Microbiome Delivery Solutions

Microbiome products often contain actives that are particularly demanding to formulate and deliver. Sensitive and living actives may lose stability or viability during manufacturing, storage, or gastric transit before they reach their intended site of action.

At Capsugel, our scientists work closely with customers on these challenges, bringing together capsule design, formulation expertise, analytical support, and CDMO capabilities.

The Innovaform® Accelerator supports early-stage pharmaceutical development, while Innovator’s Choice provides a dedicated pathway for nutritional products. Together, they offer tailored support to advance innovative capsule-based products, from concept and feasibility assessment to scale-up and manufacturing solutions where applicable.

The gut microbiome is increasingly recognized as an important factor in human health, and in how we understand disease.¹ What was once linked mainly to digestion now reaches much further: to the brain in Parkinson’s and Alzheimer’s,^2,3 to the liver in MASLD,⁴ to the heart in heart failure,⁵ and to how patients respond to cancer immunotherapy.^6,7 For many of these, the association is consistent, even where it is not yet clear whether the microbiome drives the condition or follows from it.

Acting on the microbiome can take different forms. One approach is to support or restore microbial balance with probiotics and other live or acid-sensitive actives. In therapeutic applications, the aim may also be to treat or prevent disease, whether by delivering an active to a specific intestinal site or by altering the microbial community itself, for example with live biotherapeutic products or fecal microbiota transplantation.

In each case, the active must reach the intestine with its activity preserved, while probiotics and live biotherapeutics must also remain viable. Capsugel addresses these requirements through capsule technologies designed to combine gastric protection, site-specific release, and support for the viability of living actives. Because food supplements and medicinal products fall under different regulatory frameworks, Capsugel provides two separate capsule solutions.

Notes and references:
*MASLD (metabolic dysfunction-associated steatotic liver disease) is the current term for the condition formerly known as non-alcoholic fatty liver disease (NAFLD).

1. Schoultz I, et al. Gut microbiota development across the lifespan: disease links and health-promoting interventions. J Intern Med. 2025;297:560-583. https://doi.org/10.1111/joim.20089
2. Oliver PJ, Civitelli L, Hu MT. The gut-brain axis in early Parkinson’s disease: from prodrome to prevention. J Neurol. 2025;272:413. https://doi.org/10.1007/s00415-025-13138-5
3. Jamerlan AM, An SSA, Hulme JP. Microbial diversity and fitness in the gut-brain axis: influences on developmental risk for Alzheimer’s disease. Gut Microbes. 2025;17(1):2486518.   https://doi.org/10.1080/19490976.2025.2486518
4. Schnbl B, Damman CJ, Carr RM. Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations. J Clin Invest. 2025;135(7):e186423. https://doi.org/10.1172/JCI186423
5. Snelson M, et al. Gut-heart axis: the role of gut microbiota and metabolites in heart failure. Circ Res. 2025;136:1382-1406. https://doi.org/10.1161/CIRCRESAHA.125.325516
6. Gazzaniga FS, Kasper DL. The gut microbiome and cancer response to immune checkpoint inhibitors. J Clin Invest. 2025;135(3):e184321. https://doi.org/10.1172/JCI184321
7. Bolte LA, Björk JR, Gacesa R, Weersma RK. Pharmacomicrobiomics: the role of the gut microbiome in immunomodulation and cancer therapy. Gastroenterology. 2025;169(5):813-827. https://doi.org/10.1053/j.gastro.2025.04.025

Across nutritional and therapeutic applications, delivering an active to the right site in the gut is essential. Release has to happen at the right point, not simply somewhere along the way. An active released too early, in the stomach or upper small intestine, may never reach the site where it is meant to act. To arrive intact, sensitive actives, such as proteins, bioactive molecules, and living organisms, need to be protected from the acidic conditions and enzymatic activity of the stomach. This gastric protection carries them through the stomach and enables release further along the gut. For larger and more complex molecules, including proteins and biologics, protection may also be required in the intestine to limit degradation by intestinal enzymes and help the active reach its intended site of action. For living actives, including probiotics and live biotherapeutics, viability must also be maintained throughout manufacturing, storage, and gastrointestinal transit.¹

To meet these different requirements, Capsugel offers two dedicated delivery technologies, Capsugel® Enprotect® capsules for pharmaceutical applications and Capsugel® Licaps® DUOCAP® capsules for nutrition.

