In the development of oral solid dosage forms (OSDFs), bioavailability has consistently served as the core metric for evaluating drug delivery efficiency. For acid-labile drugs or active pharmaceutical ingredients (APIs) with defined intestinal absorption windows, the selection of capsule type is not only the starting point of formulation design, but also directly determines the stability and in vivo absorption performance of the drug.

Conventional Capsules: Rapid Release with Inherent Limitations

Conventional hard capsules, primarily manufactured from gelatin or hypromellose (HPMC), feature a rapid disintegration profile and can quickly release their contents in the gastric environment. This drug release mechanism is suitable for most drugs that are stable in gastric acid and carry no risk of mucosal irritation.

However, this rapid release can pose challenges for certain APIs: for example, some drugs undergo significant degradation in the gastric acid environment with a pH range of 1.2–3.5 (e.g., omeprazole has an extremely short degradation half-life at pH < 5), while others may cause direct irritation to the gastric mucosa.

Enteric Capsules: Mechanistic Design for pH-Dependent Release

The design of enteric capsules is based on the principle of pH-dependent release: they are fabricated from functional materials such as methacrylic acid copolymers or cellulose derivatives (e.g., hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS)).

These materials have a defined dissolution threshold—typically starting to dissolve at pH 5.5 and above, up to pH 6.5—ensuring the capsule passes intact through the stomach (pH 1.0–3.5) and only initiates drug release upon entering the proximal small intestine (duodenum, pH ~6.0). HKCAPS’ investigational targeted drug delivery systems achieve precision delivery, with drug release initiated at pH 6.8 for upper small intestinal targeting, and at pH 7.2 for delivery to the ileo-colonic region.

Dual Pathways to Enhance Bioavailability

Mechanistically, enteric capsules influence bioavailability through two core pathways:

Acidic Protection: For acid-labile proton pump inhibitors (PPIs, e.g., omeprazole, pantoprazole), select antibiotics, and protein and peptide drugs, enteric design prevents premature gastric degradation of the drug, ensuring a sufficient amount of the active ingredient reaches the absorption site.

Absorption Window Alignment: For drugs with intestinal-specific absorption (e.g., some weakly basic drugs, or Biopharmaceutics Classification System (BCS) Class II/IV drugs, i.e., low solubility/low permeability drugs), release in the intestinal environment enables an optimized dissolution profile. This in turn improves absorption efficiency and reduces inter-individual variability caused by differences in gastric emptying.

It must be emphasized that an enteric system does not guarantee improved bioavailability. Its final performance is highly dependent on the drug’s intrinsic physicochemical properties (e.g., dissociation constant pKa, lipophilicity), BCS category, and the overall in vitro-in vivo correlation (IVIVC) of the formulation. The decision to adopt an enteric strategy should be based on systematic pre-formulation studies and comprehensive in vitro and in vivo evaluations.

Real-World Data and Clinical Evidence

Clinical studies have provided robust empirical evidence for the clinical value of enteric capsules:

Protection of Acid-Labile Drugs

Taking select macrolide and beta-lactam antibiotics as examples, studies have shown that formulating these drugs into enteric preparations can significantly prevent gastric acid degradation. This increases the oral bioavailability of the drug, or the retention rate of the active ingredient reaching the intestinal tract, from less than 40% to over 80%.

Local Targeted Therapy

In the treatment of ulcerative colitis, colon-targeted formulations (e.g., budesonide) can achieve 5–10 times higher local drug concentrations in the diseased colon compared to conventional oral formulations. In pivotal clinical trials, their efficacy in inducing clinical remission was 40%–50% higher than that of placebo or non-targeted preparations.

Probiotic Delivery

For probiotics such as Lactobacillus and Bifidobacterium, in vitro simulation studies show that the survival rate of unprotected strains in the gastric acid environment (pH 2.0–3.0) is often less than 1%. When encapsulated in enteric capsules, their survival rate after 2 hours in simulated gastric fluid can be stably maintained at 80%–95%, ensuring a sufficient number of viable bacteria reach the intestinal tract to exert their therapeutic effects.

Key Clinical Application Scenarios for Enteric Capsules

Based on the mechanisms outlined above, enteric capsules deliver irreplaceable clinical value in the following scenarios:

Acid-labile drugs (e.g., proton pump inhibitors, select antibiotics, enzyme preparations)

Ingredients with gastric mucosa irritation potential (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), certain antineoplastic agents)

Drugs with defined intestinal absorption windows (e.g., some peptides, fat-soluble vitamins)

Formulations requiring delayed release or local colon targeting (e.g., therapeutics for inflammatory bowel disease (IBD), live biotherapeutic products (LBPs))

Industry Trends

Currently, with the rise of peptide therapeutics, RNA drugs, and live biotherapeutic products (LBPs), functional capsules are embracing new development opportunities. Industry analysis reports estimate that more than 600 global investigational oral formulation projects involve these novel, sensitive active ingredients, accounting for approximately one-third of all new oral drug development programs worldwide.

For pharmaceutical companies, capsules are no longer mere drug delivery vehicles, but a critical component of advanced oral delivery systems. Precisely matching the selection of capsule type with the intrinsic properties of the API is a pivotal step to achieve stable and predictable in vivo drug performance.

References

Evonik. EUDRACAP® Colon: Enabling Targeted Drug Delivery to the Ileo-Colonic Region. Microbiome Times Magazine. 2025.

NIH/PMC. Acid-Neutralizing Omeprazole Formulation for Rapid Release and Absorption. Pharmaceutics. 2025;17(2):161.