Influence of Poloxamer 188 on Design and Development of Second Generation PLGA Nanocrystals of Metformin Hydrochloride

The poly(D,L-lactide-co-glycolide) (PLGA) based second-generation nanocrystals prepared by modified nanoprecipitation method, is the method of choice for encapsulation of both lipophilic and hydrophilic drugs. In this study, nanoprecipitation technique was adopted to develop second generation nanocrystals of PLGA loaded with metformin HCl (MHc). Poloxamer 188 with three different concentrations (0.5, 0.75, 1% w/v) in combination with PLGA at 1, 2, 3% concentrations (w/v) successfully produced MHc loaded PLGA second generation nanocrystals. The effects of poloxamer 188, amphiphilic triblock copolymer on carrier particle size, surface morphology, polydispersity index, zeta potential, drug entrapment efficiency and drug release of nanoformulation were investigated. The optimized formulation of second-generation nanocrystals with concentrations 0.75% w/v poloxamer 188 and 2% w/v PLGA, could produce particle size of 114.6 nm, entrapment efficiency of 63.48% and drug release 80.23% at 12 h. A blank formulation with the same composition as optimized formulation without addition of poloxamer188 compared with optimized formulation, exhibited nanoparticles of larger mean particle size of 212.9 nm with entrapment efficiency of 68.47% and 50.5% drug release at 12 h. Transmission electron microscopy (TEM) analysis of the nanoformulations revealed that poloxamer188 greatly contributed to smooth, spherical morphology of nanosize polymeric nanoparticles. Further Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) studies on nanoformulation emphasized the significance of poloxamer188 in formulation and development of optimized MHc loaded PLGA nanosuspensions of second generation nanocrystals. In conclusion, the study emphasizes that poloxamer 188 was a versatile excipient, which played a pivotal role in producing nanosize carrier with high drug release profile of MHc loaded PLGA nanosuspensions of second generation nanocrystals

Design, Fabrication and Characterization of PVA/PLGA Electrospun Nanofibers Carriers for Improvement of Drug Delivery of Gliclazide in Type-2 Diabetes

Poor solubility, erratic bioavailability and delivery challenges associated with gliclazide, which is commonly used in type 2 diabetes mellitus (T2DM) treatment, are overcome by exploring electrospun nanofibers technology. Employing emulsion electrospinning method with polyvinyl alcohol (PVA) alone and in combination with poly(d/l-lactide-co-glycolide) (PLGA), nanofibers were fabricated. Different concentrations of PLGA at 0.05%, 0.10% and 0.15% w/v were added to PVA to achieve a modified drug release profile to meet the typical physiological needs of T2DM, such as a faster drug release at meals followed by prolonged release to maintain constant plasma glucose level, which is highly desirable in T2DM management. Fabricated gliclazide-nanofibers were characterized by various studies, such as solubility, in-vitro drug release, drug release kinetic, scanning electron microscopy (SEM), differential scanning calorimetric (DSC), and Fourier transform infrared (FTIR) spectroscopy. GLZNF2, formulation of Drug:PVA:PLGA 0.1:10:0.05% w/v produced optimized gliclazide nanofibers. The optimized GLZNF2 nanofibers were incorporated into gelatin capsule for oral administration. SEM image of optimized formulation (GLZNF2) shows cylindrical shaped fiber, indicating gliclazide incorporated homogeneously in polymers with average fiber diameter 4.357 ± 0.83 µm. The solubility and dissolution rate of gliclazide nanofibers significantly improved compared to pure gliclazide. The gliclazide nanofibers produce a biphasic drug release profile, initial fast release, followed by prolonged release. Oral fabricated gliclazide fibers have tremendous potential as a drug carrier, and alternative technology for the improvement of solubility, dissolution rate, reduction in the dosing frequency and better blood glucose control could be explored in T2DM management

Exogenous metabolite feeding on altering antibiotic susceptibility in Gram-negative bacteria through metabolic modulation: a review

