Oral Biologic Delivery: Strategies to Overcome GI Barriers

New formulation strategies are beginning to yield clinically and commercially viable oral biological therapies, according to a Lonza whitepaper published alongside a fact sheet that maps each barrier to a capsule or formulation technology.

The whitepaper states that the vast majority of current therapeutic options are limited by the need for parenteral administration, and that the conditions of the gastrointestinal (GI) tract lead to poor stability and permeability of biologics. It sets out the biochemical, mucus, and epithelial barriers behind that problem, then reviews five strategies it says can overcome them. The fact sheet maps three of those challenges to a Lonza Capsugel technology and to the active pharmaceutical ingredient (API) classes each one is compatible with.

Why oral delivery is worth pursuing

The whitepaper notes that biologics have revolutionized patient care, transforming outcomes for previously untreatable diseases, and that the class is broad by definition: it cites the National Cancer Institute definition of a substance made from a living organism or its products and used in the prevention, diagnosis, or treatment of cancer and other diseases. Most are large, complex molecules, though the document notes exceptions such as glucagon-like peptide-1 (GLP-1) receptor agonists, which it describes as relatively small peptides.

Injection is described as invasive and painful, as generating sharps waste, and as often requiring a trained healthcare professional, and many conditions treated by biologics are chronic, which the document says exacerbates the burden and reduces patient adherence. It cites one survey in which 91% expressed a preference for oral delivery over their current parenteral delivery, and in which 55% of patients with twice-yearly injections would prefer daily oral administration if given the choice.

The barriers in the gastrointestinal tract

According to the whitepaper:

• Biochemical barrier: the acidic pH of the stomach poses a significant risk to biologics, and gastric enzymes activated at low pH, including pepsin, can break them down through pH-induced proteolysis. Proteolytic enzymes also pose a significant risk in the intestine, including trypsin, chymotrypsin, and pancreatic amylases in the lumen, and endopeptidases, alkaline phosphatase, and isomaltase at the brush border membrane.
• Mucus barrier: composed of water, lipids, and mucins and thickest in the gastric and colonic segments, the layer lets molecules of 200nm enter easily while macromolecules are unable to pass.
• Epithelial barrier: only a single cell thick, but intercellular junctions prevent the passage of macromolecules, particles engulfed by endocytosis are then degraded by intracellular enzymes, and large or charged compounds need channel proteins to assist uptake.
• The resulting bioavailability: these conditions lead to low bioavailability, and the document reports an estimate that 94–98% of orally administered proteins are digested by enzymes.
• Commercial constraints: some biologics may be expensive to manufacture, which can make a reduction in bioavailability commercially problematic, and commercial manufacturing can itself pose a risk to biologics, which can be sensitive to heat, pH, and solvents.

Five strategies the whitepaper reviews

• Enteric protection: the agent is coated or encapsulated in a pH-sensitive polymer that remains intact at the low pH of the gut but disintegrates at the higher pH of the intestine. Coating is traditionally applied to tablets or pre-filled capsules, which the document says adds a step and can put biological agents at risk of denaturing due to heat or the solvents used. Lonza states that it has developed a bi-layered enteric capsule technology enabling enteric delivery without a post-filling coating step.
• Permeation enhancers: the main permeation enhancer candidates used in clinical trials currently are sodium caprylate, salcaprozate sodium (SNAC), and bile salts, which the whitepaper says work by destabilizing the integrity of lipid membranes and opening tight junctions to enhance transcellular and paracellular permeability.
• Lipid-based formulations (LBFs): described as emerging as another key strategy, since lipophilicity can support absorption through the lipid bilayer. LBFs are said to suit both hydrophilic and lipophilic compounds, as self-emulsifying drug delivery systems (SEDDS) using surfactants, cosurfactants, and hydrophobic ion pairing (HIP) can be used to solubilize and stabilize hydrophilic compounds in the oil phase.
• Nanoparticles: biologics can either be attached to nanoparticles or fully encapsulated, with the function depending on the size and coating properties of the nanoparticle. Particles of a small size (30–200nm) and hydrophilic nature can be used to increase mucus penetration, with coatings of polyethylene glycol (PEG), polyvinyl alcohol, and methacrylamide copolymer (pHPMA) often used to achieve hydrophilicity. Targeting specific receptors can localize delivery, for example in inflammatory bowel disease.
• Microneedle devices: where bioavailability similar to parenteral administration is needed, the document says microneedle smart capsule devices can be considered, and that they administer drugs painlessly due to the absence of pain receptors in the stomach and intestine. Two bio-compostable devices are reported to have recently shown promising results: one dissolves in the stomach and releases a device with a spring-loaded hook that administers the drug, while RaniPill capsules dissolve in the intestine and inflate a balloon attached to dissolvable hollow drug-loaded needles. Clinical trials are reported to have demonstrated that these are well tolerated and able to deliver octreotide with 65% bioavailability.

