Rivaroxaban (RIV) is an orally active, selective, direct factor Xa inhibitor used for the prevention and treatment of venous thromboembolism, stroke prevention in non-valvular atrial fibrillation, and other thromboembolic disorders. This research developed RIV-loaded transferosomes as a non-invasive option for individuals who cannot administer oral anticoagulants. Twenty RIV transfersomal formulations (F1–F20) were prepared by the rotary evaporation–sonication method using lecithin and various edge activators (Soluplus, Span 65, Span 80, and Tween 20) at different phospholipid-to-edge activator ratios. RIV transfersomal formulations (F1–F20) were evaluated for drug content, entrapment efficiency, vesicle size, polydispersity index, and pH. The lead transfersomal RIV formulation (F4) showed 93.6% ± 0.36 entrapment efficiency, 97% ± 0.43 drug content, a vesicle size of 98.36 ± 2 nm, and a pH of 6.69 ± 0.76. F4 attained a drug release of 97.8% ± 0.72 after 24 h and markedly improved ex vivo skin permeability relative to an RIV suspension ( p < 0.05). F4 had a zeta potential of -24.16 mV and a deformability index of 9.6 ± 0.34. The absence of drug–excipient incompatibilities was confirmed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Field-emission scanning electron microscopy (FESEM) demonstrated smooth, spherical vesicles. F4 demonstrated enhanced ex vivo skin permeation and suitable physicochemical characteristics.

The development of new pharmaceutical forms with high solubility and enhanced bioavailability currently represents a significant challenge in the pharmaceutical industry. Currently, methods are still being explored to improve the oral bioavailability of Rivaroxaban, estimated to be 60%, due to its low solubility. To address these challenges, this study uses the antisolvent precipitation method to obtain three nanosuspensions of rivaroxaban (RIV), using Poloxamer 188 (P188) and hydroxypropyl methylcellulose (HPMC) by varying their concentrations (1:1:1, 1:1:2, and 1:2:1 molar ratios). The RIV nanosuspensions were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The antisolvent precipitation method led to the successful formulation of the three RIV nanosuspensions. Afterward, the formulated tablets containing dry RIV nanosuspensions were pharmaceutically characterized. RIV-P188-HPMC (1:1:1) and RIV-P188-HPMC (1:2:1) dry nanosuspensions demonstrated a uniform flow, and they were subsequently analyzed to establish the in vitro dissolution profile. The nanosuspension formulation with a higher content of P188 showed superior performance. Overall‚ the results of this study show that the antisolvent precipitation method in the presence of different amounts of HPMC and P188 is very efficient in increasing the dissolution rate of rivaroxaban to achieve its better efficiency.

The present study investigates the co-crystallization process of rivaroxaban (RIV), a poorly water-soluble potent oral anticoagulant, with niacinamide (NIA), a highly soluble and pharmaceutically acceptable co-crystal former, in two different molar ratios (1:1 and 1:2). The aim was to enhance the physicochemical and biopharmaceutical properties of rivaroxaban such as dissolution rate and aqueous solubility, by forming stable co-crystals through a solvent evaporation technique. The resulting co-crystals (RIV-NIA, 1:1 co-crystallization compound, F1 and RIV-NIA, 1:2 co-crystallization compound, F3) were characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and thermal analysis, which confirmed the formation of a new rivaroxaban-niacinamide co-crystalline phase. In vitro dissolution studies confirmed a significant enhancement in the dissolution rate of the two obtained co-crystals. These findings suggest that stoichiometric variation plays an important role in co-crystal performance and in improving solubility compared with the pure drug. Also, the obtained results suggest that niacinamide is an effective coformer for improving the dissolution and physicochemical properties of rivaroxaban.

