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

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.

Preparation, Characterization and In Vitro Evaluation of Eudragit S100-Coated Bile Salt-Containing Liposomes for Oral Colonic Delivery of Budesonide

“…In SGF and FaSSIF, less than half of the drug was released within 2 and 4 h, respectively, demonstrating the potential for ES100-SGC-Lip to prevent premature drug release in the environment of the stomach and upper intestine. In PBS pH 7.4, ES100-SGC-Lip allowed the release of most of the drug due to the rapid dissolution of the ES100 coating layer within 60 min at pH 7.4 and 37 • C [66]. The onset of degradation of Eudragit S100 films has been shown to occur within minutes at pH >7, similar to that observed in the current study [67].…”

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics

“…Similar observations have been made for prednisolone tablets prepared with four different Eudragit® coatings [38]. Unfortunately the main limitation of using bicarbonate media is the continuous evaporation of CO 2 resulting in an increasing buffer pH; in this regard, both manual and automated approaches have been developed to successfully stabilise bicarbonate buffer pH during dissolution testing [196]. A recent study reported that dissolution of Asacol® 400 mg and generic colon-targeted 5-ASA tablets in bicarbonate buffer using a novel flow-through cell system correlated well with the in vivo plasma PK measured in 48 healthy male adults [197].…”

“…More advanced systems may include multiple compartments that simulate different regions of the colon and allow fine adjustments of parameters such as pH or transit time between segments (Fig. 4) [196,211]. One such model, known as The Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME®) includes vessels representative of the stomach, small intestine, and ascending, transverse, and descending colon that allow treatment periods up to 4 weeks [212].…”

Colon-Targeted eNAMPT-Specific Peptide Systems for Treatment of DSS-Induced Acute and Chronic Colitis in Mouse

“…Ligands are an essential component of targeted drug delivery systems, and the selection of ligands with high affinity is of considerable interest [ 23 , 24 , 47 , 48 , 49 ]. Here, we used TK peptides as suitable targeting ligands with potential applications for colon-targeted therapy [ 23 ].…”