Drug Development and Industrial Pharmacy最新文献

Objective: The present study aims to develop and evaluate the voriconazole-loaded thermoresponsive hydrogel using in silico tools.

Methods: Poloxamer 407 and PEG 400 were selected as the components from in silico studies for thermoresponsive hydrogel of voriconazole. The cohesive energy density (CED) and solubility parameters (SP) were calculated using Biovia Material Studio 2022 software to predict the polymer-polymer miscibility and drug-polymer miscibility. Different evaluation techniques used to select the optimized formulation. The in vitro antimicrobial activity against Candida albicans was determined for the optimized formulation to illustrate the efficacy of the developed formulation.

Results: Hydrogel containing 15% poloxamer exhibited gelation time of 92.67 ± 3.51 s, and gelation temperature of 36.67 °C with good spreadability of 13.00 ± 0.02 cm². CED values for poloxamer 407, PEG 400, and Voriconazole individually were found to be 3.23 × 10^-8, 3.21 × 10^-8, 4.84 × 10^-8, respectively, whereas in the combination of poloxamer 407 and PEG 400 was found to 3.85 × 10^-8 and in ratio 9:1 was found to be 3.81 × 10^-8 indicated the best miscibility between poloxamer 407 and PEG 400 in 9:1 ratio. Based on solvation-free energy of voriconazole (-48.343 kJ/mol) ethanol was selected as the solvent system. Optimized formulation showed the sustained release over the 36 h and good antimicrobial effect.

Conclusion: A thermoresponsive hydrogel of voriconazole was developed using Biovia Material Studio 2022, integrating computational predictions and molecular dynamics simulations to streamline polymer and solvent selection. This approach minimized trial-and-error experiments, enabling efficient formulation while enhancing understanding of polymer-polymer and drug-polymer interactions.

Background: Tavaborole (TAV), a benzoxaborole derivative, is an FDA-approved antifungal agent for treating onychomycosis, a common and persistent fungal infection of the toenails.

Objective: This study aimed to develop a robust stability-indicating HPTLC method to determine TAV in nanostructured lipid carriers (NLC) using a comprehensive approach that includes risk assessment, and Analytical Quality by Design.

Methods: The critical method parameters influencing the HPTLC results were screened using a Plackett-Burman screening design followed by its optimization using a central composite optimization design. The developed method was validated as per ICH recommendation.

Results: Optimized method utilized pre-coated aluminum-backed HPTLC plates using 10 µL/band injection volume, and the plate was developed using an isocratic mobile phase consisting of toluene: ethyl acetate: formic acid (75:25:1%v/v/v) in twin trough chamber pre-saturated for 20 mins with vapors of 10 mL of mobile phase. The separated components were detected at a wavelength of 221 nm. The developed HPTLC method resulted in a retardation factor of 0.49 ± 0.04 for TAV. Validation results revealed the HPTLC method's specificity (peak purity ≥ 0.999), linearity over a concentration range of 2-10 μg/band, sensitivity (LOD 0.21 μg and LOQ 0.64 μg), accuracy (99.68 - 101.43%w/w), and precision (%RSD < 2.0).

Conclusion: The developed robust stability-indicating HPTLC method was successfully implemented for the sustainable testing of the TAV in the NLC formulations and stability testing.

Objective: Boron Neutron Capture Therapy (BNCT) is a novel precision radiotherapy. The key to BNCT application lies in the effective targeting and retention of the boron-10 (¹⁰B) carrier. Among the various compounds studied in clinical settings, 4-boronophenylalanine (BPA) become the most prevalent one currently. However, challenges such as inadequate solubility and restricted tumor accumulation have affected the clinical efficacy of treatment with BPA. Therefore, there is an urgent need to prepare formulations with higher tumor uptake efficiency and increased intratumoral accumulation.

Methods: polyethylene glycol 400 and BPA were added to methanol and stirred until completely dissolved. The solution was then evaporated to remove methanol, yielding a pale-yellow clear liquid of the PEG400-BPA complex. This complex was then used for in vitro and in vivo experiments, and it was evaluated for inhibition effects after BNCT irradiation in GL261 cells.

Results: Compared to the clinically used fructose-BPA, PEG400-BPA increased the boron uptake in tumor cells nearly twice and exhibited a better tumor-to-normal tissue ratio (T/N) in the in vivo studies. Due to the BNCT efficacy with PEG400-BPA through in vitro experiments, the PEG400-BPA group also had showed significant cell-killing effects.

Conclusion: We discovered that PEG400 can form a complex with BPA, significantly improving its water solubility. It provides a simple, long-term stable, easily convertible, and injectable formulation method for the delivery of BPA in BNCT treatment. It also offers new insights for BPA solubilization and formulation as well as compound forms of administration of boron drugs on the delivery of boron drugs in BNCT.

Objective: Amid the escalating global cancer incidence, the development of effective and safe anticancer drugs is a critical priority in medical research. Addressing the clinical shortcomings of ruthenium-based anticancer drugs are currently a prominent focus of research.

