Treatment of ulcerative colitis by sustained release curcumin pellets coated with ethyl ascorbic acid; in-vitro, in-vivo, and in-silico analysis

Abstract

The present work aimed to protect the rapid reduction of Curcumin (Cur) in alkaline pH by newly synthesized ethyl ascorbic acid (EAA) in dual-coated Cur pellets (CCur-P4d) used for the treatment of inflammatory bowel disease (IBD). Physicochemical and morphological analysis was performed by FTIR, DSC, XRD, and SEM-EDS and in vitro release study. 92.87±6.26% release of Cur from uncoated Cur pellets (UCur-P4) in 0.1 M HCl at pH 1.2 was controlled to 5 % by coating with Eudragit L-100 (EL-100) which interns increased to 97.99±7.35% in 100 mM phosphate buffer of pH 7.4. The scavenging activity of 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxides (H₂O₂) was 95.88±1.22% and 85.35±1.43%, respectively. Acute toxicity study and anti-ulcerative effect of CCur-P4d in ulcerative colitis (UC) induced albino rats were evaluated by microscopic and macroscopic analysis. In protein-ligand binding interaction, Cur showed a potent inhibitory effect on inflammatory markers C-reactive protein, IL-6, and TNF-α. Conclusively, CCur-P4d is considered an alternative to locally acting therapeutics agents used in IBD.

Highlights

• Application of central composite rotatable design for the optimization of the newly synthesized curcumin pellets.
• Application of RGui software for the calculation of post-hoc analysis like ANOVA, Tukey’s comparisons and Bonferroni’s pairwise t-tests among CCur-P4a-d.
• Derivatization of stable ethyl ascorbic acid from ascorbic acid and preparation of Curcumin pellets by spherization technique.
• Dual coating of ethyl ascorbic acid and Eudragit RL-100 for sustained release and site-specific targeting.
• Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometer (XRD), and elemental detection spectroscopy (EDS), dissolution studies, and stability and safety studies of dually coated Curcumin pellets were performed on rats.
• In-vivo studies proved that the use of CCur-P4d an alternative to locally acting therapeutics agents used in IBD.
• In protein-ligand binding interaction, Curcumin showed a potent inhibitory effect on inflammatory markers C-reactive protein, IL-6, and TNF-α.

Introduction

Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease (IBD) progressing to remission, prostatitis, distal colitis, left-sided colitis, pancolitis, and colon cancer if untreated .[1] Several factors without known etiology i.e., chronic inflammatory disorders, immune response disorders, and environmental factors worsen the condition .[2] Mucosal inflammation of the intestinal layer results in reduction of bowel movements and causes mucous bloody diarrhea which is hallmark of IBD .[3]

The most common treatment options are long-term use of enema, a first-line acting drug for IBD including corticosteroids (prednisone), immunomodulators (azathioprine, methotrexate), and amino-salicylates with limitations of duration for use .[4]., [5]. Turmeric (Curcuma longa) is a perennial herb commonly called turmeric, belonging to the family Zingiberaceae, native to India, China, Japan, and other countries in South Asia. Curcuma longa is rich in carbohydrates, fiber, proteins, lipids, pyridoxine, magnesium, phosphorus, potassium, and calcium, making it a nutritious food. Cur’s anti-inflammatory properties are considered to be the basis of its various biological activities and play an important role in the treatment of inflammatory disorders like IBD.

Curcumin (Cur) has historically been used to cure several ailments and possesses antioxidant, antiseptic, and anti-inflammatory properties. The therapeutic effectiveness of Cur is limited due to its restricted aqueous solubility and pH-dependent instability .[6] Prevention of the rapid breakdown of Cur at neutral and alkaline pH was done by using primary exogenous vitamins such as vitamin C (ascorbic acid-AA) which reverts phenolic radical back to Cur. Ethyl ascorbic acid (EAA) is considered more thermostable and more anti-oxidant than AA due to the presence of lipophilic and hydrophilic groups in it. Cur with EAA due to its complimentary mode of action reduces inflammation and is found to be a successful candidate for adjunct therapy in the management of IBD .[7]

The term pellets refer to spherical agglomerations created by a variety of pelletization techniques, such as powder layering, spray drying, and extrusion/spheronization. Pellets are one of the best oral dosage forms because they are easier to distribute, less irritant for the gastrointestinal tract (GIT), enhance drug absorption minimize dose dumping, have no side effects, and plasma variability. Compared to tablets and capsules, pellets have a much larger surface area, which increases their exposure and interaction with the surrounding media, speeding up the breakdown rate of the drug. EL-100 a pH-responsive polymer was chosen because of its distinctive dissolution behavior above pH 7 .[8]

An attempt was made to improve the stability of Cur by preparing dual-coated pellets having EAA as an inner and Eudragit L-100 (EL-100) as a sustained-release outer coat. EAA is a powerful antioxidant, it counteracts free radicals that damage Cur. Due to more water solubility of EAA than AA, it improves Cur stability in watery conditions with improved film-forming properties which reverts its phenolic radical back to Cur. Core and coated pellets of Cur were prepared by extruder spheronizer technique and their physicochemical evaluations were performed. In-vivo toxicity study of dual-coated Cur pellets (CCur-P4d) on acetic acid-induced UC model made the study more understandable .[9] Safety of CCur-P4d at 10-30mg/kg/BW doses was confirmed by disease severity, colon length, and inflammation. Reduction in histological scores and the grade of inflammation scores were used to prevent the accumulation of inflammatory cells in the colon proving the regulation of IBD by Cur. Drug-polymer interaction study confirmed the highest C Score binding of Cur with 3EAA and EL-100 and a protein-ligand study confirmed the inhibitory effect of Cur on TNF-α, IL-6, and C-reactive protein claimed its suitability against UC.

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Materials

Cur (M. W=368.38g/mol) was purchased from Molecule Limited UK. MCC (M. W=324.28g/mol), acetone (M. W=58.08g/mol), LM (M. W=360.31 g/mol), DMSO (M. W=78.13 g/mol), and IPA (M. W=60.1 g/mol) these all were purchased from Sigma Aldrich Germany. GMS (M. W=358.563/mol) was purchased from Fisher Scientific UK. EL-100 (M. W=231.29g/mol) and Carboxymethyl cellulose CMC (M. W=240.208 g/mol) were purchased from Evonik Pharma Pakistan. AA (M. W=176.12 g/mol), Potassium carbonate (M. W=138.21 g/mol).

Dure Shahwar, Muhammad Hanif, Qasim Umar, Muhammad Rafiq Khalid Mahmood, Muhammad Qaiser, Nabeela Ameer, Muhammad Haseeb llyas, Treatment of ulcerative colitis by sustained release curcumin pellets coated with ethyl ascorbic acid; in-vitro, in-vivo, and in-silico analysis, Colloids and Surfaces B: Biointerfaces, 2025, 114671, ISSN 0927-7765, https://doi.org/10.1016/j.colsurfb.2025.114671.

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