Rivaroxaban (RIVA) is a medication with anti-inflammatory and anticoagulant properties that may slow the progression of peripheral artery disease (PAD). This trial evaluated the effects of RIVA on functional outcomes in patients with lower extremity PAD (LEPAD) following endovascular revascularization. A six-month, double-blind, randomized controlled trial was conducted at Golestan Hospital (Ahvaz, Iran) and enrolled patients with LEPAD who had undergone endovascular revascularization within the previous 10 days. Clinical and demographic data were collected from the participants. Participants were randomly assigned to receive either RIVA (2.5 mg twice daily) plus aspirin (80 mg once daily) or clopidogrel (CLOP; 75 mg once daily) plus aspirin (80 mg once daily) for six months. The trial enrolled 104 patients with LEPAD. A total of 53 participants were assigned to the RIVA group, while 51 were assigned to the CLOP group. Among the patients, 73 were men, and 41 were women, with a mean age of 68 years. After six months, the RIVA group demonstrated significantly greater improvements in functional outcomes, pain, and claudication symptoms compared to the CLOP group. Notable between-group differences included improvements in the six-minute walk test (6MWT) distance (63.67 ± 1.34 m; p < 0.05), anklebrachial index (ABI) (0.10 ± 0.03; p < 0.05), and toe-brachial index (TBI) (0.08 ± 0.02; p < 0.05). RIVA was more effective than CLOP in improving functional outcomes, reducing claudication, and alleviating pain in patients with LEPAD. This trial was registered at irct.behdasht.gov.ir as IRCT20231117060086N1.

Background: This research aims to evaluate and contrast the effectiveness and safety profiles of Aspirin with Rivaroxaban (RA) and Clopidogrel with Apixaban (CA) in minimizing thromboembolic risks among patients diagnosed with Deep Vein Thrombosis (DVT). Methodology: A forward-looking observational study was conducted involving 40 participants with confirmed DVT, allocated evenly between two treatment groups. Parameters assessed included recurrence and progression of DVT, bleeding events, death rates, and relevant laboratory markers. Data analysis involved Chi-square and T-tests using SPSS v26.0. Findings: The patients in the CA group had a significantly lower rate of DVT recurrence (5% vs. 45%; p= 0.0035) and a tendency towards less disease progression (10% vs. 35%; p = 0.051). The incidence of major and mild hemorrhage, as well as fatality rates, did not exhibit significant differences. However, the baseline INR, haemoglobin, and platelet count were significantly different (p<0.05) from the normal range. Conclusion: Clopidogrel-apixaban seemed to be more effective in the prevention of DVT recurrence without increasing the risk to the patients’ safety compared to Aspirin-Rivaroxaban. This study needs to be followed by broader, randomised trials to confirm these findings.

Rivaroxaban (RXB) is an administered anticoagulant that attaches directly to factor Xa. Furthermore, it effectively prevents the worsening of the coagulation cascade, hence preventing the formation of blood clots. It is indicated for the management of deep vein thrombosis (DVT) and pulmonary embolism (PE) in elderly people. It is classified as a biopharmaceutical categorization system (BCS) class II drug due to its low dissolution in water (almost insoluble). The aim of this work is to prepare a nanocrystal formulation of Rivaroxaban with polymers to improve its solubility and dissolution using solvent-antisolvent technique. Different types of stabilizers (poloxamer188, pvpk-30, and Soluplus) at different stabilizer ratios were utilized in the formulation to give different particle sizes and polydispersity indices (PDIs). A precise amount of medication was dissolved in a binary solvent consisting of methanol and dichloromethane. The solution was then put into water containing a stabilizer while stirred magnetically for one hour. The RXB nanocrystal received characterization for particle size; PDI, and Zeta potential. Furthermore, the refined formula underwent additional freeze-drying. It found that formula F2, which contains Soluplus in a ratio of 1:1 in 15 mL of water and stirred at 500 rpm, had the smallest particle size (90.38 nm) and PDI (0.16), and was chosen as the selected formula for freeze-drying. It showed an increase in saturation solubility and better dissolution than the pure drug due to particle size reduction. It was 94% released in 60 minutes compared to 41% for the pure drug at the same time point.

Dantao formula alleviates hepatic fibrosis and portal hypertension via modulation of the cAMP/PKA/ROCK signaling pathway in hepatic stellate cells.

