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Formononetin (FNT) has limited application due to poor water solubility and substantial phase II metabolism. In the present study, we used phospholipid complex (PC) containing FNT and UDP-glucuronosyltransferase (UGT1A1) inhibitor piperine (PIP) to overcome FNT limitations. We characterized and compared both FNT-PC and FNT-PIP-PC complexes. Our data showed both groups improved FNT water solubility and oil-water partition coefficient. NMR, DSC, and SEM were performed to identify the interaction and the geometrical nature of complex. When compared, FNT-PIP-PC released more FNT in in vitro release and permeation through Caco-2 monolayer than FNT-PC and pure FNT. In vitro data was consistent with the in vivo pharmacokinetic profile that showed increased, Cmax and AUC(0-24) by 7.16 and 23.33-fold and 29.65 and 23.33-fold at 5 and 10 mg/kg in FNT-PIP-PC, compared to pure FNT. Additionally, co-treatment of PIP and FNT improved in vitro pharmacological action in dexamethasone-induced osteoporosis. Thus, our study showed addition of PIP in FNT-PC further increases FNT water solubility and protects it from phase II metabolism, leading to enhanced bioavailability with improved pharmacological activity. [ABSTRACT FROM AUTHOR]

This study investigates the combination of FGFR inhibitor futibatinib (FTB) and MEK inhibitor binimetinib (BTB) for KRASmt NSCLC therapy. An analytical method was developed and validated for measuring FTB and BTB concentrations in rat plasma, adhering to USFDA guidelines. Using liquid–liquid extraction on 45‐μL plasma samples, a 6.5‐min run time was achieved. The linear calibration curve ranged from 2 to 100 ng/mL. Intra‐day and inter‐day accuracy ranged between 92.06% and 100.08%. Four blank injections post high‐concentration samples resolved significant carryover. Extraction recoveries averaged 92.06% to 102.37% across concentrations. No significant endogenous interference was detected in blank plasma. The LLOQ for both drugs was 2.0 ng/mL. Selectivity, matrix effects, stability, and dilution integrity met the acceptance criteria. The method assessed FTB and BTB interaction potential in combination therapy at 5 mg/kg. The findings provide essential pharmacokinetics insights for future clinical trials. [ABSTRACT FROM AUTHOR]

Aim & objective: Combinatorial delivery of Doxorubicin (DOX) and Baicalein (BAC) has a potential to improve breast cancer treatment by mitigating the cardiotoxicity induced by DOX. The nanoformulation has been optimized and subjected to pharmacokinetic studies using LC-MS/MS. Materials & methods: Nanoformulation bearing DOX and BAC was optimized using quality by design approach and method validation was done following USFDA guidelines. Results: The particle size, PDI and zeta potential of developed nanoformulation were 162.56 ± 2.21 nm, 0.102 ± 0.03 and -16.5 ± 1.21 mV, respectively. DOX-BAC-SNEDDs had a higher AUC0-t values of 6128.84 ± 68.71 and 5896.62 ± 99.31 ng/mL/h as compared with DOX-BAC suspension. Conclusion: These findings hold promise for advancing breast cancer treatment and facilitating therapeutic drug monitoring. Graphical Abstract Mechanistic scheme of DOX-BAC-loaded SNEDDs development and its characterization using LC-MS/MS. Article highlights Baicalein (BAC) lowers cardiac oxidative stress which reduces the cardiotoxicity associated with Doxorubicin (DOX). Combination therapies enhance efficacy by targeting multiple disease pathways simultaneously, improving treatment outcomes and reducing drug resistance. The Quality by Design approach was employed in optimizing the self-nanoemulsifying drug delivery system. Currently, there is no published bioanalytical method utilizing either LC-MS/MS or HPLC for simultaneous determination of both DOX and BAC. Both DOX and BAC were resolved using mobile phase of 0.1% v/v FA in milli-Q water and 0.1% v/v FA in MeOH (20:80%v/v) with a flow rate of 0.3 mL/min. USFDA guidelines were employed for assessing several validation factors, including recovery, stability studies, specificity, accuracy and percent relative standard deviation. The co-estimation of DOX and BAC in rat plasma in order to generate an oral P.K. profile was successfully demonstrated using the developed LC-MS/MS. [ABSTRACT FROM AUTHOR]