Background The rise of antimicrobial resistance at an alarming rate is outpacing the development of new antibiotics. The worrisome trends of multidrug-resistant Gram-negative bacteria have enormously diminished existing antibiotic activity. Antibiotic treatments may inhibit bacterial growth or lead to induce bacterial cell death through disruption of bacterial metabolism directly or indirectly. In light of this, it is imperative to have a thorough understanding of the relationship of bacterial metabolism with antimicrobial activity and leverage the underlying principle towards development of novel and effective antimicrobial therapies. Objective Herein, we explore studies on metabolic analyses of Gram-negative pathogens upon antibiotic treatment. Metabolomic studies revealed that antibiotic therapy caused changes of metabolites abundance and perturbed the bacterial metabolism. Following this line of thought, addition of exogenous metabolite has been employed in in vitro, in vivo and in silico studies to activate the bacterial metabolism and thus potentiate the antibiotic activity. Key scientific concepts of review Exogenous metabolites were discovered to cause metabolic modulation through activation of central carbon metabolism and cellular respiration, stimulation of proton motive force, increase of membrane potential, improvement of host immune protection, alteration of gut microbiome, and eventually facilitating antibiotic killing. The use of metabolites as antimicrobial adjuvants may be a promising approach in the fight against multidrug-resistant pathogens

Novel antimicrobial development using genome-scale metabolic model of Gram-negative pathogens: a review

Antimicrobial resistance (AMR) threatens the effective prevention and treatment of a wide range of infections. Governments around the world are beginning to devote effort for innovative treatment development to treat these resistant bacteria. Systems biology methods have been applied extensively to provide valuable insights into metabolic processes at system level. Genome-scale metabolic models serve as platforms for constraint-based computational techniques which aid in novel drug discovery. Tools for automated reconstruction of metabolic models have been developed to support system level metabolic analysis. We discuss features of such software platforms for potential users to best fit their purpose of research. In this work, we focus to review the development of genome-scale metabolic models of Gram-negative pathogens and also metabolic network approach for identification of antimicrobial drugs targets

In silico genome-scale metabolic modeling and in vitro static time-kill studies of exogenous metabolites alone and with polymyxin B against Klebsiella pneumoniae

Multidrug-resistant (MDR) Klebsiella pneumoniae is a top-prioritized Gram-negative pathogen with a high incidence in hospital-acquired infections. Polymyxins have resurged as a last-line therapy to combat Gram-negative “superbugs”, including MDR K. pneumoniae. However, the emergence of polymyxin resistance has increasingly been reported over the past decades when used as monotherapy, and thus combination therapy with non-antibiotics (e.g., metabolites) becomes a promising approach owing to the lower risk of resistance development. Genome-scale metabolic models (GSMMs) were constructed to delineate the altered metabolism of New Delhi metallo-β-lactamase- or extended spectrum β-lactamase-producing K. pneumoniae strains upon addition of exogenous metabolites in media. The metabolites that caused significant metabolic perturbations were then selected to examine their adjuvant effects using in vitro static time–kill studies. Metabolic network simulation shows that feeding of 3-phosphoglycerate and ribose 5-phosphate would lead to enhanced central carbon metabolism, ATP demand, and energy consumption, which is converged with metabolic disruptions by polymyxin treatment. Further static time–kill studies demonstrated enhanced antimicrobial killing of 10 mM 3-phosphoglycerate (1.26 and 1.82 log10 CFU/ml) and 10 mM ribose 5-phosphate (0.53 and 0.91 log10 CFU/ml) combination with 2 mg/L polymyxin B against K. pneumoniae strains. Overall, exogenous metabolite feeding could possibly improve polymyxin B activity via metabolic modulation and hence offers an attractive approach to enhance polymyxin B efficacy. With the application of GSMM in bridging the metabolic analysis and time–kill assay, biological insights into metabolite feeding can be inferred from comparative analyses of both results. Taken together, a systematic framework has been developed to facilitate the clinical translation of antibiotic-resistant infection management