The solubilization of poorly soluble drugs belonging to Class II of the Biopharmaceutical Classification System (BCS) is often a challenge in screening studies of new chemical substances as well as in formulation design and development. One of the most difficult aspects of formulation design is the Solubility properties. A number of methods can be used to improve the solubilization of poorly water-soluble drugs and further improve their bioavailability. Rivaroxaban, an anticoagulant, is classified as a poorly soluble BCS class II drug. Solid dispersion technologies provide promising results for improving the oral absorption and bioavailability of BCS class II drugs. The present study highlights the critical role of particle size reduction and increased surface area in improving the solubility, dissolution rate and subsequent bioavailability of rivaroxaban. The purpose of this study was to investigate the efficacy of hydrophilic polymers in a inclusion complex and solid dispersion formulation in improving the solubility and dissolution rate of rivaroxaban (RXB), a poorly soluble drug. The solubility studies of drug β-CD systems in water at 25°C revealed that the solubility of drug increased linearly for the preparation of complexes by kneading method.

Abstract Background The oral route is the recommended route of administration of most therapeutic drugs. Unfortunately, due to swallowing difficulties especially for elderly and young patients, conventional oral dosage forms have low patient compliance. To overcome these difficulties, orally disintegrating tablets (ODTs) were presented in this work. Results In this study, the solubility of rivaroxaban (RXB) was enhanced using nano mixed micelles (NMMs). The optimum NMM formula was selected according to the highest drug content (8.00 ± 0.02 mg), clarity upon reconstitution, smallest particle size (PS) (161.50 ± 2.50 nm), lowest polydispersity index (PDI) (0.37 ± 0.01), and optimum zeta potential (ZP) (− 16.13 ± 0.42 mV). The optimized formula was then mixed with different ODT carriers (gellan gum, sodium alginate, and hydroxypropyl methylcellulose) and freeze dried. The ODTs were evaluated via weight variation, thickness and diameter, friability, drug content, in vitro disintegration, swelling profile, in vitro dissolution. The tablet containing 35 mg sodium alginate (SA) and 15 mg gellan gum (GG) was found to fulfill the optimum criteria for ODTs. The in vitro disintegration profile of tablets was evaluated in six human volunteers, revealed a disintegration time ranging from 31.5 ± 1.89 s to 85 ± 3.54 s. Conclusion A promising ODT formulation containing RXB-loaded NMMs has been successfully developed, offering a suitable option for special populations such as the elderly and children who experience difficulty swallowing. This advancement may enhance treatment effectiveness by improving patient compliance.

The main objective was to develop and validate the UV-spectrophotometric method for the estimation of rivaroxaban (RIV). Method was validated for different parameters like linearity, precision, and ruggedness study. Calibration curve was constructed for RIV standards by plotting the concentrations versus peak area ratios. The graph proved that the method was linear in investigation concentration range with correlation coefficient R2 value of 0.9863 The intraday and interday precision (RSD %) was found to be 1.49 and 1.11% respectively. The robustness were changed relatively between 99.8 – 102.4% within these small changes on mobile phase component and column temperature. The results were evaluated statistically, and there were no significant differences (p&gt;0.05) within the results. Applying same procedures by two different operators showed the ruggedness of the developed method. The analysis results having no significant difference indicate that the proposed method is robust. The FTIR spectra of rivaroxaban was performed and analysed. Results of IR confirmed the presence of the main functional group

IntroductionHepatic sinusoidal obstruction syndrome (HSOS) is a vascular liver disease with a high mortality rate, and treatment methods are limited. Rivaroxaban is an oral anticoagulant. This study aimed to investigate the pharmacological effect and potential mechanism of rivaroxaban on HSOS.MethodsIn this study, we induced an HSOS mouse model in male C57BL/6J mice by administering monocrotaline orally. The mice were randomly divided into four groups: the control group, the rivaroxaban (RIV) group, the monocrotaline (MCT) group, and the monocrotaline + rivaroxaban (MCT + RIV) group. Liver function and histopathology were evaluated. 16S rDNA sequencing of the small intestinal contents, transcriptomic sequencing of small intestine tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis were conducted. Antibiotic (ABX) treatment and fecal microbiota transplantation (FMT) experiments were also performed to explore the role of the gut microbiota.ResultsCompared with the MCT group, rivaroxaban alleviated serum biochemical liver function analysis and liver histopathology in the MCT + RIV group. Additionally, 16S rDNA sequencing of the small intestinal contents revealed that, compared with the MCT group, the MCT + RIV group presented increased relative abundances of Allobaculum and Pediococcus but decreased relative abundances of Streptococcus, Staphylococcus, and Candidatus Arthromitus. Mechanistically, integrated analyses, including transcriptomic sequencing of small intestin e tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis, demonstrated that rivaroxaban protected against MCT-HSOS by inhibiting the PI3K/Akt signaling pathway. In addition, antimicrobial cocktail (ABX) treatment eliminated the beneficial effects of rivaroxaban on liver function and histopathological injury, whereas fecal microbiota transplantation (FMT) from rivaroxaban-treated donors significantly ameliorated liver dysfunction and histological damage in MCT-HSOS mice.DiscussionThese findings suggest that rivaroxaban alleviates hepatic sinusoidal obstruction syndrome in mice by modulating the gut microbiota and inhibiting the PI3K/Akt signaling pathway. Rivaroxaban may be a promising therapeutic option for treating HSOS.