Single strategies and combinations

Which route is needed depends on the properties of the biological agent in question and its intended target, and the whitepaper says a single strategy may be sufficient to reach clinical efficacy. Its examples are delivery of fecal microbiota transplant and pancreatic enzymes to the intestine using enteric protection from Capsugel Enprotect capsules; Rybelsus, which uses SNAC as a buffering and permeability agent to increase absorption of semaglutide in the stomach; and microneedle devices, which it says can deliver similar bioavailability to subcutaneous injection.

In other cases multiple strategies may be needed. Alternative models of GLP-1 administration have used a combination of enteric protection, LBFs, HIP, and permeation enhancers, and preclinical models of monoclonal antibodies (mAbs) and RNA-based therapies are reported to have shown promising results with combination strategies. In one, infliximab concentration in the gut tissue was higher with oral delivery, using Phloral enteric coating alongside Soteria as an excipient, compared with intravenous injection. The GENEGUT project, a research partnership of 9 organizations from 8 European countries, is also investigating treatment for Crohn’s disease, using a combination of enteric protection and nanoparticles to support the oral delivery of RNA-based therapy.

Matching the technology to the barrier

The fact sheet sets three challenges against the technologies Lonza Capsugel offers for each, with the API classes each one is compatible with.

It states that the versatile nature of bi-layer capsules makes them particularly suited to customization, facilitating delivery systems that match the specific challenges and properties of the API. The options listed are bi-layer customization for intestinal targeting, acid protection, and compatibility with custom formulations; solid or liquid fill; and sizing options for every development stage, including pre-clinical. Among the supporting capabilities named are Innovaform Accelerator labs, supporting the development of bespoke solutions such as customized formulations to enhance bioavailability, and good manufacturing practice (GMP) manufacturing and packaging at its Tampa location.

Key takeaways

• The whitepaper groups the obstacles to oral biologic delivery into a biochemical barrier, a mucus barrier, and an epithelial barrier.
• It reports an estimate that 94–98% of orally administered proteins are digested by enzymes.
• Five strategies are reviewed: enteric protection, permeation enhancers, lipid-based formulations, nanoparticles, and microneedle devices.
• Lonza states that its bi-layered enteric capsule technology enables enteric delivery without a post-filling coating step, which the fact sheet says helps protect sensitive APIs during production and accelerates the manufacturing process.
• A single strategy is described as sufficient for some agents, while combinations have been used in alternative models of GLP-1 administration and in preclinical models of mAbs and RNA-based therapies.

See the full whitepaper on The New Frontier in Drug Delivery: Oral Biologics here:

Lonza – Oral Biologics Whitepaper

(click the picture to download the document)

See the full fact sheet on Solutions to Enable Oral Biologic Delivery here:

Lonza – Oral Biologics Factsheet

(click the picture to download the document)

Sources

1. Lonza, The New Frontier in Drug Delivery: Oral Biologics, whitepaper, 2026.
2. Lonza, Solutions to Enable Oral Biologic Delivery, fact sheet, 2026.

This article is intended for biopharmaceutical formulation, process, and regulatory professionals. It does not constitute clinical, regulatory, or formulation advice. Always refer to the current pharmacopoeial monograph, the supplier’s current technical data sheet and Certificate of Analysis, applicable ICH/FDA/EMA guidance, and your own development and stability data. Pharma Excipients International AG is not a manufacturer of the excipients discussed.

Request a sample here: