Variable Bioavailability Research Articles

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstone of management and methotrexate is broadly considered as first-line treatment. Gastrointestinal side effects and variable bioavailability however limit adherence to and effectiveness of oral methotrexate, while parenteral methotrexate remains underutilized. To explore RA patients' perspective and their level of acceptance towards parenteral methotrexate and to investigate the barriers and enablers to its use. A qualitative study was conducted using semi-structured interviews between May and August 2022. Participants were recruited using convenience and purposive sampling strategy. The Theoretical Framework of Acceptability (TFA) was used to guide the development of the interview guide and data analysis (directed content analysis). Twenty-five participants (68% female, 76% with experience using parenteral methotrexate) were interviewed. All seven TFA constructs were found to influence participants' acceptance of parenteral methotrexate. High acceptance was related to the TFA constructs "perceived effectiveness", "intervention coherence", "self-efficacy" and "ethicality". Experience with disease improvement and gastrointestinal tolerance with parenteral methotrexate was valued by the participants, and understanding these benefits was linked with high acceptability (perceived effectiveness). Participants reported a high level of confidence in using methotrexate injections and adapting to the injection-taking routine (self-efficacy). The user-friendly design of the methotrexate pre-filled syringe, along with the support from healthcare professionals, served as enablers (intervention coherence and ethicality). Minimal opportunity costs (e.g., no major lifestyle sacrifices) further supported acceptability, though some reported initial injection anxiety (affective attitude). Barriers were frequently identified in the "burden" construct, including travel inconvenience and injection-associated cost. Participants without the experience with methotrexate injections expressed the need for further information, particularly regarding the logistical and safety aspects of parenteral methotrexate (intervention coherence). Our findings highlighted that patients' comprehension of the benefits of using parenteral methotrexate, confidence in self-administration, healthcare professionals' support, and the ease of using injections may help optimize treatment acceptability, underscoring the importance of patient's education from healthcare professionals and the availability of patient-friendly devices.

Domperidone (DOM) is a BCS class II drug which widely used as an oral medication for the control of nausea and vomiting. It showed a very low and variable bioavailability related to its very poor solubility and pre-systemic metabolism. Polymeric nanofibers (PNFs) exhibit unique properties that make them a favorable choice for drug delivery applications. The study aimed to develop an optimum fast-dissolving oral polymeric electrospun nanofiber of DOM using Eudragit L100/Polyvinyl alcohol (EL-100/PVA) polymer blend. The fabrication process was optimized through a set of formulation parameters (composition of the polymer blend, polymer blend concentration, and electrospinning voltage). The DOM-loaded EL-100/PVA NFs were characterized for surface shape, nanosize, % drug loading, DOM in vitro release, drug/polymer interaction, and in vivo prokinetic study. The optimization process showed defect-free DOM-loaded NFs with very low nano diameter, high DOM loading, and superior in vitro dissolution of DOM at intestinal pH (about 90% of the drug released within 5min). The drug/polymer interaction study demonstrated the conversion of DOM into an amorphous form, which facilitated its dissolution. No physicochemical interaction between DOM and the polymer blend was observed. In vivo prokinetic study signified the orally enhanced prokinetic activity of DOM-loaded NF relative to pure DOM and commercial DOM product. The DOM-loaded EL-100/PVA NFs exhibited a better effect on the gastrointestinal reactivity relative to free DOM and commercial DOM product. The superior in vitro dissolution and in vivo prokinetic activity proved the promising potential of polymeric NFs to improve the oral delivery of DOM. The optimized DOM-loaded EL-100/PVA NFs may allow for dose reduction and low cardiovascular risk compared to conventional DOM tablets.