Amiodarone (AMI) is a potent inhibitor of Cytochrome P450 (CYP) 2C9 and P-glycoprotein (P-gp), as well as a weak inhibitor of CYP3A4. Concomitant administration of AMI with digoxin (DIG), rivaroxaban (RIV), or phenytoin (PHT) can significantly increase the exposure of the victim drugs. Elevated RIV exposure raises the risk of bleeding, whereas DIG and PHT have narrow therapeutic windows, potentially leading to severe toxicity when co-administered with AMI. Physiologically based pharmacokinetic (PBPK) modeling was employed to simulate, validate, and predict the impact of drug-drug interactions (DDIs) between AMI and DIG, RIV, or PHT on the pharmacokinetics (PK) of victim drugs. The findings aim to provide evidence-based recommendations for optimizing combination therapy regimens. PBPK models for AMI, RIV, and PHT were developed using PK-Sim, while the DIG model was adopted from previously published literature. DDI scenarios were simulated to assess exposure levels. Model performance was evaluated by comparing predicted plasma concentration-time (PCT) profiles and PK parameter values with clinical trial data from healthy subjects in previously published PK studies. Finally, dosing regimens for combination therapy were adjusted based on changes in exposure levels. According to model simulations, when the perpetrator drug AMI was co-administered with DIG, RIV, or PHT following label-recommended dosing regimens, the steady-state exposure of the victim drugs increased by 79%, 38%, and 59%, respectively. Compared to monotherapy, reducing the doses of DIG, RIV, and PHT by 40%, 25%, and 45%, respectively, achieved similar steady-state concentrations. We have successfully developed PBPK models for AMI, RIV, and PHT. These models effectively simulate the DDIs that occur when AMI is co-administered with DIG, RIV, or PHT, thereby providing guidance for dosing regimens in clinical combination therapies.

Phosphorus and nitrogen co-doped carbon quantum dots (PNCQDs) were utilized as facile fluorescent probes for accurate monitoring of naftidrofuryl oxalate (NAFT) and rivaroxaban (RIVA). These luminescent templates have shown two emission ratiomeric bands at 335 and 444 nm upon excitation at 273 nm. Successive titration of the carbon dots with NAFT solution showed enhanced fluorescence at 335 nm band, leaving the other band unchanged, while by consecutive addition of RIVA increments to the PNCQDs-NAFT complex, a fluorescence quenching occurred only to the same band. All measurements were performed in phosphate buffer; pH 7.40 ( 3.00 × 10-3 M) for ≈ 2 min reaction time. The method was validated according to the International Conference on Harmonization (ICH) guidelines with percentage relative standard deviation values (%RSD) not more than 2.90%. The studied analytes have shown excellent sensitivity with limits of quantitation (LOQ) of 1.50 × 10-3 and 3.00 × 10-3 μg/mL for NAFT and RIVA, respectively, as well as outstanding selectivity towards a wide range of interfering species. Recovery percentages of 97.00-98.00 were obtained upon application to tablets and spiked plasma samples. The developed method was successfully employed in estimating the pharmacokinetics of both analytes in male rabbits.