Aim & Objective: This study evaluates the potential of combining paclitaxel (PTX) and bortezomib (BTZ) for breast cancer therapy. Materials & Methods: The nanoformulation was optimized via Box-Behnken Design (BBD), with method validation adhering to US-FDA guidelines. Results: Multiple reaction monitoring transitions for PTX, BTZ and internal standard were m/z 855.80→286.60, 366.80→226.00 and 179.80→110.00, respectively. Elution done on C18 Luna column with 0.1% FA in MeOH:10 mM ammonium acetate. The size of nanoformulation was 133.9 ± 1.97 nm, PDI 0.19 ± 0.01 and zeta potential -19.20 ± 1.36 mV. Pharmacokinetics showed higher Cmax for PTX-BTZ-NE (313.75 ± 10.71 ng/ml PTX, 11.92 ± 0.53 ng/ml BTZ) versus free PTX-BTZ (104 ± 13.06 ng/ml PTX, 1.9 ± 0.08 ng/ml BTZ). Conclusion: Future findings will contribute to the treatment of breast cancer using PTX and BTZ. Graphical Abstract Article highlights The importance of paclitaxel (PTX) and bortezomib (BTZ) in combination with chemotherapy is demonstrated by recently published studies. An obstacle to measuring the results of translational research is the lack of an analytical or bioanalytical approach for simultaneously estimating PTX and BTZ. A gap in the scientific literature has been filled by the development and validation of an LC-MS/MS method for the co-estimation or simultaneous measurement of PTX and BTZ. Both moieties were resolved in a Phenomenex Luna (C18), (7.5 × 4.6 mm, 3μ) column with a 0.1% FA in MeOH:10 mM ammonium acetate, 80:20 (% v/v) mobile phase at 0.6 ml/min flow rate. According to the US-FDA, the developed method was validated in female Sprague–Dawley rats plasma for different characteristics, such as linearity, precision and accuracy, LLOQ and stability studies. The oral P.K profile of PTX and BTZ co-loaded in a nanoformulation has been investigated in young female Sprague–Dawley rats to support the applicability of the established LC-MS/MS methodology. With an LLOQ of 1.0 ng/ml for each drug and a run time of 6.0 min, the calibration curve was found linear for the 1–600 ng/ml concentration range. The proposed LC-MS/MS method was confirmed to be repeatable, precise and accurate. The developed LC-MS/MS method was successfully illustrated for the co-estimation or simultaneous estimation of both drugs in rat plasma to generate an oral P.K profile. US-FDA Guidance of Industry and Bioanalytical Method Validation criteria was followed for the co-estimation of PTX and BTZ and was applied to nanoformulation development and bioanalytical investigations. [ABSTRACT FROM AUTHOR]

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures. [ABSTRACT FROM AUTHOR]

Aim & objective: Levormeloxifene (L-ORM) and raloxifene (RAL) are selective estrogen receptor modulators used in the treatment of postmenopausal osteoporosis and breast cancer. Here, we developed and validated a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the simultaneous estimation of both drugs. Materials & methods: A quality-by-design (QbD) approach was used for the optimization of the nanoemulsion, and US FDA guidelines were followed for method validation. Results: Multiple reaction monitoring transitions were used for L-ORM (459.05→98.50), RAL (475.00→112.02) and internal standard (180.10→110.2). Analytes were resolved in a C18 column with 80:20 v/v% acetonitrile (ACN), 0.1% formic acid in triple-distilled water as a mobile phase. The developed method was linear over a concentration range of 1–600 ng/ml. Pharmacokinetic results of free L-ORM–RAL and the L-ORM–RAL nanoemulsion showed Cmax of free L-ORM – 70.65 ± 16.64, free RAL 13.53 ± 2.72, L-ORM nanoemulsion 65.07 ± 14.0 and RAL-nanoemulsion 59.27 ± 17.44 ng/ml. Conclusion: Future findings will contribute to the treatment of postmenopausal osteoporosis and breast cancer using L-ORM and RAL. Graphical abstract Summary points To coestimate levormeloxifene and raloxifene, an LC–MS/MS method has been developed and validated as per the US FDA industry guidance and bioanalytical method validation standards. A C18 Phenomenex Luna column (7.5 × 4.6 mm, 3 μm) was used to resolve both moieties. The mobile phase consisted of 80 v/v% acetonitrile and 20% v/v 0.1% formic acid in triple-distilled water at a flow rate of 0.5 ml/min. According to the FDA guidelines, the developed method was validated for a variety of characteristics, including linearity, precision and accuracy, lower limit of quantification and stability tests. The final nanoformulation was optimized using the Box–Behnken design technique. The final optimized formulation had a particle size of 94.01 ± 1.79 nm, a ζ-potential of -22.20 ± 0.10 mV and a polydispersity index of 0.24 ± 0.002 mV. The pharmacokinetic profile of free drug was compared with that of the developed nanoformulation, suggesting improved bioavailability. In vitro cellular uptake studies revealed a higher uptake of the developed nanoformulation as compared with free fluorescein isothiocyanate solution. The applicability of the developed LC–MS/MS method was presented by performing oral pharmacokinetic profiling of the levormeloxifene and raloxifene coloaded nanoformulation in female Sprague Dawley rats. [ABSTRACT FROM AUTHOR]