Significance and methods: Since the pioneering work with platinum derivatives, significant progress has been made in the fundamental studies of metal complexes for the treatment of a wide range of cancers, and there has been a growing interest in their properties and biomedical applications. Although chemotherapy is crucial in clinical tumor management, platinum(II) anticancer drugs like cisplatin and carboplatin suffer from severe toxicity and drug resistance issues. Among various metal-based drugs, ruthenium(III) complexes are notable for their selectivity, cytotoxic activity in vitro, and effective anticancer properties in vivo. Despite some drug candidates reaching late-stage clinical trials, their clinical application remains constrained by problems such as low solubility, poor stability, and inadequate cellular uptake.

Results: The development of efficient and stable nanocarrier-based drug delivery systems for ruthenium(III) complexes, enhancing pharmacokinetic properties, and enabling slow, controlled release and targeted drug delivery, offers potential solutions to these limitations.

Conclusions: This review delves into the recent strides in nanomaterial-based drug delivery for ruthenium complexes, encompassing research on platinum (II) and ruthenium (III) metal complexes, nano-delivery system designs, and addresses pivotal challenges and future trajectories in this domain.

Objective: It has been reported that cancer cells get protected by a complex and rich multicellular environment i.e. the tumor microenvironment (TME) consisting of varying immune cells, endothelial cells, dendritic cells, fibroblasts, etc. This manuscript is aimed at the characteristic features of TME considered as potential target(s) for developing smart anticancer hydrogels.

Significance: The stimuli-specific drug delivery systems especially hydrogels that can respond to the characteristic features of TME are fabricated for treating cancer. For developing anticancer formulations, TME targeting can be considered an alternative way as it enhances the cytotoxic potential and reduces the unwanted effects. This manuscript shall be of quite interest to academicians, researchers, and clinicians engaged in oncology.

Methods: The manuscript was prepared by using the data available in the public domain in online resources such as Google Scholar, PubMed, Science Direct, Scopus, Web of Science, Research Gate, etc.

Results: Smart hydrogels, sensitive to some specific features of TME such as low pH, high concentration of glutathione, specific enzymes, etc., are promising anticancer formulations as these improve the efficacy and lower the side effects of chemotherapy.

Conclusion: The stimuli-responsive hydrogels have been gaining more attention for delivering cytotoxic drugs to the TME in response to specific stimuli. The stimuli-responsive hydrogels, comprising of cytotoxic drug(s) and specific polymers have some special features such as similarity with biological matrix, ability to respond to various internal as well as external stimuli, improved permeability, porosity, biocompatibility, resemblance with soft living tissues, etc.; and are considered as the promising anticancer candidates.

Objective: This study aimed to formulate Morus alba leaf extract (MAE) loaded solid lipid nanoparticles (SLNs) and investigate its cytotoxic potential using MDA-MB231 cell line.

Significance: SLNs can protect MAE from degradation, enhance cytotoxicity potential, and making them suitable for various therapeutic areas.

Methods: SLNs were developed using high-pressure homogenization method, and the formulations were optimized based on particle size, zeta potential, % entrapment efficiency (EE), and % cumulative drug release (CDR). The in vitro cytotoxic efficacy of MAE-loaded SLNs was evaluated through apoptosis assays and compared to that of free MAE.

Results: The particle size, zeta potential, % EE, and % CDR of optimized SLNs were found 116.3 nm, -26.18 mV, 89.30%, and 79.4%, respectively. MAE-loaded SLNs demonstrated significantly greater cytotoxic effects than the MAE (p < 0.05). SLNs induced less inhibition in the G0/G1 phase but showed marked inhibition in the S phase (9.7 ± 1.7%) and G2/M phase (2.2 ± 0.6%), indicating effective disruption of DNA replication and cell division, with significant cytotoxicity compared to control cells. The percentage of total apoptosis was 72.49 ± 2.7% for MAE alone and 81.46 ± 2.9% for MAE loaded SLNs, demonstrating a notably higher apoptosis rate for the SLNs formulation (p < 0.05). These findings indicated that MAE loaded SLNs significantly enhance the apoptotic and cytotoxic impact compared to MAE.

Conclusion: These results proved that MAE loaded SLNs as a promising nano carrier system to improve the therapeutic performance of MAE.

Background: The neglected tropical disease leishmaniasis has significant adverse effects from current treatments and limited therapeutic options are currently available.

Objective: The aim of this study was to develop a surface-modified nano-liposomal drug delivery system, anchored with chondroitin sulfate (CS), to effectively transport Amphotericin B (AmB) to macrophages.

Methods: Conventional liposome formulations (CL-F) and CS-coated surface-modified liposome formulations (CS-SML-F) were formulated by the thin film hydration method and characterized for particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency with long-term stability. In-vitro drug release using simulation medium, deformability index (DI) by using a polycarbonate membrane, and cell uptake studies among murine macrophages via flow cytometry were analyzed. Scanning and transmission electron microscopy were used to study the surface morphology and shape of the particles.

