Biodegradable polymers have played an important role in the delivery of drugs in a controlled and targeted manner. Polylactic-co-glycolic acid (PLGA) is one of the extensively researched synthetic ...biodegradable polymers due to its favorable properties. It is also known as a 'Smart Polymer' due to its stimuli sensitive behavior. A wide range of PLGA-based drug delivery systems have been reported for the treatment or diagnosis of various diseases and disorders. The present review provides an overview of the chemistry, physicochemical properties, biodegradation behavior, evaluation parameters and applications of PLGA in drug delivery. Different drug-polymer combinations developed into drug delivery or carrier systems are enumerated and discussed.
Display omitted
•Intranasal nanolipidic micelles-based Co-delivery of Artemether-Lumefantrine (AM-LMF).•Robust method for simultaneous analysis of AM & LMF in various sample types.•Validation of ...developed method as per ICH Q2R1 guidelines.•Application of developed method in quantifying drug levels in brain.
Cerebral malaria (CM) is a deadly neural disease caused by Plasmodium falciparum, affecting predominantly the immunosuppressed people. A combination of artemether (AM) and lumefantrine (LMF) is indicated as the first-line therapy in CM. Being a UV-inactive molecule, AM is difficult to analyse in large set of samples using a routine approach. Wide usage and analytical challenges with AM-LMF call for developing a simple, robust and economical method for simultaneous estimation of AM and LMF. The current studies endeavour to develop and validate a derivatization-based HPTLC densitometry methodology, wherein the influence of various derivatization parameters on the sensitivity and assay of both the drug(s) has been studied and optimized too. Effective chromatographic separation of AM and LMF was achieved with mobile phase, consisting of n-hexane: ethyl acetate (8:2 v/v), with good linearity in the concentration range 25–800 ng/spot and 10-800ng/spot for AM and LMF, respectively. High degree of accuracy, precision, robustness, ruggedness, and sensitivity were observed during validation studies. Well-resolved peaks along with high recovery of both the molecules were attained from biological and formulation matrices. The aforesaid method was subsequently employed to evaluate the brain biodistribution of the drugs following intranasal administration of their co-loaded lipid-based nanoformulation in C57BL/6 mice. In a nutshell, the developed method showed immense utility in the simultaneous estimation AM and LMF for analysis of large number of in-process samples, lipid-based nanoformulations and biological matrices.
Ceftazidime, a third-generation cephalosporin, is widely used in the treatment of lung infections, often given as "off-label" nebulization. There is need for developing a sensitive and robust ...analytical method to compute aerodynamic properties of ceftazidime following nebulization.
The current study entails development of a simple, accurate and sensitive high-performance liquid chromatography method (HPLC) for ceftazidime estimation, employing the principles of analytical quality-by-design (AQbD) and Monte Carlo simulations.
Selection of critical material attributes (CMAs) affecting method performance was accomplished by factor screening exercise. Subsequently, the influential CMAs, i.e., mobile phase ratio and flow rate, were systemically optimized using a face-centred cubic design for the chosen critical analytical attributes (CAAs). The factor relationship(s) between CMAs and CAAs was explored employing 3 D-response surface and 2 D-contour plots, followed by numerical as well as graphical optimization, for establishing the optimal chromatographic conditions. The obtained method operable design region was validated by Monte Carlo simulations for defect rate analysis.
The optimized HPLC conditions for estimating ceftazidime were acetonitrile to acetic acid solution (75:25) as mobile phase at a flow rate of 0.7 mL/min, leading to Rt of 4.5 min and peak tailing ≤ 2. Validation studies, as per ICH Q2(R1) guidance's, demonstrated high sensitivity, accuracy and efficiency of the developed analytical method with LOD of 0.075 and LOQ of 0.227 µg/mL. Application of this chromatographic method was extrapolated for determining aerodynamic performance by nebulizing ceftazidime at flow rate of 15 L/min using next-generation impactor. The study indicated superior performance, sensitivity and specificity of the developed analytical system for quantifying ceftazidime.
