Journal of Pharmaceutical Innovation最新文献

Cosmos caudatus is a traditional Indonesian medicinal plant commonly used in the treatment of cancer, hypertension, diabetes, osteoporosis, and other potential health conditions. However, the mechanisms behind its compounds, targets, diseases, disease pathways, and their molecular profiles in treating lung cancer remain unclear. Therefore, a comprehensive approach is required to study these mechanisms by integrating metabolomics, bioinformatics, and in vitro experimental validation to explore the active compounds, targets, diseases, disease pathways, and molecular mechanisms involved in the treatment of lung cancer. The active compounds were identified through analysis using ultrahigh-performance liquid chromatography-quadrupole-orbital ion trap-high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), and the screening of active compounds was conducted based on ADMET parameters. Potential compounds from C. caudatus and lung cancer-related targets were retrieved from public databases, such as SwissTargetPrediction, DisGeNET, DrugBank, GeneCards, PharmGKB, and TTD. Gene Ontology (GO) analysis of the targets was performed using DAVID, and protein–protein interactions (PPI) were analyzed using STRING and Cytoscape. A pharmacological network was constructed with Cytoscape. Finally, molecular docking analysis was conducted to predict and validate the interactions between C. caudatus compounds and core lung cancer targets. The metabolomic approach identified 66 compounds in the leaves, of which 13 met the criteria for gastrointestinal drugs. The compounds 3’,4’,5,7-tetrahydroxyflavone, AKT1 target, lung neoplasms diseases, and PIP3 activating AKT signalling pathway, became the core target with the highest degree value in the pharmacological network formed. In the protein-protein interaction (PPI) network, AKT1 again became the core target with the highest degree value. Gene Ontology (GO) functional enrichment analysis revealed that the biological processes, molecular functions, cellular components, and KEGG pathways in lung cancer were phosphorylation, cytoplasm, protein binding, and cancer pathways, respectively. The three compounds with the best binding energy and hydrogen bonding were 3’,4’,5,7-tetrahydroxyflavone-AKT1 (9C1W), gamma-mangostin-EGFR (3P0V), and cratoxyarborenone E-TNF (1XU1), with binding energies of − 10.8, − 8.9, and − 9.6 kcal/mol, respectively. The methanol extracts inhibited A549 cells at a concentration of 156.12 µg/mL. The combination of these methods provides insights into the pharmacological mechanisms of C. caudatus compounds in the treatment of lung cancer.

Background

This work aimed to formulate Dabigatran etexilate, a BCS class II medication, as self-micro-emulsifying drug delivery system (SMEDDS) to increase its rate of dissolution. By doing solubility experiments of the medication in various oils, surfactants, and cosurfactants, the three primary formulation components of a SMEDDS formulation were chosen. Formulation design and optimization were done by Box-Behnken design in Design Expert software. A comparative study was conducted with artificial neural networks (ANN) using MATLAB Software for better prediction of the selected output variables. The formulations were made and tested for transmittance and drug release percentages. The desirability function was used to create an optimal formulation, which was then made and tested for emulsification time, centrifugation, viscosity, cloud point, dilution and phase separation. Neusilin was used as an adsorbent to further solidify the optimized formulation and produce a stable product. The solidified optimized formulation was then subjected to fourier transform infrared spectroscopy and x-ray diffraction studies.

Results

The optimized SMEDDS Dabigatran etexilate formulations contained mixtures of Kollisolv MCT70 (oil), Kolliphor EL (surfactant), and PEG 400 (cosurfactant). The higher R² values and lower MSE values of percentage drug release and percentage transmittance for ANN compared to Box-Behnken design-based quadratic model indicate better predictability of ANN. In vitro release of optimized SMEDDS was 81.09 ± 1.37% within 1 h. It exhibited a significant transmittance of 89 ± 0.63%.

Conclusion

The results indicated that SMEDDS capsules could be effectively used to improve the solubility rate of Dabigatran etexilate. ANN can be successfully used as a better model for predicting characteristics of formulations.

Graphical Abstract

Purpose

A multitude of inflammatory cells and chemical mediators initiate a complex cascade that ultimately leads to hepatocyte death and a systemic inflammatory response. This research aimed to investigate the potential effects of sildenafil and neem (Azadirachta indica) extract, in both conventional and nanoparticle (NP) forms, in the treatment of moderate acute liver damage induced by orogastric carbon tetrachloride (CCL₄).

Methods

To induce moderate acute hepatic damage a single oral dosage of CCL₄ (2.5 mL/kg body weight) was provided 24 h before euthanasia. In liver damage-induced CCL₄, sildenafil and neem extract were given in conventional and nanoparticle (PLGA or niosome) forms. To find histological anomalies and hepatic changes, behavioral, biochemical, histopathological, and immunohistochemical methods were used.

