diacerein + aceclofenac

Innovative rhein and hydroxy fatty acid ester prodrugs for the treatment of chronic inflammation.

Han Lu L, Zang Tao T, Li Zhi-Peng ZP, Deng Yao Y et al.

Chronic inflammation is related to heart disease, diabetes, cancer, arthritis, and bowel diseases. The rhubarb-derived natural product rhein is highly effective at treating chronic inflammation. However, the gastrointestinal side effects and liver disorders of rhein have limited the long-term clinical application. Herein, we developed a series of rhein-hydroxy fatty acid prodrugs to alleviate the side effects of rhein while enhancing its therapeutic activity. We developed a novel method to overcome the side effects of rhein and enhance its pharmacological activity. The aim was to synthesize rhein hydroxy fatty acid ester prodrugs that retain anti‑inflammatory activity and alleviate gastrointestinal side effects. A series of rhein hydroxy fatty acid ester prodrugs were synthesized by linking rhein with hydroxy fatty acid. The chemical structure of these prodrugs was characterized by Fourier transform infrared spectroscopy (FTIR), hydrogen proton nuclear magnetic resonance (1H NMR), and high-resolution mass spectrum (HRMS). The cytotoxicity of rhein-hydroxy fatty acid ester prodrugs was evaluated using RAW 264.7 and Caco-2 cells. Additionally, in vitro anti-inflammatory, antioxidant, and anti-apoptotic effects were assessed. The targeted rhein-hydroxy fatty acid ester prodrug was verified using the DSS-induced mouse colitis model. In vitro studies demonstrate that the target compound R-15HA is markedly superior to both the free drug and diacerein in mitigating inflammation, oxidative damage, and apoptosis, while showing almost no cytotoxicity at final concentrations below 160 μmol·L⁻¹. Furthermore, Western blot analysis revealed that R-15HA inhibited the TLR4/NF-κB/MAPK more effectively than free rhein and 15-hydroxypentadecanoic acid. Molecular dynamics simulations demonstrated that the R-15HA compound exhibits a good binding capability with the TLR4 protein. Rhein can partially prevent weight loss, liver and spleen indices colon shortening, expression of proinflammatory cytokines, and epithelial damage, while rhein-hydroxy fatty acid prodrugs R-15HA have a more pronounced effect than rhein in dextran sulfate sodium (DSS)-induced colitis. Overall, our novel rhein-hydroxy fatty acid ester prodrugs are promising candidates for chronic inflammation in clinical therapy. This study might reveal an avenue to develop rhein hydroxy fatty acid ester prodrugs with satisfactory pharmacological activity to resolve various inflammatory diseases.

Sustainable miniaturized smartphone-coupled TLC platform for innovative cleaning validation: application to tizanidine combinations under challenging concentration ratios.

Abd El-Aziz Mariam O MO, Nadim Ahmed H AH, Monir Hany H HH, Nebsen M M et al.

Cross-contamination in pharmaceutical industry is a critical threat to patient safety, potentially reducing therapeutic efficacy and causing adverse effects and addiction. Drugs with narrow therapeutic index and high abuse potential are high-risk candidates, such as tizanidine (TZN). Its carryover may trigger harmful effects, withdrawal symptoms, and unintended dependence. Although cleaning validation minimizes these risks, rapid and reliable tools are still needed to support routine monitoring. To address this need, a portable at-line analytical platform was developed for TZN determination in combination with aceclofenac (ACF), ibuprofen (IBF), and paracetamol (PRC). It employs FDA-recommended swabbing approach, followed by smartphone-based TLC coupled with Color Analyzer and ImageJ for image processing. It provides a rapid, simple, and eco-friendly on-site tool for cleaning validation, enabling both quantitative analysis and qualitative screening via color density charts; a combination not achieved by reported methods. The mobile phase was optimized as toluene-acetone-ethanol (2.3:2.7:0.6 v/v/v), and smartphone-based analysis parameters were optimized. Validation according to ICH guidelines demonstrated good linearity and high sensitivity for the investigated drugs, with quantitation limits below established acceptance limits. Multidimensional sustainability was confirmed using moGAPI, CACI, VIGI, and RGB-12 assessments, highlighting the method as a novel sustainable tool for reliable cleaning validation of TZN combinations.

Aceclofenac Nanocrystals with Enhanced in vitro, in vivo Performance: Formulation Optimization, Characterization, Analgesic and Acute Toxicity Studies [Expression of Concern].

Co-assembly of dipeptide and hydrophobic drug in hyaluronic acid through Schiff base reaction for the treatment of osteoarthritis.

Chen Guixin G, Li Qin Q, Yu Chen C, Liu Hao H et al.

The development of multiple drugs for the synergistic osteoarthritis (OA) therapy is essential, particularly in light of the limited efficacy of existing clinical interventions. However, the poor bioavailability and systemic toxicity of hydrophobic drugs and their incompatibility with hydrophilic components largely hindered the co-delivery of multi-drugs. In this study, we present a dynamic covalent assembly strategy within a hyaluronic acid (HA) matrix to fabricate cationic dipeptide-based carrier particle (CGCP/HA). This carrier is designed to encapsulate hydrophobic nonsteroidal anti-inflammatory drug (NSAID) celecoxib and IL-1β inhibitor diacerein via a one-step co-assembly method, facilitating targeted drug delivery and combination therapy for OA. The resulting particles demonstrated exceptional stability, injectability, and biocompatibility in vitro, while mitigating the adverse effects associated with conventional oral OA medications. In a rat OA model, intra-articular administration of these co-assembled materials significantly suppressed inflammatory cytokines (TNF-α, IL-1β, and PGE2) and demonstrated enhanced cartilage repair by integrating multiple functions of hydrophilic HA, supramolecular carriers, and hydrophobic drugs. This work established a simple strategy for co-assembly of biomolecules and hydrophobic drug molecules and holds significant clinical promise for the treatment of OA.