This study investigated the protective effects of Rivaroxaban (RVX) against testicular ischemia-reperfusion (IR) injury in rats with a secondary aim of studying the involvement of hypoxia-inducible factor1-alpha testicular protection against ischemic insults. Twenty-four male rats were divided into four groups: sham control, testicular IR, and two RVX treatment groups (7 and 14mg/kg) administered for one week prior to IR. Testicular IR led to significant impairment in testicular function, evidenced by an 86.5% reduction in testosterone levels and marked oxidative stress with an 189.3% increase in malondialdehyde (MDA). IR injury also triggered substantial elevations in apoptotic markers (271% increase in Bax (Bcl2-associated X protein) and 65.9% decrease in BCL2 (B-cell lymphoma 2), and inflammatory mediators (285.7% increase in NFκB (nuclear factor-kappa B). Additionally, angiogenic markers showed dramatic increases, with VEGF (vascular endothelial growth factor) and HIF-1 (Hypoxia inducible factor-1) rising by 431.8% and 519%, respectively. RVX treatment demonstrated dose-dependent protective effects, with the 14mg/kg dose showing superior outcomes compared to 7mg/kg. The higher dose significantly improved hormonal function (486.8% increase in testosterone), reduced oxidative stress (51.8% reduction in MDA), modulated apoptotic markers (68.3% decrease in BAX, 159.1% increase in BCL2), and normalized angiogenic factors (71.8% reduction in HIF-1). In conclusion, RVX demonstrated significant therapeutic potential in protecting against testicular IR injury, with the 14mg/kg dose showing optimal protective effects. Reduction in HIF-1α and VEGF protein expression mediated RVX's anti-oxidant, anti-inflammatory, and anti-apoptotic effect in rats subjected to testicular IR.

A recent surge in deep vein thrombosis (DVT) has urged researchers to find potential candidates and new ways of drug delivery to treat the condition. Rivaroxaban (RIVA) is one of the active pharmaceutical agents used to treat DVT due to its unorthodox Xa-inhibiting therapeutic efficacy. However, its poor solubility and toxicity have restricted its therapeutic use. Herein, we prepared RIVA-NLCs to improve the biopharmaceutical performance of the drug. RIVA-NLCs were prepared using high-pressure homogenization and were evaluated based on particle size, zeta potential, polydispersity index, and entrapment efficiency. Differential scanning calorimetry (DSC), X-ray diffractometry (XRD), in vitro release, and in vivo pharmacokinetics studies were performed and compared with the pure drug. Additionally, toxicity studies and prothrombin time assessments were analyzed using cell viability and hemolysis assays. RIVA-NLCs demonstrated optimum particle properties with a particle size of 129.6 nm, zeta potential of -29.41 mV, polydispersity index of 0.012, and suitable entrapment efficiency of 95.7%. DSC and XRD respectively showed thermal stability and the amorphous nature of RIVA in NLCs. Moreover, a significantly improved release of RIVA was observed from the RIVA-NLCs compared to the pure drug at all the time periods and an overall improved release (6-folds) was observed in 24 h. Similarly, a 9.01-fold improved bioavailability of RIVA was detected in the RIVA-NLCs when compared with the pure drug. More importantly, the maximum concentration (Cmax) and area under the curve (AUC) of RIVA-NLCs were found 6344 ± 456 ng/mL and 19,367.43 ± 3148.12 ng.h/mL, that were significantly improved as as compared to RIVA suspension. It was concluded that NLCs have the potential to improve the dissolution, anticoagulant properties, and bioavailability of RIVA, as demonstrated in this study.