Rosuvastatin is considered as the cornerstone therapy for primary and secondary prevention of cardiovascular diseases. Although clinical efficacy of rosuvastatin is well established, but wide inter-individual variations have been observed in its plasma levels, lipid lowering efficacy and adverse effects. So the current study was undertaken to evaluate the impact of genetic polymorphism of rosuvastatin efflux transporters on variable bioavailability, clinical efficacy and adverse effects. For this study, three hundred and eightyfour hyperlipidemic patients with low density lipoprotein more than 130mg/dl and serum creatine phosphokinase level within normal range > 190 U/L were enrolled. Study design was quasi experimental and non-probability purposive sampling was done for recruitment of patients. It was conducted from June 2022 to December 2023 in two tertiary care hospitals of Pakistan. All the enrolled patients were treated with rosuvastatin (10mg) once daily for 12 weeks. Fasting lipid profile, serum creatine phosphokinase, liver and renal function tests were measured at the start of study. After 12 weeks of intervention with rosuvastatin, biochemical tests, genotyping and plasma rosuvastatin levels were determined. Frequency of ABCG2 34C > T polymorphism for wild type CC, heterozygous mutant CT and homozygous mutant TT genotypes were 55.2, 35.9 and 8.9% respectively. Patients with TT and CT have significantly higher plasma levels of rosuvastatin with mean value of 30.37 ± 6.4 ng/mL and 22.27 ± 4.68 ng/mL respectively as compared to CC genotypes 15.57 ± 8.94 ng/mL (p = < 0.001) which ultimately has improved lipid lowering efficacy. After 12 weeks of intervention, rosuvastatin significantly reduced total cholesterol (mean % decrease: CC 23.04 ± 10.05%, CT 37.43 ± 7.64%, TT 41.32 ± 6.97%, p = < 0.001), low density lipoprotein (mean % decrease: CC 31.11 ± 11.6% CT 47.27 ± 8.22% TT 53.29 ± 8.03%, p = < 0.001), very low density lipoprotein (mean% decrease: CC 36.23 ± 13.27%, CT 44.41 ± 10.29%, TT 54.5 ± 9.63%, p = < 0.001), triglycerides (mean% decrease: CC 24.34 ± 12.66%, TC 35.2 ± 10.47%, TT35.94 ± 8.6%, p = < 0.001) and high density lipoproteins (mean% increase: CC 9.19 ± 10.29%, CT 16.51 ± 9.33%, TT 23.10 ± 8.32%, p = < 0.001). Patients with TT and CT genotype has greater improvement in lipid profile compared with CC genotypes. Frequency of myopathy and hepatotoxicity in study population was 5.2 and 3.13% respectively. We conclude that rosuvastatin 10mg is highly efficacious and well tolerated by most of the patients, however genotype profiling should be done before initiating rosuvastatin therapy to reduce the risk of adverse effects and to improve the compliance.

Solubility, a key physicochemical property, determines a substance’s ability to dissolve in a solvent. Glimepiride, a BCS Class II drug for type 2 diabetes, exhibits very low aqueous solubility and high lipophilicity, which complicates formulation and may cause variable bioavailability and therapeutic failure. Hydrotropy which enhances aqueous drug solubility without micelle formation can allow higher drug loading with low toxicity. This study aimed to improve glimepiride’s aqueous solubility and bioavailability using hydrotropic agents. Solubility was measured in water, saline phosphate buffer, ethanol, and methanol, and in solutions of five hydrotropic agents (sodium benzoate, mannitol, urea, sodium acetate, and sodium citrate at 10–40% w/v). Drug solubility was also evaluated in binary and ternary mixtures of these hydrotropic agents'. The in vitro dissolution of glimepiride was assessed for a physical mixture and for solid dispersions with sodium citrate prepared by solvent evaporation and kneading. Glimepiride solubility in water was 2.83 µg/ml. The greatest solubility enhancement (ratio 284.33) was achieved with 40% sodium citrate, yielding 803.79 ± 0.015 µg/ml. Production yields for the physical mixture and solid dispersions ranged from 95.44 ± 1.95% to 101.80 ± 2.36%, and drug content varied from 87.00 ± 0.32% to 101.34 ± 0.26%. The fastest and complete in vitro dissolution; 99.95 ± 0.78% (DE 80.51%) within 30 minutes was observed for the solid dispersion prepared by the kneading method, compared with 62.35 ± 0.54% (DE 50.95%) for the pure drug. FTIR analysis indicated hydrogen-bond interactions between glimepiride and sodium citrate. In conclusion, sodium citrate, enhance glimepiride’s solubility and dissolution from solid dispersion especially by kneading method.

