Novel tablet formulation with dual control concept for efficient colonic drug delivery: in vitro optimization, in silico modeling, and in vivo evaluation

Doggwiler, Viviane. Novel tablet formulation with dual control concept for efficient colonic drug delivery: in vitro optimization, in silico modeling, and in vivo evaluation. 2023, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/94196/

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To date, oral delivery of drugs to the large intestine is primarily employed for the local treatment of inflammatory bowel disease (IBD). Research further aims to orally deliver peptides, proteins, and chronotherapeutics to the colon for systemic therapy by taking advantage of the long residence time and low proteolytic conditions of the large intestine.
Most of the marketed products utilize enteric coatings as sole pH-based release control for colonic targeting. However, inherent variability of pH values along the entire gastrointestinal tract reportedly caused premature drug release in the stomach and upper small intestine, or insufficient coating removal and defecation of intact formulations. In both cases the products fail to deliver drugs to the target site. Despite the introduction of multiple coatings and additional mechanisms such as enzymatic trigger and matrix systems, efficient and selective delivery of drugs to the colon has not yet been achieved.
Therefore, the purpose of the present work is to develop and evaluate a novel tablet formulation for controlled colonic release (CCR) of drugs. In vitro dissolution experiments and in vivo preclinical studies in domestic pigs aim to assess the performance of the CCR tablets with two model drug substances, while an in silico model aims to elucidate the mechanisms underlying drug release.
In this work, two internally triggered release controlling mechanisms are implemented in the CCR formulation for efficient and selective colonic drug delivery by employing a coated matrix tablet: A pH-sensitive coating layer based on Eudragit® FS 30 D is used to prevent drug release in the upper gastrointestinal tract, and dissolves above a pH threshold that is always reached along the small intestine in vivo. The matrix consisting of the plant-derived polysaccharide xyloglucan is used to delay drug release after coating removal, and to allow microbiome triggered drug release by enzymatic action in the colon.
In the first study, performance of CCR tablets containing either 5-aminosalicylic acid (5-ASA) or caffeine as model drug was assessed in vitro in dissolution tests simulating the passage through the entire gastrointestinal tract with a four-stage protocol. Microbial xyloglucanase was added in physiologically relevant concentrations as microbiome surrogate to the colonic dissolution medium. Matrix erosion was monitored in parallel to drug release by measurement of reducing sugar equivalents resulting from xyloglucan hydrolysis.
Limited drug release in gastric and small intestinal test stages and predominant release in the colonic stage was achieved. The xyloglucan matrix controlled drug release after dissolution of the enteric coating through the formation of a gummy polysaccharide layer at the tablet surface. Matrix degradation was dependent on the enzyme concentration in the colonic medium and significantly accelerated drug release, resulting in erosion-controlled release process. Drug release at physiologically relevant xyloglucanase concentrations was completed within the bounds of colonic transit time. This study demonstrated the applicability of the dual control concept to two drug substances with different solubility, and provided similar release rates in colonic environment containing xyloglucanase. Drug solubility mechanistically affected release profiles, in which case diffusion of caffeine, but not of 5-ASA, contributed to the overall release rate out of the matrix tablet.
The second study is tightly linked to the first one, aiming to investigate and elucidate the control mechanisms underlying the measured drug release from CCR tablet formulations in the presence of microbial xyloglucanase. Flat-faced replicas with identical composition and porosity to the CCR tablet cores were exposed to aqueous dissolution media to investigate matrix metamorphosis, water, and drug content in distinct regions. A mathematical model encompassing aqueous media ingress into the tablet cores, xyloglucan dissolution and swelling of the matrix, and simultaneous enzymatic hydrolysis of the polysaccharide was developed to describe surface erosion of the CCR tablet cores and the concomitant drug release.
Spontaneous formation of a swollen gummy layer at the surface of CCR tablet cores and the replicas thereof was demonstrated, with increased water and reduced drug content compared to the regions immediately below. The gummy layer thickness was inversely correlated to enzyme level but remained roughly constant throughout the duration of the measurement. Drug diffusion rate was reduced in the gummy layer compared to water, and enzymatic reaction parameters were determined using a re-created gummy layer. By fitting the model to CCR tablet core erosion data, reasonable values of medium ingress velocity and xyloglucan dissolution rate constant were deduced for two enzyme concentrations and both drug substances, whereas an adequate description of the data was obtained. Surface matrix erosion fully explained the release rate of 5-ASA from CCR tablet cores, demonstrating this to be the sole release controlling mechanism, while drug diffusion – postulated to take place only in the gummy layer – contributed to the release rate of caffeine at early timepoints. A positive correlation between xyloglucanase concentration and enzymatically triggered acceleration of both gummy layer erosion and drug release was demonstrated. However, the dependence of this effect on the enzyme level was weak, suggesting colonic delivery rate not to be critically dependent on the xyloglucanase concentration in the large intestine.
Finally, the third study focused on the in vivo performance evaluation of CCR tablets. The aim was to demonstrate specific colonic drug delivery in a preclinical study using domestic pigs as animal model. Plasma concentration profiles of drug and metabolite measured after administration of CCR tablets were evaluated by physiologically based pharmacokinetic modeling. In vivo drug release rates and absorbed amounts from small and large intestine were estimated by model-dependent deconvolution using immediate release tablets and intravenous solutions as reference.
Overall adequate data approximation was achieved. The time (tmax) and magnitude (cmax) of maximum concentrations of both CCR 5-ASA and caffeine tablets suggested delayed drug absorption from the colon. Deduced amount of drug absorbed from the small intestine was rather small, whereas absorption took place overwhelmingly from the large intestine. Drug release from CCR tablets occurring predominantly in the large intestine was inferred, and the estimated caffeine release rate was much larger in the colon compared to the small intestine. This demonstrated enzymatically triggered release by colonic bacteria and was supported by measured xyloglucanase activity in porcine rectal and cecal samples.
Results of this study thus provided evidence of the functionality of the xyloglucan-based matrix by preventing premature drug release and allowing for target specific delivery in the large intestine. Co-administration of caffeine and the microbially cleaved marker molecule sulfasalazine with CCR tablets confirmed colonic drug release. Gastrointestinal transit times derived from telemetry measurements showed prolonged gastric retention, which however was not universally applicable to the monolithic CCR tablets. Compound recovery in fecal droppings confirmed complete release of both 5-ASA and caffeine from CCR tablets, and was consistent with extensive pre-systemic 5-ASA metabolism leading to diminished 5-ASA bioavailability of CCR tablets. This in vivo study provides evidence of efficient colonic drug delivery by the developed formulation. Clinical relevance based on the comparability between pigs and humans is discussed.
Overall, this work demonstrates the CCR tablet formulation to be very promising for controlled colonic drug delivery. Understanding of native xyloglucan metamorphosis in contact with aqueous media and its simultaneous hydrolysis by enzymes of the colonic microbiome is fundamental for performance evaluation of the CCR tablets. Adaptation of the formulation to deliver other drugs to the colon is facilitated by the developed in silico erosion model, and the presented in vitro dissolution setup can be used for screening due to the adequate in vitro – in vivo correlation demonstrated with regards to colonic drug release rates.
Advisors:Imanidis, Georgios
Committee Members:Ricklin, Daniel and Griffin, Brendan
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular Pharmacy (Ricklin)
UniBasel Contributors:Imanidis, Georgios and Ricklin, Daniel
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15009
Thesis status:Complete
Number of Pages:iii, 212
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss150099
edoc DOI:
Last Modified:09 May 2023 04:30
Deposited On:08 May 2023 14:54

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