The hard empty capsule (HEC) market is experiencing significant growth, and it is not difficult to understand why. HECs can be used with enabling technologies to ensure high active pharmaceutical ingredient (API) bioavailability and to facilitate localized drug delivery. Additionally, their composition enables rapid disintegration in the stomach or small intestine, making them a convenient, non-invasive, and relatively cost-effective dosage form.
The increasing popularity of HECs is largely driven by their ability to enhance patient compliance, deliver delayed release, and offer potential cost reductions for drug developers. Those factors are influencing regulatory review and drug developer decision-making when selecting a partner. Consequently, drug product and capsule manufacturers, including contract drug manufacturing organizations (CDMOs), need to stay abreast of new technologies to meet industry demand for new innovative solutions.
Addressing Current Industry Challenges
Advancing a drug candidate from the discovery phase to the clinic is a process fraught with challenges, any one of which can impede progress and delay development of a potentially lifesaving medication. For example, problems arising in preclinical research — including inconsistent dosing, poor drug absorption, and risk of drug degradation in the gastrointestinal (GI) tract — can derail the development of an orally administered product before it has a chance to enter clinical trials.
Facilitating oral enteric delivery is one of the major challenges facing HEC manufacturers. The conventional approach is to coat capsules after filling them, a time- and labor-intensive process that can negatively affect APIs. Additionally, most new drug entities face bioavailability challenges that can delay the development of oral formulations for both small molecule and biologic therapies. For innovators and manufacturers seeking to develop a truly enteric capsule that retains the advantages of simplicity and convenient oral dosing, these challenges can be mitigated through exploring innovative delivery solutions such as those listed in Table 1.
Leveraging the Advantages of Bi-Layer Technology
Among recent innovations, bi-layer capsules with built-in enteric properties, adjustable to the needs of the customer’s API, are perhaps the most promising. Produced via double-layered manufacturing technology, bi-layer capsules enable targeted delivery of APIs to the small intestine while eliminating the need for post-filling sealing, banding, or coating, reducing the risk of API degradation. Bi-layer capsules can be used for many classes of APIs that could not traditionaly be delivered orally. The technology’s potential for accelerating drug manufacturing and development processes makes bi-layer capsules an intriguing option for drugmakers.
For example, at Lonza we have developed an off-the-shelf bi-layer capsule with an inner, or structural layer, consisting of hydroxypropyl methylcellulose (HPMC), which has good gelling properties, to provide shape and appropriate mechanical properties for high-speed filling. The outer, or functional layer, is made of HPMC acetate succinate (HPMC-AS), an enteric polymer that dissolves from pH 6.2, ensuring targeted release in the small intestine. Both polymers are established cellulose derivatives that are well-known in solid dosage formulations, offering good compatibility and long-term stability — important qualities for both the capsule and the API within it. Characterization studies have demonstrated the Lonza bi-layer capsule’s ability to protect sensitive compounds from the harsh and acidic gastric environment. Additionally, in vivo evaluations of the capsule have confirmed delivery of drug content to the distal intestine, with consistency between fasted and post-prandial (fed) conditions.
Those findings support the rationale for bi-layer capsules as a ready-to-use solution for oral administration of fragile compounds such as acid-sensitive or enzymatic degradation prone small molecules, proteins, peptides, monoclonal antibodies, live biotherapeutic products (LBPs), and messenger RNA. They may also be suitable for drugs that are not acid-sensitive but must be delivered specifically to the small intestine. Moreover, HPMC-based bi-layer capsules are particularly well-suited for APIs with poor oral bioavailability needing specific enabling technologies, such as amorphous solid dispersions.
Bi-layer technology can facilitate design of bespoke capsules with specific release timings, whether delayed or rapid, based on the therapeutic needs of an API. The capsules can be manufactured in small batches for proof-of-concept validation, or scaled up for later-phase trials and commercialization. Their flexibility and scalability can ensure highly targeted drug delivery and enhanced therapeutic efficacy.
Looking to the Future
Advances in bi-layer technology portend several exciting trends in capsule manufacturing. For starters, the emerging field of microbiome-based drugs offers opportunities for capsules as a new mode of administration and targets a wide array of disorders such as psoriaisis, cancer, and infectious diseases. Capsule-based delivery of fecal microbiota transplant (FMT) therapy represents one such opportunity, given patients’ preferences for oral therapies over nasogastric tubing or enema administration. We expect to see new guidance from regulatory authorities on orally administered FMT as the field continues to evolve.
Advances in artificial intelligence (AI) and machine learning (ML) are disrupting numerous industries, and capsule manufacturing is no exception. In particular, AI-based technolgoies can be deployed to enable automated inspection, enhancing manufacturers’ ability to detect capsule defects such as cracks, size/dimension variations, and color inconsistencies at high speed. Automated inspection data can also be used in process optimization by facilitating monitoring and adjustment of melt properties and dipping/drying parameters, creating a feedback loop that enables continuous learning and improvement.
As new manufacturing technologies become more widely used, we can expect drug designers and developers to push the limits of oral solid dose delivery by introducing capsules with enhanced functionality and tailored solutions. Innovative capsule technology could potentially enable delivery of oral and inhalable biologic therapies, for example, and facilitate delivery of APIs that previously could not be administered orally. As another example, it may soon be possible to develop a capsule that targets a specific segment in the intestine, a feature that may benefit patients with Crohn’s disease or other inflammatory GI ailments. Bi-layer technology, in particular, may enable the conversion of certain vaccines into oral dosage forms, potentially improving patient comfort.
We can also expect to see capsules become more sustainable as manufacturers develop new methods to facilitate more environmentally conscious production and distribution. In a recent survey of more than 800 pharma and biopharma professionals, almost two-thirds (62%) identified sustainability as their number one priority over the next five years. That finding reflects the industry-wide imperative to reduce its carbon footprint, particularly in producing final dosage forms. Indeed, the continued push for sustainable manufacturing methods, combined with the ongoing quest to develop more cost-effective therapies, will likely elevate the profile of bi-layer capsules, and of other types of hard empty capsules, as a responsible, convenient delivery solution.
References
Jannin, V. et al. (2023). In vitro evaluation of the gastrointestinal delivery of acid-sensitve pancrelipase in a next generation enteric capsule using an exocrine pancreatic insufficiency disease model. International Journal of Pharmaceutics. 630:12241.
Rump, A., et al. (2022). In vivo evaluation of a gastro-resistant HPMC-based “next generation enteric” capsule. Pharmaceutics. 14:1999.
Grimm, M., et al. (2023). In vivo evaluation of a gastro-resistant Enprotect capsule under postprandial conditions, Pharmaceutics. 15:2576.
Survey reveals biopharma sustainability lacks momentum. (2024 Aug 27). Drug Discovery World.