Results

The findings indicated that sildenafil and/or neem extract, especially in NP combination, significantly mitigated CCL₄-induced acute moderate liver damage. Indicators of liver function, including aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), albumin, bilirubin and gamma-glutamyl transferase (GGT), shown improvement, particularly with the nanoparticulation of both therapies. Treatment, particularly in NP forms, improved the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase activity (GPx) in liver tissues. A significant reduction in NF-κB expression in hepatic tissue was shown in treatment groups. Also, medication resulted in lower levels of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), caspase-3, and transforming growth factor-beta (TGF-β) in the liver tissue homogenates. Liver function was more significantly improved by the drug-NP combination.

Conclusions

This study verified the beneficial therapeutic effects of the combination of sildenafil and neem extract, particularly in NP forms, using biochemical, histological, and immunohistochemical analyses in a rat model of liver damage.

Purpose

Bacterial ghosts (BGs) are the bacterial shells of Gram-positive and Gram-negative bacteria devoid of internal contents. This study aimed to utilize S. aureus BGs loaded with pre-prepared nanoparticles (NPs) of DTX as a novel delivery system targeting BC with minimal toxicity. A novel protocol for S. aureus ghost preparation using 7% v/v tween 80 and formic acid was developed.

Methods

The ghosts were characterized by SEM, and protein and DNA release were analyzed spectrophotometrically and via gel electrophoresis. DTX nanoparticles (NPs) were fabricated using antisolvent precipitation, optimized for particle size, zeta potential, and physicochemical properties. The antiproliferative activity of DTX-loaded S. aureus ghosts on breast cancer cells were assessed. In vitro release studies and mathematical release kinetics of DTX from the ghosts were evaluated, along with their cytotoxic activity in MDA-MB-231 cells.

Results

Findings revealed that the S. aureus ghosts were successfully produced by employing our proposed protocol. All tests confirm that the produced ghosts are free of internal and genetic content. The results showed a maximum loading capacity of 37.3 ± 0.8% with a maximum entrapment efficiency of 75.5 ± 0.8%. According to the in vitro release studies conducted on DTX-loaded ghosts over 16 days, there was an initial burst release rate of 53.3% in the first six hours, followed by a sustained release that continued for the entire 16-day period, reaching a maximum release rate of 69.2%. Mathematical analysis of the release kinetics of DTX from S. aureus ghosts indicated that it followed the Higuchi model, suggesting a diffusion process. The application of the Krosmeyer-Peppas model revealed an n value of 0.9473, indicating that the release was non-Fickian or anomalous. The assay of the antiproliferative activity of the prepared loaded S. aureus ghosts by the chemotherapy NPs on the BC cell line was relatively safe with no cytotoxicity. S. aureus BGs loaded with DTX-NPs show sustained release and significant antiproliferative activity against BC cells presenting a promising drug delivery system.

Conclusion

Our study highlights several benefits, such as improved stability and sustained release, which could enhance therapeutic outcomes. The BG-loaded drug approach offers a promising therapeutic strategy for delivering drugs to the targeted tissues for cancer treatment.

Purpose

Posaconazole (POS) is widely used as an antifungal agent effective against Candida infections. Because of its very low water and high fat solubility, it falls under the Biopharmaceutics Classification System (BCS) Class II. It showed considerable differences in absorption rates among individuals when administered orally. To overcome these obstacles, the current research concentrates on creating a solid self nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of POS to enhance its dissolution rate and bioavailability.

Methods

The choice of formulation components, Capmul MCM C8 as an oil, Tween 20 as a surfactant, and Acrysol K140 as a co-surfactant depended on their ability to solubilize POS and their capacity to form emulsions. Ternary phase diagrams were drawn to pinpoint and delineate the micro-emulsification region. The D-optimal mixture design was employed to facilitate the selection of the most optimized formulation by evaluating vital product characteristics including globule size, zeta potential, transparency percentage as well as emulsification efficiency. The optimized liquid SNEDDS (L-SNEDDS) was then converted into a solid state by employing Neusilin^® US2 as a porous carrier, improving the product’s stability and handling ease. The prepared formulation was further evaluated by in vitro and in vivo study.

Results

Examination of the S-SNEDDS structure through scanning electron microscopy showed spherical, granular particles, suggesting favourable flow characteristics. Dissolution tests conducted in vitro revealed that the rate of POS release from the S-SNEDDS was superior to that of unprocessed drug and marketed formulation. In vivo bioavailability study showed 2.27 and 1.96 fold higher bioavailability as compared to pure drug and marketed formulation respectively.

Conclusion

Present study revealed that the ability to self-emulsify was preserved when the L-SNEDDS was solidified. Further it demonstrated enhancement in dissolution and bioavailability of POS which depicted use of developed POS loaded S-SNEDDS for successful oral administration.

Purpose

Bezafibrate (BZF), a fibrates lipid-lowering drug, is primarily used in clinical practice for hyperlipidemia with significantly elevated triglycerides (TG). Its effect on reducing TG is more pronounced than that of statins, compensating for the shortcomings of statin medications. However, BZF is a BCS class II drug due to its low solubility in water and its poor oral bioavailability. To enhance the solubility and bioavailability of BZF, a co-amorphous complex comprising BZF and a hydrotrope was prepared.

