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Tight development timelines and accelerated approval pathways favor simple, cost-effective capsule formulations.
Capsules are a common oral solid dosage form and are produced in a variety of shapes, materials, and sizes. The popularity of capsules can be somewhat attributed to the ease and simplicity of their manufacture, particularly when compared with other forms. Another benefit of capsules is the potential of shorter development times, which is an ever-increasing priority for developers.
To find out more about the importance of capsules in drug development, innovations that have occurred to the dosage form over time, and the specific challenges facing developers looking to use this dosage form, Pharmaceutical Technology spoke with Sven Stegemann, head of Global Scientific Business Development, ACG.
PharmTech: What specific formulations are suitable for use in capsules?
Stegemann (ACG): The performance of any pharmaceutical drug product is the result of its single components and the materials that are going into the formulation, the processing, and, finally the packaging. If you understand the material properties and the processing parameters, you can basically use any formulation in capsules today, be it powder, granule, pellet, semi-solid, or liquid.
The capsule formulation can serve oral administration as a single dose, as sprinkles on soft food, or as an orally inhaled dry powder. With the development and introduction of new capsules made from polymers, such as hydroxypropyl methylcellulose (HPMC), it is now possible to provide a capsule with very specific characteristics that can broaden and simplify the use of capsules in product development. To give an example, for therapeutics that are very sensitive to water activity, or head space humidity, such as microbiota, it is possible to specify and guarantee a very narrow humidity range to provide longer shelf life, especially if moisture-protective packing is being used.
Moreover, as microbiota normally requires enteric protection these capsules are also optimized for enteric coating or coating for targeted release. A capsule that already provides a certain degree of enteric protection could be another option, dependent on the specific needs of the therapeutic entity or formulation. In summary, there is no reason to exclude any type of formulation in a capsule dosage form. Working closely with the capsule supplier and using their expertise and capabilities throughout development and manufacturing is encouraged.
PharmTech: What beneficial features can capsules offer over other dosage forms?
Stegemann (ACG): The most important thing is that you first establish a comprehensive target product profile (TPP). This should also include the targeted patient profile and should take into account, that according to the International Council on Harmonization (ICH) Q8 guideline, ‘in all cases, the product should be designed to meet patients’ needs and the intended product performance’ (1). These TPPs will guide you in selecting the best dosage form for the specific product.
Looking at the actual industrial and regulatory trends, some particular capsule features are gaining importance. For example, 60% of new drug launches in 2019 by the FDA were designated in one or more expedited categories of fast track, breakthrough, priority review, and/or accelerated approval (2). The very tight timelines in development favor the use of simple, yet effective, capsule formulation development.
Increasing focus on a special population, such as pediatric or geriatric patients, require a higher number of different dose strengths, easy to swallow forms like sprinkles, and, to address the issue with increasing polypharmacy, the provision of fixed-dose-combination products. Without compromising on the release characteristics, multiparticulates (e.g., pellets, mini-tablets) manufactured at large scale, can be customized to serve any of these populations and needs by capsule filling. Different sizes, color combinations, and imprints will make these customized products unique. Or, take for example, inhalation drug therapy, where capsule-based dry-powder inhaler (DPI) products are the most cost-effective form, and can be manufactured on standard capsule filling equipment that is available around the world.
PharmTech: Are there specific disadvantages of capsules over other dosage forms?
Stegemann (ACG): As for any dosage form, there are advantages and disadvantages that need to be balanced against each other during the TPP process. Probably, the most significant disadvantage occurs when formulators are initially requested to develop a tablet formulation. When this dosage form is not feasible due to technical reasons, the formulators are then requested to push the formulation into a capsule. Even though it might work, the formulation is normally suboptimal for capsules, leading to a lot of issues along the commercial phase, which is then perceived as a general capsule dosage form problem.
Another disadvantage is that for a high dose formulation, the capsule size might become prohibitive. In my experience, patients generally do not want to accept larger, brick-like tablets and, as a result, tend to crush the tablets or capsules for administration. For cases where the largest (size #000) capsule might be required, why not instead consider employing a sprinkle formulation, which can be administered with soft food that the patient prefers?
PharmTech: How can capsules aid in speeding up drug development timelines?
