Development of intestinal colonic drug delivery systems for diverticular disease: A QbD approach

This study aimed to advance the development of intestinal colon-coated sustained-release matrix tablets of metronidazole for diverticulitis treatment, employing the Quality by Design (QbD) methodology. Comprehensive Risk analysis and Risk evaluation were conducted to assess the potential risks associated with Critical Material Attributes (CMA) and Critical Process Parameters (CPP). Ishikawa diagram, color-coded risk classification and the Risk Priority Number (RPN) were used as tools for risk evaluation. A Design of Experiments (DoE) was executed using a fractional factorial design, incorporating five key factors derived from the Risk analysis and Risk evaluation. Two levels and a central point were established for each factor, resulting in 28 batches of coated tablets. The manufacturing process involved direct compression, followed by a coating process using pH-dependent or time-dependent polymers. Characterization and dissolution studies were conducted on all batches, and the obtained results underwent analysis of variance (ANOVA).

Highlights

Quality by design principles were considered in the development process of colonic-coated matrix tablets.

A DoE based on a previous FMEA analysis was performed using a fractional factorial design.

In vitro drug release profiles were fitted to describe the drug release behavior.

Type of coating polymer, the % increase in total weight after coating, and the interaction ratio HPMC/CH and mixing times statistically impact the drug release.

Multivariate regression equations were optimized for critical variables and a design space for % drug dissolved was developed.

The findings demonstrated the robustness and reproducibility of both the direct compression and coating processes. Statistical analysis identified HPMC/chitosan ratio, blending time, coating polymer, and coating weight gain as factors significantly impacting drug release. A Design Space was established to delineate the interplay of these factors, offering insights into various combinations influencing drug release behavior. Thus, the design space for 10 % weight gain formulations includes a range of HPMC/CH ratios between 2.7–3 and mixing times between 10 and 12 min; for 20 % weight gain formulations it includes a range of HPMC/CH ratios up to 2 and mixing times between 10 and 16 min. Multiple Linear Regression between technological and biopharmaceutical variables were optimized facilitating scale-up operations. Batches with a 10 % weight increase and varied HPMC viscosity grades and coating polymers achieve ∼50 % drug release at 24 h; however, batches with a 20 % weight increase along, with either high proportions of HPMC and short blending times or low proportions of HPMC and longer blending times, achieve slow release of metronidazole. This study contributes to optimizing metronidazole colonic delivery systems, enhancing their potential efficacy in diverticulitis treatment.

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Materials

Metronidazole was purchased from Fagron Ibérica, Spain. HPMC 15K was donated by Colorcon Ibérica (Spain), and HPMC 35K of Ashland was donated by Saffic Alcan. Chitosan (CH) 1000-2000 cps; 1,500,000 (avg.) molecular weight; degree of deacetylation ≥ 90.0%, was obtained from Glentham Life Science. Colloidal dioxide silica, Aerosil® 200 VV Pharma, was donated by Evonik Spain and Glyceryl Behenate was donated by Gattefossé Spain. Polysorbate 80 and Glyceryl monostearate (GMS) was purchased from Acofarma (Spain). Triethyl citrate from Acros Organics was purchased from Fisher Scientific. Finally, Eudragit® FS30D, Eudragit® RL30D and PlasACRYL® T20 were received as samples generously donated by Evonik Spain.

Roberto Arévalo-Pérez, Cristina Maderuelo, José M. Lanao, Development of intestinal colonic drug delivery systems for diverticular disease: A QbD approach, European Journal of Pharmaceutical Sciences, Volume 203, 2024, 106918, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106918.