantly greater reduction in systolic-diastolic blood pressure.12

Furthermore, treatment with combinations in a single dosage form for hypertension have been associated with increased patient adherence. By choosing drugs with compatible pharmacokinetic properties, a single dosage form can substantially reduce the pill burden for patients.13

Owing to the above factors, the use of combination therapies containing two or more drugs in a single dosage form is particularly desirable.

Drug-drug interactions

A drug-drug interaction is a phenomenon wherein two incompatible drugs reacts with each other and either generate impurities or lead to API degradation. Hence, the encapsulation of such drugs as a fixed-dose combination in hard capsules provides a viable delivery route.

Combination therapies in hard capsules

Although the benefits of combination therapies have been recognised for many years, there are certain challenges that are yet to be resolved — such as impurity generation and incompatibilities between two APIs (active pharmaceutical ingredients), which can lead to various developmental hurdles.

Here, hard capsules have come to the rescue; ever-evolving encapsulation technologies make it possible to not only use different drugs, but also combine various dosage forms in a single capsule.

With a history of more than 150 years, hard capsules remain one of the most popular dosage forms. This is as a result of their many advantages in terms of ease of formulation development, encapsulation possibilities and patient compliance.

Capsules have evolved, particularly in recent years, to include options in a plethora of sizes, colours and print designs, which offer companies increased ways to differentiate their product.

Capsules are manufactured with polymers such as gelatin and HPMC (hydroxypropyl methylcellulose), which are stable, stronger and able to meet increasingly specific requirements (Figure 1).

Figure 1: Gelatin (yellow/red) capsule and HPMC (green/green) capsule

Gelatin capsules are conventionally produced using animal sources. They deliver fast dissolution in all biological media, wherein drug release is achieved in 5–10 minutes.

By contrast, HPMC is a plant-origin capsule, with better stability and flexibility compared with gelatin capsules. Various possibilities of solid-solid and solid-liquid combinations in capsules are available to encapsulate different APIs in a single shell.

Advances in encapsulation technology make it possible for hard capsules to help pharmaceutical companies to maintain a competitive edge — enhancing product lifecycles along with being patient-centric.

A complete list of citations will be included in part II.