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Discovery & Development Formulation, Ingredients, Drug Delivery, Small Molecules

Three in One

Today, there are more effective therapies for major diseases than ever before – and we now have a better understanding of disease comorbidities and the likely combinations of medications that patients may be taking. The efficacy of these therapies, however, can be limited by patient compliance challenges; the burden placed on patients who must take multiple tablets daily can limit the success of any treatment protocol.

One potential solution is to combine multiple APIs, or release profiles for the same API, in a single dose. In a survey of oral solid dosage developers (1), controlled release formulations and fixed dose combinations (FDCs) were identified as the technologies companies are most likely to use when formulating new products. In the same survey, however, 47 percent of respondents also said that controlled release formulations were their greatest challenge.

I believe that multilayer tablets, multiparticulates, and mini tablets (mini-tabs) have emerged as the most elegant means of delivering more effective and patient-friendly products. Each offers its own versatility when it comes to controlled release profiles and the ability to deliver multiple therapeutic payloads in a single dose. Here, I dissect each option in terms of pros and cons.

i) Made up of two to four layers, the multilayer tablet allows for two or more chemically incompatible APIs with similar release profiles to be incorporated into a single tablet. Alternatively, they can be used to deliver two or more drugs with unique in vivo release profiles, or facilitate release of the same drug in two or more release profiles – offering both immediate and sustained release for an API for instance. 

The challenge during formulation is that multilayer tablets must have adequate mechanical strength and hardness to endure processing, handling, packaging, and transport. Some of the common problems associated with the manufacture of multilayer tablets include delamination at the interface of the layers due to insufficient adhesion, incomplete segregation of layers, slower throughput, and relatively low yield compared with conventional tablets. There are also challenges in achieving the desired weight of individual layers.

ii) Multiparticulates are multi-unit dosage formulations that offer flexibility in target-specific delivery. They can be tailored for controlled and/or delayed targeted drug release depending on the polymer coating, and different polymer-controlled release profiles can be blended to achieve more sophisticated products. It’s also increasingly common for inert cores to be coated with different APIs to create a FDC in a single capsule or tablet. For manufacturers, they offer a number of benefits when they have the experience and capability to handle multiparticulates.

Beads are usually 0.2–2 mm in size, and the spherical shape and compact structure allow for good flow behavior, making them easy to dose. Multiparticulates also disperse freely in the GI tract, which enables developers to achieve both the correct potency and controlled release

One of the challenges with multiparticulates, however, is gaining control over the size of the substrate sphere, so processing often requires tedious sieving. Some of those challenges can be overcome with the use of an extrusion-spheronization process, which gives manufacturers better control of the size of the multiparticulates as well as uniformity of drug loading.

Multiparticulates may also be compressed on a rotary tablet press to create substrates with different release profiles, and makes them easier to coat with technologies such as pan coaters and fluid-bed processing units. Other dosage form options include orally disintegrating tablets (ODTs), suspensions, sachets, and sprinkle capsules – giving developers significant flexibility.

iii) The small size of mini-tablets makes them ideal for children, the elderly, and patients who have difficulty swallowing – ultimately increasing safety, convenience of administration, and patient compliance. Mini-tablets typically have a diameter of 4mm or less and can be as small as 1mm. Their size, uniformity, shape, and mechanical strength allow them to be filled into a capsule or a sachet/stick-pack. They also provide similar filling flexibility  to multiparticulates. A few typical approaches include dosing a capsule with two different minitablets containing chemically incompatible APIs, or dosing a capsule with minitablets containing the same API, but with different release profiles.

As with multiparticulates and multilayer tablets, immediate release, delayed release and/or extended release profiles can be dosed in one capsule to achieve the desired drug delivery. Mini-tablets can also be used to deliver two actives together in two separate tablets within the same capsule. In fact, approaches involving the combination of immediate release and sustained release mini-tablets in one capsule are becoming increasingly popular (2). The development of processing equipment that has the capability to deliver precise filling by counting the number of mini-tablets per dose has made mini tablets a more attractive option.

Offering versatility across varied patient populations and highly precise dosing options, these novel technologies are helping drug formulators bring the benefits of oral administration to molecules that previously had to be delivered by other routes. Reformulation of large molecules, that were previously injectables, into oral solid dosage forms is a growing trend in this space – Novo Nordisk for example is currently developing oral formulations of GLP-1 receptor agonists and insulin. With the right dosage forms, molecules can be protected from gastric acid allowing them to be taken in pill form. Given that patients invariably prefer oral doses over injections, these new forms have the potential to improve patient compliance. This and the sustained growth of these technologies are testament to their benefit in enhancing patient compliance and experience (3).

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  1. American Pharmaceutical Review, “Oral Solid Dosage Trends,” (2019). Available at https://bit.ly/3dMggRg.
  2. P Priyanka, K Kumar, D Teotia, “A comprehensive review on pharmaceutical mini tablets,” Journal of Drug Delivery and Therapeutics, 8, 382-390 (2018). DOI: 10.22270/jddt.v8i6.2060
  3. KC Kwon, C Lee, “Analysis of Fixed-Dose Combination Products Approved by the US Food and Drug Administration, 2010-2015: Implications for Designing a Regulatory Shortcut to New Drug Application,” Ther. Innov. Regul. Sci., 51, 111-117 (2017). DOI: 10.1177/2168479016663263

About the Author

Thomas B “Brad” Gold

Vice President, Pharmaceutical Development, Metrics Contract Services, North Carolina, USA

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