Application of AQbD approach, coupled with Monte Carlo simulations, aided in developing a robust HPLC method for estimation of ceftazidime per se and on various stages of impactor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lumefantrine (LMF) is first-line antimalarial drug, possesses activity against almost all human malarial parasites, but the in vivo activity of this molecule gets thwarted due to its low and ...inconsistent oral bioavailability (i.e. 4-12%) owing to poor biopharmaceutical attributes.
Lumefantrine phospholipid complex (LMF-PC) was prepared by rota-evaporation method following job's plot technique for the selection of apt stoichiometric ratios. Docking studies were carried out to determine the possible interaction(s) of LMF with phosphatidylcholine analogue. Comparative in vitro physiochemical, solid-state characterization, MTT assay, dose-response on P. falciparum, in vivo efficacy studies including pharmacokinetic and chemosuppression on NK-65 P. berghei infected mice were carried out.
Aqueous solubility was distinctly improved (i.e. 345 times) with phospholipid complex of LMF. Cytotoxicity studies on Hela and fibroblast cell lines demonstrated safety of LMF-PC with selectivity indices of 4395 and 5139, respectively. IC
50
value was reduced almost 2.5 folds. Significant enhancement in C
max
(3.3-folds) and AUC (2.7-folds) of rat plasma levels indicated notable pharmacokinetic superiority of LMF-PC over LMF suspension. Differential leukocytic count and cytokine assay delineated plausible immunoregulatory role of LMF-PC with nearly 98% chemosuppression and over 30 days of post-survival.
Superior antimalarial efficacy and survival time with full recovery of infected mice revealed through histopathological studies.
The current studies entail systematic development of self-nanoemulsifying drug delivery systems (SNEDDS) containing medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) for ...augmenting the biopharmaceutical performance of artemether. Equilibrium solubility and pseudoternary phase diagram studies facilitated selection of Captex 355 and Ethyl oleate as MCTs and LCTs, and Cremophor RH 40 and Tween 80 as surfactants, while Transcutol HP as cosolvent for formulating the SNEDDS. Systematic optimization was performed employing the Box-Behnken design taking concentrations of lipid, surfactant and cosolvent as the critical material attributes (CMAs), while evaluating for globule size, emulsification time, dissolution efficiency and permeation as the critical quality attributes (CQAs). In situ single pass intestinal perfusion (SPIP) studies in Wistar rats substantiated significant augmentation in the absorption (5- to 6-fold) and permeation (4- to 5-fold) parameters from the optimized MCT and LCT-SNEDDS vis-à-vis the pure drug. In vivo pharmacodynamic studies in Plasmodium berghi infected laca mice exhibited superior reduction in the levels of percent parasitemia, SGOT, SGPT and bilirubin, followed by higher survival rate of the animals by optimized MCT-SNEDDS followed by LCT-SNEDDS vis-à-vis the pure drug, which was subsequently ratified through histopathological examination of liver tissues. Overall, the studies construed successful development of the optimized SNEDDS of artemether with distinctly improved biopharmaceutical and antimalarial potential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cerebral malaria is a serious plasmodial infection that calls for immediate treatment for parasitic clearance from brain. Oral regimen of cerebral malaria is an impracticable option, it being often ...associated with problems like impaired consciousness, nausea and anorexia. The current research studies were, accordingly, undertaken to develop a patient-friendly non-invasive and rapid therapy via intranasal delivery of artemether (AM) and lumefantrine (LMF) employing their surface-modified lipidic nanocarriers (LNCs) using N, N, N trimethyl chitosan (TMC) as the polymer. Systematically developed employing Quality-by-Design (QbD) principles, LNCs and TMC-LNCs exhibited particle size of 63.7 and 80.8 nm, polydispersity of 0.19 and 0.28, respectively, along with modulated drug release profile for a period of 48 h. TMC-LNCs indicated nearly 2- and 7-folds enhancement in the mucoadhesive strength and nasal mucosal permeation vis-à-vis conventional LNCs and pure drug(s) suspension, respectively. In vitro nitric oxide assay unraveled the potential of both TMC-LNCs and LNCs to trigger macrophages for stimulating innate immune response against the parasites. Brain biodistribution studies in female C57BL/6 mice indicated higher drug concentrations in mice brain with intranasally delivered TMC-LNCs over intranasal and peroral AM-LMF suspension. Further, the speed and effectiveness of TMC-LNCs and LNCs in eradicating Plasmodium berghei ANKA strain in the murine model was also evaluated. Intranasal TMC-LNC demonstrated considerable in vivo anti-plasmodial efficacy with over 95% parasite suppression on day 7, followed by intranasal LNCs (82.5%), intranasal AM-LMF (79.1%) and peroral AM-LMF (46.3%). Overall, the surface-modified formulation, i.e., intranasal TMC-LNCs demonstrated markedly superior efficacy and parasitic suppression in brain.
