Drug Development and Industrial Pharmacy最新文献

Introduction: Optimization of pharmaceutical formulations requires advanced tools to ensure quality, safety, and efficacy. quality-by-design (QbD), introduced by the FDA, emphasizes understanding and controlling processes early in development. Advanced optimization methods, such as desirability, have surpassed traditional single-objective techniques. Others, such as weighted goal programming (WGP) offers unique advantages by integrating decision-maker preferences, enabling balanced solutions for complex drug delivery systems. This study applies WGP to optimize timolol (TM)-loaded nanoliposomes aligning with QbD principles.

Methods: The optimization process followed six steps: identifying factors and responses, developing a Design of Experiments (DoE) plan, defining ideal and anti-ideal points, setting aspiration levels, assigning relative weights, and applying WGP compared to desirability function. Minimized and balanced deviations from aspiration levels served as criteria for selecting the most robust optimization results. Six responses were analyzed: vesicle size $\left(z_1\right)$, polydispersity index $\left(z_2\right)$, zeta potential $\left(z_3\right)$, deformability index $\left(z_4\right)$, phosphorus content $\left(z_5\right)$, and drug entrapment efficiency $\left(z_6\right)$.

Results: WGP produced a more balanced formulation that simultaneously optimized multiple responses. By incorporating the importance of each response, the WGP approach improved control over size, colloidal stability, and drug entrapment, based on its mathematical formulation. Comparative analysis with the desirability function confirmed that WGP effectively addressed potential tradeoffs without oversimplifying conflicting objectives.

Conclusions: This case-study demonstrates WGP potential as an advanced multi-objective optimization tool for pharmaceutical applications, improving upon traditional methods in complex formulations. Its ability to harmonize multiple critical attributes in line with QbD highlights its value in developing high-quality pharmaceutical products.

Objective: This study evaluates the chemical and enzymatic stability of naringin (NRG), identifies its degradation metabolites, assesses its in vitro cytotoxicity, and validates a high-performance liquid chromatography (HPLC) method for precise quantification.

Significance: NRG, a flavonoid with antioxidant, anti-inflammatory, and anticancer properties, faces clinical limitations due to poor solubility, rapid degradation, and low bioavailability. While research efforts on this promising compound have largely focused on overcoming these limitations through formulation strategies, it is equally necessary and complementary to focus on preformulation studies to enhance NRG's therapeutic potential. These studies represent a fundamental step in drug development, providing key insights into the physicochemical and biological properties of NRG and serving as the basis for the rational design of safe and effective formulations in future research.

Methods: NRG stability was analyzed under various temperature and pH conditions. Cytotoxicity was evaluated in 3T3 cells, and an HPLC method was developed and validated to quantify NRG and its primary metabolite, naringenin (NRGN).

Results: NRG remained stable up to 100 °C and under physiological pH (1.2, 5.8, and 7.4) but degraded at extreme pH, forming NRGN. Cytotoxicity assays showed low toxicity at ≤1 mM (viability >80%), whereas 5 mM significantly reduced viability. The validated HPLC method exhibited high precision, specificity, and accuracy in distinguishing NRG from NRGN.

Discussion: This study provides critical insights into NRG's stability, safety, and quantification, supporting its potential therapeutic development. These findings establish a foundation for future research aimed at enhancing NRG bioavailability and clinical applicability.

Background & rationale: Celecoxib (CXB), with its anti-inflammatory and recently discovered antibacterial activity, especially against sensitive and methicillin-resistant Staphylococcus aureus (MRSA), could be promising in treating local pain, superficial skin infections, wounds and infected wounds. The study aims to develop and compare commercially scalable topical formulations of CXB to explore their antimicrobial and wound-healing potential.

Methods: Carbopol gel, o/w cream, polyethylene glycol (PEG) ointment, and paraffin ointment were selected as the vehicles for the preparation of 3% CXB topical formulations. Appearance, pH, viscosity, spreadability, drug content, stability, in vitro release and permeation, and skin retention studies were performed. Further, antimicrobial assay, in vivo wound-healing and histopathology studies were carried out for each formulation.

Results: The formulations had an acceptable appearance, viscosity, spreadability, and drug content. The drug release at 6h was the highest from gel (2428.8ug/cm²), followed by PEG ointment (2230.1ug/cm²), cream (1897.8ug/cm²), and lastly, the paraffin ointment (1217.2ug/cm²). PEG ointment and gel showed the highest skin permeation, whereas cream and gel were better able to retain the drug in the skin. All the formulations exhibited appreciable zones of inhibition against sensitive and the resistant strains of Staphylococcus aureus. PEG ointment exerted a significantly greater (p < 0.001) wound-healing effect. Accelerated stability studies confirmed good physicochemical stability of the formulations.

Conclusion: PEG ointment, with its optimal drug release profile, skin permeation ability, and greater wound-healing action, can be considered as a promising topical delivery vehicle for CXB. CXB's antimicrobial potential could further aid in the prevention as well as treatment of wound infection.

Significance: Electrospinning presents a promising avenue for drug delivery applications by integrating traditional solid dispersion methods with nano-medicinal strategies. Electrospun nanofibers (NFs) can be tailored to control the composition, diameter, and orientation of the NFs based on the intended application.

Objectives: Herein, we aim to fabricate novel polymeric NFs loaded with sulpiride (SUL) utilizing Eudragit L100-55 (EL100-55) polymers to improve the dissolution and permeability of a model class IV drug.