Direct oral anti-Xa inhibitors are widely used in thrombosis treatment or prophylaxis. Despite the high safety profile, in clinical practice, the measurement of drug concentration in plasma is sometimes needed. The aim was to compare results of three branches of reagents/calibrators/coagulometers for Heparin Calibrated Anti Xa assays (HC-Anti Xa) in samples from patients taking apixaban (APIXA) or rivaroxaban (RIVA). Population: 49 samples from patients receiving APIXA (32-703 ng/mL) and 40 receiving RIVA (< 8-573 ng/mL) taken at peak or trough. RIVA and APIXA measurement: HemosIL Liquid Anti Xa (Werfen) in ACL TOP 300 and STA-Liquid Anti Xa in STA Compact Max (Stago) with specific calibrators. HC-Anti Xa activity (1) HemosIL Heparin (Werfen) in ACL TOP 300; (2) Innovance Heparin (Siemens) in Sysmex CS-2500 (Siemens Health Care); (3) STA-Liquid Anti Xa (Stago) in STA COMPACT MAX coagulometer. HC-Anti Xa values paired compared showed statistically significant differences between the three systems, with the highest values obtained with the Stago system. An r 2 > 0.94 was found for Werfen and Siemens with samples with any drug, but r 2 of 0.800 for APIXA and 0.792 for RIVA was observed in the Stago System due to a tendency to plateau at high drug concentrations. Analyzing only samples with concentrations ≤ 200 ng/mL, an r 2 > 0.93 with the three systems in APIXA (n = 30) samples and 0.913, 0.875, and 0.906 in RIVA (n = 31) samples with Werfen, Stago, and Siemens systems, respectively. Important differences inter systems in HC-Anti Xa calculated from regression lines were observed at 30, 50, 75, and 200 ng/mL of both drugs. Drug concentration measured by the Anti Xa assay calibrated with specific calibrators in 45 samples with APIXA and 27 with RIVA in Werfen and Stago systems showed very good correlation (r 2 = 0.991 and 0.976, respectively). Estimation of APIXA or RIVA concentration through HC-Anti Xa is possible, but values obtained are different for each reagent/calibrator/instrument system. Knowledge of the HC-Anti Xa values corresponding to anticoagulant concentrations at clinical decision points in the system used by each laboratory is mandatory to be able to use them correctly in the clinic.

Background/Objectives: This study aimed to develop a dry powder inhalation (DPI) formulation of rivaroxaban (RVX) using a combination of bead milling (BM) and jet milling (JM) to enhance lung-targeted delivery for the effective treatment of pulmonary embolism while minimizing systemic exposure. Methods: A carrier-free DPI formulation of RVX was developed using sequential BM and JM, with L-leucine incorporated at various concentrations (1%, 5%, and 10%) as a force control agent. The formulations were characterized for particle morphology, size distribution, crystallinity, and thermal properties. The in-vitro aerodynamic performance was evaluated using a next-generation impactor, while ex-vivo studies assessed anticoagulant activity. Pharmacokinetic and tissue distribution studies were carried out in Sprague Dawley rats following intratracheal administration, and the effects of inhaled RVX were compared with those of oral administration. Results: The optimized BM-JM-5L formulation achieved a Dv50 of 2.58 ± 0.01 µm and a fine particle fraction of 72.10 ± 2.46%, indicating suitability for pulmonary delivery. The two-step milling effectively reduced particle size and enhanced dispersibility without altering RVX's physicochemical properties. Ex-vivo anticoagulation tests confirmed maintained or improved activity. In-vivo studies showed that pulmonary administration (5 mg/kg) led to a 493-fold increase in lung drug concentration and 2.56-fold higher relative bioavailability vs. oral dosing, with minimal heart tissue accumulation, confirming targeted lung delivery. Conclusions: The two-step milled RVX DPI formulations, particularly BM-JM-5L with 5% leucine, demonstrated significant potential for pulmonary administration by achieving high local drug concentrations, rapid onset, and improved bioavailability at lower doses. These findings highlight the feasibility of RVX as a DPI formulation for pulmonary delivery in treating pulmonary embolism.