Display omitted
•Surface-anchored lipidic nanoconstructs (TMC-LNCs) with improved therapeutic efficacy & safety potential.•Enhanced brain drug(s) levels using TMC-LNCs co-loaded with artemether & lumefantrine.•Explicit pharmacodynamic studies exhibiting notably superior biopharmaceutical potential.•Markedly improved serum biomarkers, NO levels & quicker parasitic eradication via intranasal route.•QbD-steered robust drug delivery development yielding holistic product & process understanding.
Pulmonary infections have long represented one of the major threats to humans. These vary from acute to chronic conditions, depending upon the underlying disease of the airways. Pulmonary ...aspergillosis (PMAP) has raised vital concerns in the immunocompromised patients. The fungal infection is difficult to diagnose in the early stages, often making the disease more complicated. Currently, three classes of antifungal agents are available on the market for the treatment of pulmonary infections. These agents are available in oral and intravenous forms only, which limits the availability of therapeutic concentrations of drug in the lungs for longer durations. Consequently, this leads to therapeutic failure and/or resistance of the organism(s) towards the antifungal agents because the optimum amount of drug does not reach the infection site. To combat the issues associated with the conventional regimens, inhalation of antifungal agents is gaining importance because administration to the lungs offers huge advantages of localized and targeted delivery. A wide range of inhalational devices such as nebulizers, dry powder inhalers, and metered dose inhalers are available on the market to deliver drug molecules to the lungs effectively. However, their clinical utility is limited to conditions such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis only. For a few decades, inhalation therapy has also been gaining importance to treat infectious diseases such as tuberculosis and aspergillosis, though more research efforts are required to make the transition from bench to bedside. The current review provides an explicit account of the potential role of inhalation drug delivery in PMAP.
The present work involved development of phospholipid‐based permeation enhancing nanovesicles (PENVs) for topical delivery of ketoprofen. Screening of phospholipids and process parameters was ...performed. Central composite design was used for optimization of factors, that is, amount (%, w/w) of phospholipid and ethanol at three levels. The optimized nanovesicles (NVs) were loaded with different terpenes and then incorporated into a gel base. Optimized NVs exhibited 69% entrapment efficiency, 51% transmittance, 328 nm mean vesicle size, and polydispersity index of 0.25. In vitro release kinetics evaluation indicated best fitting as per Korsemeyer–Peppa's model and drug release via Fickian‐diffusion mechanism. The optimized NVs loaded with mint terpene showed minimal degree of deformability and maximal elasticity as compared with the conventional NVs and liposomes. Rheology and texture analysis indicated pseudoplastic flow and smooth texture of the vesicle gel formulation. Ex vivo permeation studies across Wistar rat skin indicated low penetration (0.43‐fold decrease) and high skin retention (4.26‐fold increase) of ketoprofen from the optimized PENVs gel vis‐à‐vis the conventional gel. Skin irritancy study indicated lower scores for PENVs gel construing its biocompatible nature. Stability studies confirmed cold storage is best suitable for vesicle gel, and optimized PENVs were found to be suitable for topical delivery of ketoprofen.
Structural virality is a measure for how much information spreads across multiple user generations. It is important because it can help us better understand how information spreads online and develop ...new, useful techniques for influencing and limiting it. The application of recent developments in artificial intelligence to the analysis and understanding of the structural virality of online information diffusion is discussed in this paper. In the paper, the proposed techniques are verified as well and compared against other state-of-the-art approaches. The study's conclusions suggest that artificial intelligence (AI) possesses the potential to significantly expand our understanding of how information diffuses online and to develop novel, useful strategies for regulating and influencing the diffusion.
PDF