Sorafenib Tosylate (SRT), a multikinase inhibitor originally approved for several solid tumors, has been repurposed for potential application in triple-negative breast cancer (TNBC) due to its multitargeted antitumor mechanisms. However, its clinical use is limited by poor aqueous solubility, low and variable oral bioavailability, rapid systemic clearance, and dose-limiting toxicities. To address these challenges, this study aims to develop SRT-loaded PEGylated liposomes prepared by solvent evaporation followed by a hydration method and optimized using a Box-Behnken design. A lipid extrusion process was employed to reduce vesicle size and enhance uniformity, yielding an average vesicle size of 104.5 ± 4.0 nm, a low PDI of 0.097 ± 0.004, and a high entrapment efficiency of 82.5 ± 2.2%. Comprehensive characterization confirmed successful encapsulation and crystalline-to-amorphous transition of SRT. In vitro evaluation demonstrated a controlled and sustained release profile, with PEGylated liposomes releasing 70.89 ± 4.9% over 48 h, compared to 96.8 ± 3.1% free SRT within 12 h. In vitro cytotoxicity assays on MDA-MB-231 cells showed enhanced anticancer activity (IC50 reduced from 35.63 ± 4.6 to 18.25 ± 1.8 μg/mL for 24 h), increased cellular uptake, ROS generation, and mitochondrial depolarization with PEGylated liposomes. Hemolysis assays confirmed excellent hemocompatibility, supporting the safety of intravenous administration. In vivo pharmacokinetic studies revealed a 5.6-fold increase in half-life and a 10.8-fold rise in AUC for PEGylated liposomes, alongside reduced hepatic and renal toxicity. Biodistribution studies demonstrated lower off-target organ accumulation, indicating improved circulation and stability. Overall, the lipid-extruded PEGylated liposome formulation overcomes key delivery limitations of SRT and offers a potent, safe, and effective platform for TNBC therapy.

Oral cyclosporine a nanosuspension for improved immunosuppressive efficacy: In vivo cytokine profiling in rats.

Acalabrutinib (ACP) is one of the first-in-line treatments for hematological malignancies with minimal adverse drug reactions. However, ACP has low and variable bioavailability due to pH-dependent solubility, CYP3A4 metabolism, and P-gp efflux. This research aims to modify the dissolution behavior of ACP and improve its oral bioavailability through formulation of polymer-lipid hybrid nanoparticles (PLHNs). ACP-loaded PLHNs (ACP-PLHNs) were prepared by the emulsification-solvent evaporation method using a high shear homogenizer and optimized using a spherical and rotatable circumscribed central composite design. The optimized ACP-PLHNs exhibited a spherical morphology with an average particle size of 150.2 ± 10.7 nm, a PDI of 0.284 ± 0.06, and sufficient drug loading (20.79 ± 3.61%). In vitro dissolution studies showed that over 50% of ACP was released from the PLHNs at pH 1.2 within 4 h, reaching nearly 100% release by 24 h. While, at pH ≥ 4.5, 43-55% of ACP was released by 8 h, with sustained release observed for up to 2 days. In vivo hemolysis assay indicated that ACP-PLHNs were safe for oral administration. Storage stability studies over 6 months demonstrated optimal physico-chemical stability when stored at 5 °C. In vivo oral pharmacokinetic studies revealed that ACP-PLHN nanosuspension resulted in a 3.41-fold increase in bioavailability (p < 0.001) compared to the conventional ACP suspension, along with a >2-fold increase in drug distribution towards the spleen (p < 0.001), a critical target site for B-cell accumulation and proliferation.