Methods: Various factors were assessed to optimize the electrospun NF formulation, including polymer concentrations, flow rate, and drug amount.

Results: The electrospinning process yielded defect-free SUL-loaded EL100-55 NFs. The physicochemical analysis demonstrated favorable attributes in all formulations, encompassing high drug loading, encapsulation efficiency, and rapid drug release. Nanofiber formulations exhibited superior dissolution due to their extensive surface area. Modified non-everted sac experiments revealed a twofold increase in SUL permeation through the intestinal membrane upon EL100-55 encapsulation, emphasizing its impact on tight junction modulation in both NF and solid dispersion formulations. Enhanced drug permeation in the NF formulation involved dual mechanisms: transcellular diffusion and widening of the paracellular pathway. In contrast, the solid dispersion formulation prepared via solvent evaporation predominantly widened the paracellular pathway. Visualization techniques illustrated the NFs' robust affinity for the transcellular pathway.

Conclusion: Sulpiride encapsulation into EL100-55-NF is a promising solution for BCS class IV drugs facing solubility and permeability challenges.

Background: The presented study aimed to evaluate the effect of aging on the quality attributes of ODTs.

Experimental: ODTs prepared in one of our previous studies, packed in standard blister packing, were stored at ambient conditions in a laboratory (protected from direct sunlight) for 5 years and evaluated for their quality attributes, including physical parameters, mechanical strength (crushing strength, specific crushing strength, tensile strength, and friability), disintegration behavior (in vitro disintegration time, oral disintegration time, and wetting time), assay and dissolution rates. Drug content of all the samples was determined by HPLC.

Results: Physically, the ODTs were oval (10 mm), shallow, and convex with a bisection line, and their compression weight was 200 mg/tablet. With the passage of time, the moisture content of the ODTs increased from 2.4 ± 0.39% to 3.48 ± 0.62%. After 5 years, the drug content decreased to 92.38 ± 0.93%.

Discussion: Initially, there was an increase in the crushing strength of the ODTs (up to 3 years), and then it gradually decreased. At the time of preparation, disintegration time of the ODTs was 53 s, which gradually increased up to 89 s, at the 4th year. After completion of the study, it slightly decreased to 85 s. The dissolution rate of domperidone from the ODTs remained unaffected by aging. The FTIR spectra of the ODTs showed insignificant cahnges, indicating absence of degradation during the study period.

Conclusion: ODTs remained stable for five years and insignificant changes were observed in their quality attributes.

Objective: This review aims to explore innovative therapeutic strategies, with a particular focus on recent advancements in drug delivery systems using bioinspired nanomaterials such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for the idiopathic pulmonary fibrosis (IPF).

Significance of the review: Current treatments for IPF, including the FDA-approved anti-fibrotic agents pirfenidone and nintedanib, primarily aim to slow disease progression rather than reverse fibrosis. Bioinspired nanomaterials like SLNs and NLCs have shown promise in enhancing the efficacy of anti-fibrotic agents by improving drug solubility, stability, and targeted delivery. These systems not only minimize systemic side effects but also maximize therapeutic impact in lung tissues, offering a new hope for improved patient management and outcomes in this debilitating disease.

Key findings: SLNs facilitate sustained drug release and have demonstrated potential in delivering phosphodiesterase type 5 inhibitors effectively to lung cells. NLCs, on the other hand, exhibit superior biocompatibility and controlled release properties, making them suitable for pulmonary applications. Studies indicate that both SLNs and NLCs can enhance the bioavailability of drugs like ciprofloxacin and montelukast, thereby improving treatment outcomes in pulmonary conditions.

Conclusion: The integration of nanotechnology into anti-fibrotic therapy represents a significant advancement in addressing the challenges posed by IPF. By leveraging the unique properties of SLNs and NLCs, there is potential to overcome the limitations of current treatments and provide new therapeutic options that offer better management and improved outcomes for patients suffering from this debilitating disease.

Objective: The objective of the study was to tackle the recurrence of prostate cancer (PCa) post-surgery and to re-sensitize the docetaxel (DTX)-resistant PC-3 cells to chemo-therapy using NIC.

Significance: Prolonged DTX therapy leads to the emergence of chemo-resistance by overexpression of PI3K-AKT pathway in PCa along with tumor recurrence post-surgery. Suppression of this pathway could be essential in improving the anticancer activity of DTX and re-sensitizing the resistant cells.

Method: Niclosamide (NIC), an anthelmintic drug has shown tremendous anticancer potential and has re-sensitized the resistant cells to various drugs. To mitigate the post-surgical tumor recurrence, an implant-based system facilitating the sustained release of DTX and NIC could be beneficial. DTX and NIC were incorporated within a nanofiber (NF) system to prevent on-site recurrence by local release and re-sensitize the DTX-resistant cells.

Key findings: The fabricated DTX-NIC NF via electrospinning were 334 ± 96.14 nm in diameter and demonstrated sustained release profile till 6 d. Elevated mitochondrial damage, reactive oxygen species levels and apoptotic index revealed improvement in the cytotoxicity of DTX-NIC post incorporation into the NF owing to their sustained release profile. Re-sensitization of PC-3/DTX cells was observed by introduction of NIC which could be due to the suppression of p-Akt1, which was overexpressed in resistant cells.

Conclusion: From superior activity of DTX-NIC NF and re-sensitization of resistant cells, we conclude that DTX-NIC NF could be a beneficial therapeutic regimen in preventing tumor recurrence in PCa.

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).

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 300 μg/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: 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 CF 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.

Conclusion: 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: 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.