Apixaban (API) and rivaroxaban (RIVA) are orally available inhibitors of coagulation factor Xa and are commonly used to treat cancer-related venous thrombosis. Ribociclib (RIBO), a first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer, is an inhibitor of CYP3A4, P-gp, and BCRP. Given the potential for these drugs to be co-administered in clinical settings, there is limited information regarding the pharmacokinetic drug-drug interactions (DDIs) between ribociclib and these anticoagulants. This study aimed to evaluate the extent of DDIs between ribociclib and rivaroxaban or apixaban in rats and to explore the optimization of drug dosing strategies. Male Sprague-Dawley rats were divided into 9 groups (n = 6), receiving ribociclib, apixaban, rivaroxaban, ribociclib with rivaroxaban, ribociclib with apixaban, and combinations with reduced doses and time intervals. Blood concentrations were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetic parameters such as AUC, Cmax, CLz/F, and Vz/F. Ribociclib significantly increased exposure to both rivaroxaban and apixaban, with a greater impact on rivaroxaban. Specifically, ribociclib increased the AUC0-t, AUC0-∞ and Cmax of rivaroxaban (normal dose) by about 2.4-fold, 2.1-fold and 1.8-fold, while increasing apixaban exposure by about 60.82%, with a trend towards an increase in Cmax that was not statistically significant. When co-administered with ribociclib, even at a reduced dosage of 1 mg/kg, rivaroxaban exhibited a significant increase in exposure, with the AUC increasing by 2.3-fold and Cmax by 1.3-fold. Despite the reduction in dosage, the pharmacokinetic effect of ribociclib on rivaroxaban persisted. While administration of rivaroxaban 12 h after ribociclib resulted in a less pronounced increase in exposure compared to the normal-dose group. The results of qRT-PCR showed that ribociclib reduced the expression of Cyp3a1 and Abcg2 in rat intestine. This research highlights the need for careful consideration of dosing regimens to minimize toxicity risk and optimize the safety of clinical co-administration of ribociclib with rivaroxaban.

Chronic inflammation and immune dysregulation are key drivers of diabetes complications. Rivaroxaban (RX) and sitagliptin (SITA) are established therapies for thromboembolism and glycemic control, respectively. This study evaluated the novel therapeutic potential of nano-rivaroxaban (NRX) alone and in combination with sitagliptin (SITA) in mitigating inflammation and restoring immune balance in streptozotocin (STZ)-induced diabetic rats. Type 2 diabetes was induced in rats using a single injection of STZ (60 mg/kg). Animals were divided into five groups: control, STZ-diabetic, RX-treated (5 mg/kg), NRX-treated (5 mg/kg), and NRX+SITA-treated (5 mg/kg + 10 mg/kg). After 4 weeks of treatment, blood glucose, coagulation markers, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10) were analyzed. Histopathological examination of the liver, kidney, pancreas, and spleen was conducted. Immunohistochemistry was used to assess hepatic NF-κB expression. STZ significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10), along with increased hepatic NF-κB expression and histopathological abnormalities in immune organs. NRX significantly reduced inflammatory cytokines, improved histopathological changes in organs, and decreased hepatic NF-κB expression. The combination therapy (NRX + SITA) achieved superior immune modulation, with enhanced cytokine profile restoration, reduced hepatic NF-κB expression, and near-complete histopathological normalization. This study underscores the promise of combining nanoparticle-based drug delivery with established therapies like sitagliptin to achieve superior immune modulation and inflammation control, presenting a potential therapeutic strategy for managing diabetes complications.

The study is based on applying Artificial Neural Network (ANN) based machine learning and Response Surface Methodology (RSM) as simultaneous bivariate approaches in developing controlled-release rivaroxaban (RVX) osmotic tablets. The influence of different types of polyethylene oxide, osmotic agents, coating membrane thickness, and orifice diameter on RVX release profiles was investigated. After obtaining the trial formulation data sets from Central Composite Design (CCD), an ANN-based model was trained to get the optimized formulations. The Physiological-based Pharmacokinetic (PBPK) modeling of the predicted formulation was performed by GastroPlus™ to simulate in vivo plasma profiles under fasting and fed conditions. In vitro release tests showed zero-order RVX release for up to 12 h. Using graphical and numerical methods, the predicted formulation generated by the prediction profiler was cross-validated by the CCD-based optimized formulation. Analysis of Variance (ANOVA) findings revealed no significant difference between the predicted and optimized formulations and these formulations have a shelf life of 22.47 and 17.87 months, respectively. The PBPK modeling of RVX push-pull osmotic pump (PPOP) tablets suggested enhanced bioavailability in the fasted (up to 82%) and fed (up to 98.5%) state compared to immediate-release tablets. The results indicated that ANN can be effectively used for osmotic systems due to their complex nature and nonlinear interactions between dependent and independent variables.