Therapeutic drug monitoring (TDM) is recommended for posaconazole oral immediate release suspension due to saturable absorption and variable bioavailability; however, it has been suggested that TDM may not be necessary for the delayed-release tablet or intravenous formulations. Our study evaluated target trough attainment with the delayed-release tablet and intravenous solution. This retrospective, single-center study included adult patients who received posaconazole at a dose of 300mg every 24 h with at least one steady-state (SS) trough while on the delayed-release tablet or intravenous solution exclusively. Outcomes included the percentage of patients who achieved an initial SS trough ≥ 1300, ≥ 1000, or ≥ 700ng/mL, in addition to a risk factor analysis. Among the 142 patients included, 74 (52.1%), 102 (71.8%), and 122 (86%) patients had an initial SS trough ≥ 1300, ≥ 1000, and ≥ 700ng/mL, respectively. More patients achieved an initial SS trough ≥ 1300ng/mL under the following conditions: total body weight < 90kg, body mass index < 30kg/m2, or no receipt of acid suppressive therapy. No significant differences were found for median initial SS troughs or percentage of patients with an initial SS trough ≥ 1000 or ≥ 700ng/mL. With 47.9% of initial SS troughs < 1300ng/mL and 28.8% < 1000ng/mL, we recommend TDM for all patients receiving posaconazole for treatment, irrespective of formulation. Initial doses higher than 300mg q24h should be considered for all patients and strongly considered for patients with risk factors for subtherapeutic troughs.

Pomegranate (Punica granatum L) is a rich source of bioactive compounds, including punicalagin, ellagic acid, anthocyanins, and urolithins, which contribute to its broad pharmacological potential. This review summarizes evidence from in vitro and in vivo experiments, as well as clinical studies, highlighting pomegranate's therapeutic effects in inflammation, metabolic disorders, cancer, cardiovascular disease, neurodegeneration, microbial infections, and skin conditions. Mechanistic insights show modulation of pathways such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), alpha serine/threonine-protein kinase (AKT1), and nuclear factor erythroid 2-related factor 2 (Nrf2). Notably, punicalagin exhibits antifungal activity via sterol 14-demethylase P450 (CYP51) inhibition, supported by molecular docking studies. While evidence supports the promising bioactivity of pomegranate compounds, their clinical application is hindered by low and variable bioavailability, inconsistent dosing and formulations, and limited data on adverse effects largely due to interindividual differences in gut microbiota metabolism of punicalagin into urolithins. Although pomegranate demonstrates an excellent safety profile with minimal reported adverse events, further long-term, well-designed clinical trials are essential to validate its efficacy, determine optimal dosing, and enable standardized therapeutic use. This review contributes to the discourse on the medicinal value of pomegranate, offering a comprehensive understanding of its role in addressing diverse health conditions and highlighting the importance of integrating medicinal plants such as pomegranate into modern nutrition and clinical practice.

Pediatric neuropathy poses significant challenges in pain management due to the limited availability of approved pharmacological options. Gabapentin, commonly used for neuropathic pain, offers therapeutic potential but necessitates careful dosing due to its variable bioavailability. This study investigates the integration of Hot Melt Extrusion and Fused Deposition Modeling in the development of polycaprolactone-based implants for sustained release of Gabapentin. A preliminary screening using Vacuum Compression Molding optimized formulations for Hot Melt Extrusion, enhancing material efficiency and process streamlining. Filaments with a diameter of 1.75 mm were successfully extruded and used for 3D printing of Gabapentin implants. Several tests were undertakento characterize the prepared filaments and implants. Energy-Dispersive X-ray spectroscopy confirmed the uniform distribution of Gabapentin within the implant matrix. Solid-state characterization techniques were employed to assess the compatibility of implant components and to verify the solid-state of Gabapentin within the implant structure. In vitro drug release studies were conducted. Filaments with varying drug loadings were examined, revealing that a20% w/wdrug loadingachieved an optimal balance between rapid and sustained release. Additionally, implants with different infill densities wereanalyzed, demonstrating that varying infill densities allow control over the amount and percentage of drug released. The100% infill densityresulted in the most sustained release effect, achieving approximately40% drug release by day 28. These findings underscore the feasibility of3D printingfor producing personalized implants, emphasizing the potential for tailored drug release profiles to meet specific needs of pediatric patients.

