Drug Development and Industrial Pharmacy最新文献

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 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 exhibit 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, 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.

Introduction: This study aims to develop immediate release tablet formulations of lornoxicam (LRX) using hot melt extrusion (HME)-based fused deposition modeling (FDM) focusing on the adjustment of drug release by arranging infill densities and evaluating microcrystalline cellulose II (MCC II) as a disintegrating agent for HME-FDM purposes. LRX is a poorly soluble drug that exhibits pH-dependent solubility with a high thermal degradation temperature. These characteristics make it an ideal model drug for the HME-based FDM technique.

Methods: Various filament formulations were extruded using an extruder, and suitable filaments were used to produce 3D-printed tablets. Filaments and tablets were characterized. Dissolution studies were performed on tablets with different infill densities. DSC, FTIR, XRD, and SEM analyses were conducted.

Results: Although the solubility of LRX increases with pH, disintegrating agents such as MCC II had a more significant effect on the dissolution of LRX than sodium bicarbonate, which was used as the alkalinizing pore-forming agent. Dissolution studies revealed that the dissolution of LRX was enhanced by tablet erosion. Tablet erosion increased as the infill density decreased, and an immediate release profile was reached with tablets having 25% infill density. Despite the availability of conventional immediate release LRX tablets, this newly developed formulation offers the potential to be modulated for personalized therapy via the 3D printing technique.

Conclusion: This study demonstrates the feasibility of HME-based FDM printing technology for producing immediate-release LRX tablets with consistent quality, highlighting the utilization of MCC II as a disintegrating agent that enhances LRX dissolution in this process.

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: 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.

Background: Tontelea micrantha, a notable plant species, has garnered interest for its medicinal properties, including anti-inflammatory, antibacterial and antiviral effects. A vaccine for Chikungunia virus is still under evaluation and no specific antiviral drug has been licensed to date.

Objective: The work investigated antiviral activity of ethyl acetate (EAEF) and methanolic (EMF) extracts from T. micrantha leaves in mammalian cells exposed to Alphavirus chikungunya (CHIKV). This plant species showed remarkable medicinal properties including anti-inflammatory, antiviral and antibacterial effects.

Methods: The cytotoxicity, antiviral activity, selectivity index, effect on viral gene expression, virus production, and mechanisms of action were evaluated.

Results: EAEF and EMF extracts showed anti-CHIKV effects at non-cytotoxic concentrations, with CC₅₀ above 300μg/mL, EC₅₀ of 18 and 43 μg/mL respectively, and selectivity Index above 4. These concentrations drastically reduce viral yields and CHIKV gene expression and have shown activity both directly on viral particles and at different stages of the viral cycle.

Conclusion: EAEF and EMF showed robust antiviral activity against CHIKV, making them promising candidates for the development of anti-CHIKV drugs.

Objective: Genotoxicity assays include micronucleus test, comet assay, and malformed sperm head used to investigate the protective potential of quercetin (Que) and Que nanoparticles against imidacloprid (IMI)-induced genotoxicity in Swiss albino mice.

Methods: The ionic gelation procedure was used to synthesize the Que nanoparticles and characterized for their hydrodynamic diameter, zeta potential, scanning electron microscopy (SEM), transmission electron microscopy (TEM), FT-IR, and encapsulation efficiency. A total of 48 mice were taken in eight groups with six animals in each group. Groups 1, 2, 3, and 4 received 3% gum acacia, 22 mg/kg IMI, 25 mg/kg Que and 25 mg/kg Que nanoparticles high dose (QNPs (HD)), respectively. Groups 5, 6, 7, and 8 received 22 mg/kg IMI + 25 mg/kg Que (IMI + Que), 22 mg/kg IMI + 25 mg/kg Que nanoparticles (IMI + QNPs (HD)), 22 mg/kg IMI + 12.5 mg/kg Que nanoparticle medium dose (IMI + QNPs (MD)), and 22 mg/kg IMI + 6.25 mg/kg Que nanoparticles low dose (IMI + QNPs (LD)), respectively.

Results: The IMI causes genotoxicity in bone marrow cells by increasing the frequency of micronuclei and the comet tail length. Additionally, IMI is mutagenic to germ cells, as determined by a test for aberrant sperm heads. Both Que and Que nanoparticles lessen the genotoxicity that IMI induces when administered together or separately. Histopathological findings also revealed degenerative changes in bone marrow and testes in IMI administered group as compared to control.

Conclusion: Quercetin and Que nanoparticles showed marked ameliorative effect by restoring the degenerative changes produced by IMI.

Objective: Highly branched poly(β-amino ester) (HPAEs)-based gene therapy holds promise for treating lung cystic fibrosis (CF). However, the translation of HPAEs/DNA nanoparticles into clinical applications poses a significant challenge due to the requirement for high concentrations of the formulation.

Methods: In this work, a straightforward and scalable concentration method was developed for concentrating HPAEs/DNA polyplexes. A series of different buffers with various pH values and ionic components were initially tested to develop the optimized HPAEs/DNA polyplex formulation. Subsequently, the optimized HPAEs/DNA polyplex formulation was concentrated through lyophilization and ultrafiltration.

Results: The ultrafiltration outperformed the lyophilization in concentration capacity, showing a 24-fold increase in the concentrated formulation compared to the original non-concentrated formulation. The concentration does not disturb the transfection efficiency in lung CF epithelial cells, indicating its potential for lung delivery applications. Moreover, the concentrated HPAEs/DNA polyplex successfully restored the production of cystic fibrosis transmembrane conductance regulator (CFTR) protein in primary lung CF epithelial cells, surpassing the performance of the non-concentrated common gene transfection reagents such as Lipofectamine 3000 and Xfect.

Conclusions: The concentrated HPAEs/DNA formulation represents a promising step forward for preclinical testing (e.g., in vivo evaluation), with further research needed to confirm its potential for clinical use.

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.

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.