Both technologies eliminate the need for a separate coating step after filling. Applied externally, an enteric coating can expose an active ingredient to heat and solvents, potentially affecting sensitive compounds. Building the release function into the capsule shell avoids this additional stress on the active and can simplify manufacturing by reducing processing steps.

References:
1. Wendel U. Assessing viability and stress tolerance of probiotics: a review. Front Microbiol. 2022;12:818468. https://doi.org/10.3389/fmicb.2021.818468

For pharmaceutical applications, the Capsugel® Enprotect® capsule provides enteric delivery in a ready-to-use format. Its enteric function is built into the capsule shell, a bilayer with an outer HPMC-AS layer over an inner HPMC layer. The shell resists the acidic stomach and releases its content as intestinal pH rises, without a separate coating step.

In compendial dissolution testing, the capsule remains intact in acidic media up to pH 6.0 and opens rapidly from pH 6.4, in line with the dissolution point of the outer HPMC-AS layer. This has also been shown in human studies under both fasted¹ and fed² conditions and in a dynamic gastrointestinal model,³ and these properties remained stable after six months of accelerated storage.⁴

This supports microbiome-directed therapies such as live biotherapeutic products and fecal microbiota transplantation, alongside a broad range of other acid-sensitive pharmaceutical actives, from small molecules and enzymes⁵ to biologics.

For projects requiring a more customized approach, the Innovaform® Accelerator can leverage the versatility of the Enprotect® bi-layer platform to develop tailored capsule solutions. Polymer composition, layer structure, capsule design, and release characteristics can be adjusted to address specific drug delivery challenges and maximize formulation performance.

Learn more about Capsugel® Enprotect® capsule here.

References:
1. Rump A, et al. In vivo evaluation of a gastro-resistant HPMC-based “next generation enteric” capsule. Pharmaceutics. 2022;14(10):1999. https://doi.org/10.3390/pharmaceutics14101999
2. Grimm M, et al. In vivo evaluation of a gastro-resistant Enprotect® capsule under postprandial conditions. Pharmaceutics. 2023;15(11):2576. https://doi.org/10.3390/pharmaceutics15112576
3. Knopp MM, Jannin V, Gonzalez V, Müllertz A. Utilizing the dynamic gastrointestinal model (DGM) to evaluate the gastric integrity of Capsugel® Enprotect® capsules in fasted and fed states. Eur J Pharm Biopharm. 2026;219:114962. https://doi.org/10.1016/j.ejpb.2025.114962
4. Enteric performance of Capsugel® Enprotect® capsules maintained after six months under accelerated storage conditions.

For nutritional applications, the Capsugel® Licaps® DUOCAP® capsule-in-capsule technology helps protect moisture- and acid-sensitive actives such as probiotics and digestive enzymes as they pass through the stomach. The HPMC-based capsule-in-capsule design provides a vegetarian- and vegan-suitable designed-release system, helping keep sensitive actives protected until they reach their intended site of release.

An inner capsule sits inside an outer one: the outer forms a barrier against ambient moisture, while the designed-release inner capsule holds the content through gastric transit. Different combinations of the two capsules determine where the content is released, including the colon, the main site of action for many probiotics. In a validated in vitro gut model, the format delivered up to 46 times more viable probiotics to the target region than a single standard capsule,¹ and up to 4 times greater digestive enzyme activity in the upper small intestine than immediate-release capsules.²

The format can also carry several ingredients in one dose, including combinations that are otherwise hard to formulate together, such as a liquid and a solid. Each component can follow its own release profile, from immediate to delayed.

Capsugel® Licaps® DUOCAP® capsules can be filled on standard capsule-filling equipment equipped with the appropriate tooling, avoiding the need for dedicated custom machinery.

Fill formats, colors, and finish can be adapted through Innovator’s Choice, the concept-to-market Innovation Services covering product design, development, manufacturing, distribution, and post-launch support.

Learn more about Capsugel® Licaps® DUOCAP® capsule here.

References:
1. Marzorati M, et al. Comparison of protection and release behavior of different capsule polymer combinations based on L. acidophilus survivability and function and caffeine release. Int J Pharm. 2021;607:120977. https://doi.org/10.1016/j.ijpharm.2021.120977
2. Karimian Azari E, et al. Evaluation of targeted-release capsule formulations for protection of the acid-sensitive enzyme pancreatin under fasted and fed intestinal conditions in vitro. Pharmaceutics. 2026;18(3):285. https://doi.org/10.3390/pharmaceutics18030285