Methods

Arginine (Arg) was selected as a hydrotrope for BZF. The BZF-Arg co-amorphous complex was prepared by the freeze-drying method and characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). Moreover, the complex was evaluated by stability test, in vitro release experiment and pharmacokinetic study.

Results

The characterization results demonstrated that the formation of hydrogen bonds between BZF and Arg, and the crystalline state of the drug was transformed into the amorphous state in the BZF-Arg complex. Moreover, the complex exhibited good stability and better release in vitro. The pharmacokinetic study revealed that the peak concentration (C_max) and the area under the curve (AUC_0→36) of the BZF-Arg complex were significantly improved compared to those of the BZF suspension, following the relative bioavailability of 255%.

Conclusion

BZF-Arg co-amorphous complex prepared by the combination of hydrotropy and solid dispersion technique provides a promising strategy for enhancing the solubility and bioavailability of BZF.

Graphical Abstract

Purpose

Dabigatran etexilate mesylate, a BCS Class II drug used in the prevention of deep vein thrombosis and brain stroke, exhibits poor bioavailability and polymorphic tendencies. To address these challenges, this study focuses on formulating liquisolid compact tablets of dabigatran etexilate mesylate.

Methods

The liquisolid technique uses propylene glycol as a non-volatile solvent, with Neusilin US2 and microcrystalline cellulose (MCC) serving as carrier materials, and Syloid 244FP employed as a coating agent. The formulation was optimized through a central composite design to evaluate the effects of excipient ratio and super disintegrant concentration on flow properties and dissolution behavior.

Result

The optimized liquisolid formulation demonstrated enhanced solubility and drug release, with 91.07% cumulative drug release compared to directly compressible tablets. Differential scanning calorimetry (DSC) measurements and powder X-ray diffraction (PXRD) analyses confirmed the molecular dispersion of the drug and the preservation of its crystalline Form III. Stability studies indicated no significant changes in dissolution profiles or physical properties over three months.

Conclusion

This study demonstrates the effectiveness of the liquisolid technique in enhancing the solubility, dissolution rate, and stability of dabigatran etexilate mesylate while also preventing polymorphic transformation.

Background

Valsartan, an angiotensin II receptor blocker, is commonly prescribed for managing hypertension and heart failure. However, its poor aqueous solubility and extensive first-pass metabolism limit its bioavailability, necessitating the development of an alternative delivery system. This study aimed to optimize the formulation of a sublingual fast-dissolving tablet of Valsartan to enhance drug dissolution and absorption for rapid therapeutic action.

Methods

A Box-Behnken Design (BBD) was employed to evaluate the influence of three super disintegrants—Sodium Starch Glycolate (SSG), Crospovidone (CP), and Croscarmellose Sodium (CCS)—on critical formulation parameters: disintegration time (DT) and cumulative drug release (CDR%). The optimized formulation (OVSF-18) was selected based on desirability criteria and further subjected to in vitro dissolution studies, release kinetics, and stability assessment to ensure formulation robustness.

Results

The response surface analysis revealed that SSG had the most significant impact on reducing DT, followed by CP, while CCS contributed moderately. The optimized formulation (OVSF-18) exhibited a disintegration time of 33.33 s and achieved 92.33% cumulative drug release within 15 min, demonstrating superior performance compared to marketed tablets. Stability studies confirmed the formulation’s physicochemical integrity over the test period.

Conclusion

The optimized sublingual Valsartan significantly enhances drug dissolution and absorption by circumventing first-pass metabolism, offering a promising alternative to conventional oral formulations. Its rapid onset of action and improved bioavailability make it particularly suitable for hypertensive emergencies and heart failure management. This study establishes a foundation for further clinical evaluation and potential commercialization of sublingual Valsartan tablets as an effective therapeutic option.

Discrete Element Method (DEM) simulations of cohesive particles are of great importance in understanding powder flows in processing equipment. Calibration of the particle–particle or particle–wall interaction parameters is important, and although there are many studies on DEM simulations of cohesive powders, most of them do not differentiate between particle–particle cohesive and particle–wall adhesive forces. In this work, a bench-top experimental setup was designed to demonstrate the effect of particle–wall adhesive forces. A simulation-based sensitivity analysis was also performed using a commercial scale tablet press feeder (TPF) and hopper screw feeder (HSF), by independently varying the particle–particle and particle–wall cohesive energy density values to illustrate their effect on powder flowability. Both the feeders experienced blockages for highly cohesive particles whose cohesive energy density exceeds 80 kJ/m³ in case of TPF and 110 kJ/m³ for HSF. The occurrence of such blockages was eliminated by reducing the particle–wall adhesion to 30 kJ/m³ in case of TPF and 50 kJ/m³ for HSF while keeping the particle–particle cohesion at the same high value. Thus, this work demonstrates that the particle–particle cohesion and particle wall adhesion should be considered as separate entities and must be calibrated separately in DEM so that the materials interaction effects of both powder and equipment can be captured adequately.