A novel cannabidiol:tetramethylpyrazine cocrystal (CBD:TMP, ART12.11) improves the efficacy and bioavailability of cannabidiol in reducing stress-induced depressive and anxiety symptoms.

Beta-glucans, naturally occurring polysaccharides derived from fungi, yeasts, cereals, and bacteria, have emerged as potent cancer therapeutics due to their multifaceted immunomodulatory, anti-inflammatory, and direct anti-tumor properties. These compounds engage pattern recognition receptors (PRRs) such as Dectin-1, Toll-like receptors (TLRs), and complement receptor 3 (CR3), activating macrophages, natural killer (NK) cells, and dendritic cells to enhance anti-tumor immunity. Beta-glucans suppress pro-inflammatory cytokines (e.g., TNF-α, IL-6) and tumor-promoting pathways like NF-κB, while modulating T-regulatory cells (Tregs) and downregulating PD-L1 to overcome immune evasion. They induce apoptosis via Bax/Bcl-2 regulation, arrest cell cycles at G1/S or G2/M phases, and inhibit angiogenesis by targeting VEGF and MMPs. Clinical trials (2023-2025) demonstrate significant survival benefits, such as improved overall survival (OS) in melanoma (hazard ratio [HR] 0.65, 95% CI 0.48-0.87) and lung cancer (HR 0.72, 95% CI 0.55-0.94), alongside reduced chemotherapy toxicity. Synergy with PD-1/PD-L1 inhibitors enhances immunotherapy efficacy, particularly in immunogenic tumors. Advanced nano-delivery systems, including micelles and exosomes, improve bioavailability and tumor targeting. However, challenges like variable bioavailability, dosing inconsistencies, side effects (e.g., gastrointestinal discomfort in 10-15% of patients, allergic reactions in 2-5%), and conflicting efficacy data across tumor types necessitate further research. This review consolidates beta-glucan mechanisms, clinical evidence, delivery innovations, and challenges, positioning them as promising adjuncts in precision oncology.

Glucosinolates (GSLs) and their breakdown products, isothiocyanates (ITCs), are bioactive compounds with anti-inflammatory, antioxidant, and anticancer properties, mediated through key pathways such as Nrf2, NF-κB, and epigenetic regulation. However, their limited and variable bioavailability remains a key challenge. This review summarises the current clinical evidence on GSLs and ITCs, with a focus on their health effects and metabolic fate in humans. Recent findings on enzymatic and microbial metabolism are discussed, along with results from interventions involving whole vegetables, sprouts, and extracts. Although promising effects on blood pressure, lipid profiles, and glycaemic control have been observed, clinical studies are often limited by small sample sizes, study heterogeneity, and high inter-individual variability, particularly related to gut microbiota and host metabolic phenotype. Challenges like inconsistent biomarkers, formulation variability, and tolerability issues complicate data interpretation. To realise their full potential, larger, standardised, microbiome-informed trials with validated biomarkers and optimised delivery are needed to clarify host-compound-microbiome interactions and support evidence-based disease prevention strategies.

Colchicine is a potent alkaloid with well-established anti-inflammatory properties. It shows significant promise in treating classic immune-mediated inflammatory diseases, as well as associated cardiovascular diseases, including atherosclerosis. However, its clinical use is limited by a narrow therapeutic window, dose-limiting systemic toxicity, variable bioavailability, and clinically significant drug-drug interactions, partly mediated by modulation of P-glycoprotein and cytochrome P450 3A4 metabolism. This review explores advanced delivery strategies designed to overcome these limitations. We critically evaluate lipid-based systems, such as solid lipid nanoparticles, liposomes, transferosomes, ethosomes, and cubosomes; polymer-based nanoparticles; microneedles; and implants, including drug-eluting stents. These systems ensure targeted delivery, improve pharmacokinetics, and reduce toxicity. Additionally, we discuss chemical derivatization approaches, such as prodrugs, codrugs, and strategic ring modifications (A-, B-, and C-rings), aimed at optimizing both the efficacy and safety profile of colchicine. Combinatorial nanoformulations that enable the co-delivery of colchicine with synergistic agents, such as glucocorticoids and statins, as well as theranostic platforms that integrate therapeutic and diagnostic functions, are also considered. These innovative delivery systems and derivatives have the potential to transform colchicine therapy by broadening its clinical applications while minimizing adverse effects. Future challenges include scalable manufacturing, long-term safety validation, and the translation of research into clinical practice.

