In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

Felipe Varum,Peter Langguth,Mauricio A García,Jozef Al-Gousous,Susanne Page,Michael Hofmann

doi:10.3390/pharmaceutics14020291

Felipe Varum, Peter Langguth + Show 4 more

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https://doi.org/10.3390/pharmaceutics14020291

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Abstract

Several locally acting colon-targeted products to treat colonic diseases have been recently developed and marketed, taking advantage of gastrointestinal physiology to target delivery. Main mechanisms involve pH-dependent, time-controlled and/or enzymatic-triggered release. With site of action located before systemic circulation and troublesome colonic sampling, there is room for the introduction of meaningful in vitro methods for development, quality control (QC) and regulatory applications of these formulations. A one-size-fits-all method seems unrealistic, as the selection of experimental conditions should resemble the physiological features exploited to trigger the release. This article reviews the state of the art for bio-predictive dissolution testing of colon-targeted products. Compendial methods overlook physiological aspects, such as buffer molarity and fluid composition. These are critical for pH-dependent products and time-controlled systems containing ionizable drugs. Moreover, meaningful methods for enzymatic-triggered products including either bacteria or enzymes are completely ignored by pharmacopeias. Bio-predictive testing may accelerate the development of successful products, although this may require complex methodologies. However, for high-throughput routine testing (e.g., QC), simplified methods can be used where balance is struck between simplicity, robustness and transferability on one side and bio-predictivity on the other. Ultimately, bio-predictive methods can occupy a special niche in terms of supplementing plasma concentration data for regulatory approval.

Highlights

Colon-targeted formulations have been developed and commercialized over the past decades mainly aiming at local therapeutic action for the treatment of colonic diseases
Taking into account that typical diffusional times during dissolution are in the order of deci-seconds, it can be inferred that while proton transfer reactions are practically at equilibrium during dissolution processes, CO2 -H2 CO3 interconversion is not [101]. This sets bicarbonate apart from the other buffers, the action of which typically involves solely proton transfer reactions. This is because the effective pKa governing the buffering action at the interface between the dissolution medium and the dosage form/active pharmaceutical ingredient (API) will be a function of the diffusion rates of CO2 and H2 CO3, which will in turn depend on the hydrodynamics and viscosity [96,101,102]
The lack of bio-relevance of compendial methods limits their application during formulation development

Summary

Introduction

Colon-targeted formulations have been developed and commercialized over the past decades mainly aiming at local therapeutic action for the treatment of colonic diseases (e.g., inflammatory bowel disease or colon cancer). Colonic targeting is gaining more attention with ambitious goals of achieving local as well as systemic delivery of some compounds, which could be degraded in the stomach and the small intestine, such as therapeutic proteins and other novel format molecules (e.g., oligonucleotides). Acting drug products present a particular challenge when it comes to biopharmaceutic assessment. Bioavailability is defined as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the Pharmaceutics 2022, 14, 291. The traditional method for bioavailability assessment is based on using plasma drug concentration as a surrogate indicator for drug availability at the site of action

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