Results: Optimized conventional liposome CL-F6, CL-F9 and surface-modified liposomes CS-SML-F6 and CS-SML-F9 exhibited particle size diameters around 280 nm with a PDI of approximately 0.3 over six months of storage at 5 °C, maintaining stable surface charge (circa -30 mV). Sustained drug release peaked between 4 and 12 h and surface morphology showed a uniform distribution of spherical liposome particles. Cell uptake measured by flow cytometry showed the highest rate of macrophage targeting by the CS-SML-Fs.

Conclusion: These findings have demonstrated that CS surface-modification has enhanced nanoparticle targeting to macrophage binding sites, particularly the cysteine-rich domain, potentially advancing macrophage-targeted drug delivery systems.

Objective: The aim of this research study was to formulate a cost-effective, stable, less toxic and more efficacious intravenous nanoformulation that could rapidly augment the process of hemostasis.

Significance: Silver nanoparticles (AgNPs) evoked platelet activation, whereas alum (AM) neutralized the plasma proteins, causing blood coagulation. Tranexamic acid (TA) inhibited fibrinolysis and stabilized the formed blood clot.

Methods: The nanoformulation (NF) was subjected to characterization techniques such as UV-Vis spectrophotometry, FTIR, XRD, TGA and DSC analysis, which elucidated successful drug conjugation.

Results: Zeta-sizing confirmed the particle size of NF to be 256.6 nm with 0.497 PDI and a zeta potential of + 9.24 mV. In-vitro release profile exhibited first-order kinetics, indicating sustained release, conferring sustained release of NF for 12 h. NF was hemocompatible at the tested doses, as its extent of hemolysis was < 0.8% and < 1%, following EU and FDA guidelines, respectively. Ex-vivo studies revealed that NF recorded the highest viscosity, i.e. 36.5 cP, and maximum mass of clotted blood, i.e. 17.4 mg, in comparison to other combinations. In-vivo studies indicated a 100-fold dose reduction, i.e. 0.1 mg/kg, compared to the marketed formulation, Transamin®, i.e. 10 mg/kg. 10 folds dose reduction, i.e. 1 mg/kg, exhibited more efficacious results than Transamin®, owing to the synergistic effect and nano-sizing of components.

Conclusion: A safe, cost-effective, and relatively less toxic hemostatic nanoparticles were formulated, that can be intravenously administered to halt bleeding within seconds.

Objective: This pilot study aimed to develop a liquid formulation of tenapanor and evaluate taste and palatability with different sweetener and flavor combinations.

Significance: Tenapanor is a first-in-class, minimally absorbed, small molecule inhibitor of intestinal sodium/hydrogen exchanger 3, indicated (as tablets) to treat adults with constipation-predominant irritable bowel syndrome. It is also approved as add-on therapy to reduce serum phosphorus in adults with chronic kidney disease on dialysis who are intolerant of, or unacceptably responsive to, any dose of phosphate binder therapy. Since many patients have difficulty swallowing pills and pediatric studies are underway, a liquid formulation was developed, and taste profiles were evaluated for overall acceptability.

Methods: Formulation of liquid tenapanor targeted a concentration of 5 mg/mL, for a dosing range of 1-50 mg twice daily. Improvements in solubility and stability of tenapanor in water were investigated with the use of buffers, cosolvents, and preservatives. Seven liquid formulations with different sweetener/flavor combinations were assessed for taste and palatability by healthy adult participants using the sip-and-spit method in a randomized design.

Results: An aqueous solution of tenapanor (5 mg/mL), pH 3.4, with 0.05 % (w/v) benzoic acid, was stable at 2-8 °C for 12 months. The formulation with sucralose and raspberry flavor had the greatest improvement in overall acceptability and taste when compared to the reference solution without sweeteners or flavors.

Conclusions: A suitable liquid formulation was identified for progression to patient studies.

Objective: Alectinib HCl (ALB-HCl) is a BCS class IV molecule with low solubility and low oral bioavailability. Owing to its low bioavailability, a high dose of ALB-HCl is recommended with food to meet clinical efficacy. Thus, there is a need for a delivery system to overcome the bioavailability concerns.

Methods: Three solid dispersion (SD) formulations (I, II, and III) were evaluated for in-vitro dissolution and in-vivo pharmacokinetics (PK) study in Wistar rats. An in-vitro and in-vivo correlation (IVIVC) model was developed to establish a relationship between in-vitro dissolution data and in-vivo PK data. The formulations were subjected to stability studies.

Results: All formulations showed enhanced dissolution in all the media except Formulation I in FaSSIF media. In-vivo PK studies displayed that Formulation I was inferior to API alone. Formulations II and III (amorphous SD [ASD]) exhibited two-fold higher C_max and AUC_0-last than API alone. Level A IVIVC model was established for C_max and AUC_0-last with an acceptable % prediction error (PE). When evaluated for external predictability, the model was found validated for C_max (% PE <10%), however, it was inconclusive for AUC_0-last (%PE -14.03). Stability studies showed ASD formulations were stable during storage.

Conclusion: A stable ASD formulation of ALB-HCl was successfully developed with improved bioavailability. Developing an IVIVC model can act as a surrogate to predict in-vivo performance. The selection of formulation components in ASD shall be rationalized for bioavailability and stability before clinical evaluation.