Combining high-throughput ASD screening with the rDCS to streamline development of poorly soluble drugs.

Human Immunodeficiency Virus (HIV) is a global public health concern due to its progression to acquired immunodeficiency syndrome (AIDS) and the associated high morbidity and mortality rates. Efavirenz (EFV), an antiretroviral drug, is widely used to manage HIV/AIDS. However, EFV exhibits poor aqueous solubility and variable bioavailability, necessitating techniques to enhance its solubility and dissolution for improved therapeutic efficacy. This study reviewed methods to enhance EFV solubility using data from research published between 2019 and 2023. Various approaches, including Nano Micelles, Wet Milling, Co-crystals, Physical Mixtures, Nanocrystals, Dry Milling, and Liquisolid techniques, were analysed. The results demonstrated significant solubility enhancements. For instance, Fuentes (2024) achieved a 50% dissolution efficiency using Nano Micelles, while wet milling by Prado (2024) increased dissolution from 83.48% to 99.10% over 150 minutes. Co-crystals, such as those studied by Gowda (2022), improved solubility from 94.16 µg/mL (pure EFV) to 197.32 µg/mL (EFV-DL-Alanine). Sartori's (2022) Nanocrystals technique demonstrated a dissolution efficiency of 98.41%. Furthermore, physical mixtures like Nel's (2022) combination of EFV with pea protein isolate achieved a solubility increase from 1.00 mg/mL to 2.30 mg/mL. These methods highlight advancements in solubility enhancement techniques that improve EFV’s pharmacokinetic profile. These findings can guide the development of more effective pharmaceutical formulations, improving treatment outcomes for individuals living with HIV/AIDS.

Poor solubility remains a significant obstacle in drug administration, adversely affecting the bioavailability and therapeutic efficacy of many drugs. It is also recognized as a primary factor contributing to issues with bioavailability, such as poor, inconsistent, limited, and highly variable bioavailability of marketed products. It is estimated that 40% of marketed drugs face bioavailability challenges primarily due to poor water solubility, and about 90% of pharmacological compounds exhibit poor water solubility in their early development stages. Addressing this issue is crucial for improving drug performance, efficacy, and patient outcomes. This review provides an overview of the challenges associated with poorly soluble drugs, including low bioavailability, limited dissolution rates, inconsistent absorption, decreased patient compliance, formulation difficulties, and associated costs and time constraints. Numerous strategies have been now investigated to tackle the issue of poor solubility. This review offers an updated overview of commonly used macro and nano drug delivery systems, including micelles, nanoemulsions, dendrimers, liposomes, lipid-based delivery systems, microemulsions, cosolvents, polymeric micelle preparation, drug nanocrystals, solid dispersion methods, crystal engineering techniques, and microneedle- based systems. Additionally, the review examines advanced techniques like cyclodextrin- based delivery systems, co-solvency and co-crystallization approaches, polymeric micelles, spray drying, co-precipitation, and amorphous solid dispersion. The role of computational modeling and formulation prediction is also addressed. Recent advancements in protein-based approaches, 3D printing, mesoporous silica nanoparticles, supramolecular delivery systems, magnetic nanoparticles, nanostructured lipid carriers, and lipid-based nanoparticles are highlighted as novel solutions for enhancing the solubility of poorly soluble drugs. The review concludes with predictions for the future, emphasizing the potential for further innovation in drug delivery methods to overcome the challenges associated with poorly soluble drugs.