Stegemann (ACG): More than 25 years ago, when I began my career in capsule science, there was a collaborative effort that led to the formation of group basics for capsule formulations (3), which are absolutely still valid today and have substantially evolved with new types of capsules and excipients. Not surprisingly, drug in a capsule alone, or a simple blend, is still the preferred approach for the first-in-human trials. The majority of these Phase I formulations are already achieving the desired performance and remain in capsules for the fast track or breakthrough therapies through to the market.
And to be a little bit provocative, we as pharmaceutical scientists prefer more challenging formulation programmes than applying a simple blending and encapsulation process. However, with the increasing cost pressure, it is inevitable that we will be increasingly questioned regarding the over-engineering of products in development.
PharmTech: What are the advantages and disadvantages of soft gel versus hard gel capsules?
Stegemann (ACG): This question suggests that I can use soft gel or hard gel for any type of formulation and that these dosage forms are interchangeable from a technical standpoint, which is not necessarily true. However, looking at the liquid-filled products on the market in soft and hard gels, we see very different portfolios. For example, soft gels are suited for hydrophilic liquids, but they are not suited for hot melt products. Hard capsules can also be filled with combinations of liquids and solids, like pellets, smaller capsules of tablets. Only oily formulations are suitable for both soft and hard gels.
With regard to the capsule polymer, pharmaceutical soft gels are still gelatin-based, while liquids and hot melts can be filled in a hard capsule made of gelatin or HPMC. Whereas, the shell composition of soft gels can be adapted to tailor the shell to certain formulations. When we consider all of this, we are talking about two distinct and complementary technologies and dosage forms, that can generally not be interchanged without reformulation.
PharmTech: Are there any significant innovations in capsule formulations that you believe have impacted industry or will in the near future?
Stegemann (ACG): Pharmaceutical sciences will continue to be one of the highly dynamic sciences. There are many innovative formulations and drug delivery technologies under investigation, and only clinical evidence and real-world data will give us the final answer.
One of the areas where we see substantial innovation right now is in the field of enhanced therapeutic entities, so-called 505(b)(2) or hybrid applications. Known drugs are being reformulated using advanced drug delivery technology to achieve a better ‘effectiveness’ (efficacy under real-world conditions) and drug safety, by reducing medication errors.
Many innovations are taking place in the field of capsule-based DPI. The delivery of high drug doses and large biomolecules, enabled by particle engineering (e.g., spray drying), provide new avenues to treat now life-threatening diseases, such as cystic fibrosis.
Looking toward microbiome research and the microbiota as the therapeutic entity, capsules will be the preferred choice and become a functional excipient, protecting the sensitive microbiota from moisture, as well as gastric juice, and releasing it at the defined site of the intestinal tract.
PharmTech: Are there specific regulatory considerations surrounding capsule formulations?
Stegemann (ACG): Capsules are well-known and, regulatory-wise, a well described and accepted dosage form. Nevertheless, regulatory science continues to drive towards more global quality standards, digitalization, and patient focus and centricity. If we just look to digitalization, we see global efforts to combat falsified or substandard medicines by tagging and tracing each box and, soon, each dosage form from the factory through to the patient. The increasing focus on patients and patient centricity stems from the patient’s growing awareness as one of the most important factors in achieving the therapeutic outcomes.
Starting with the geriatric population, the European Medicines Agency (EMA) has put forward another reflection paper on the pharmaceutical development of medicines for use in the older population (4), followed by an FDA initiative of patient-focused drug development (5). All these regulatory and industrial initiatives require much more trans- and multidisciplinary collaboration, including the pharmaceutical supply industry. The next generation of capsule products to serve these emerging regulatory and industrial requirements will definitively benefit from co-development, if not co-creation, in close partnership with capsule manufacturers.
PharmTech: What impact has the COVID-19 pandemic had on capsule formulation, if any?
Stegemann (ACG): As a result of SARS-CoV-2, the pharmaceutical industry will go through a complete rethink of the pharmaceutical supply chain and the relationship with suppliers over the next two to three years. The revival of more regional and flexible manufacturing, as well as further governmental cost pressure, will raise several questions on investments into efficient manufacturing infrastructure. This manufacturing adjustment will be another opportunity to consider capsules due to the simplicity and flexibility in capsule product manufacturing and other innovative approaches, such as continuous manufacturing.
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Vol. 44, No. 9
When referring to this article, please cite it as F. Thomas, “Capsule Innovations: Speeding Up Drug Development,” Pharmaceutical Technology 44 (9) 2020.