Cancer remains a leading cause of morbidity and mortality worldwide, prompting growing interest in preventive strategies that target early molecular changes. Functional foods (FFs), defined as bioactive-rich dietary components with health-promoting properties, have emerged as promising modulators of cancer-related biomarkers. This article reviews clinical and preclinical evidence on the influence of FFs and food bioactive compounds(FBCs) on key biomarkers, such as including HER2, Ki-67, PSA, and CEA, across various cancer types. Mechanistic insights reveal that these dietary compounds exert their effects through epigenetic modulation, anti-inflammatory signaling, reduction of oxidative stress, and regulation of apoptosis and the gut microbiome. Applications of these findings extend to biomarker-based early detection, dietary chemoprevention, and personalized nutrition strategies. However, limitations such as biomarker specificity, variable bioavailability, and a lack of long-term randomized trials continue to hinder clinical translation. Future directions emphasize the need for integrated omics approaches, development of multi-marker panels, and personalized dietary interventions supported by novel delivery systems. FFs hold significant promise in oncology, but rigorous, longitudinal studies are essential to validate their role in cancer prevention and precision medicine. Novelty: This article uniquely synthesizes current clinical and preclinical evidence linking FFs and BCs to specific cancer-related biomarkers, while emphasizing mechanistic pathways and translational challenges. It further proposes integrated omics-based strategies and personalized nutrition approaches to enhance biomarker-guided cancer prevention, —an area that remains underexplored in current literature. Keywords: Functional foods, Bioactive Compounds, cancer biomarkers, chemoprevention, epigenetics, metabolomics, personalized nutrition, sulforaphane, bioavailability, dietary intervention, early detection.

Keloids are a challenging dermatological condition characterized by excessive scar formation beyond the original wound site, high recurrence rates, and limited treatment efficacy. Current therapies, such as corticosteroids, surgery, and radiotherapy, often yield suboptimal outcomes and adverse effects. This review evaluates the potential of plant-derived metabolites as safer and more effective alternatives for keloid management. Preclinical and clinical studies demonstrate that compounds like curcumin, epigallocatechin gallate (EGCG), and asiaticoside exhibit anti-fibrotic, anti-inflammatory, and antioxidant properties by modulating key pathways (e.g., TGF-β/Smad, NF-κB, and oxidative stress). Espite promising preclinical and early clinical findings, critical challenges hinder the clinical translation of these metabolites. These include poor and variable bioavailability, inconsistencies in extract standardization, and a paucity of large-scale, rigorously designed trials. Moreover, some metabolites may yield conflicting results or exhibit off-target effects in in vitro systems, necessitating caution in interpreting their true therapeutic potential. Future research should focus on optimizing drug delivery systems, conducting large-scale trials, and integrating personalized medicine approaches. Plant-derived metabolites represent a multi-targeted therapeutic strategy with the potential to address unmet needs in keloid treatment.

The fusion of Artificial Intelligence (AI) with modern drug delivery systems marks a pivotal shift in the way therapeutics are designed, administered, and monitored. Traditional drug delivery platforms have long struggled with issues like off-target effects, variable bioavailability, and poor patient adherence. Smart drug delivery systems aim to overcome these limitations by responding to internal or external physiological stimuli—offering precise, targeted, and often self-regulated release of medications. When integrated with AI, these systems gain further intelligence: enabling real-time decision-making, predicting release kinetics, optimizing formulations, and personalizing dosing strategies. This review explores the evolving landscape of AI-assisted smart drug delivery systems, highlighting how machine learning, deep learning, and predictive analytics are redefining the design and deployment of nanocarriers, wearable devices, and hybrid platforms. Special focus is given to AI’s role in material selection, pharmacogenomics, patient stratification, and theranostics. We also address critical challenges related to data privacy, regulatory ambiguity, algorithmic transparency, and ethical accountability. Moreover, emerging opportunities such as digital twins, closed-loop systems, and open-source AI platforms are discussed for their transformative potential. Together, AI and smart delivery platforms offer a promising vision of personalized, adaptive, and data-driven healthcare. As innovation continues to bridge computation with clinical application, the next generation of therapeutics may be as intelligent as they are effective—heralding a future where precision medicine is not just ideal, but inevitable.