Development of niosomes for encapsulating captopril-quercetin prodrug to combat hypertension.

Novel and effective anti-hypertensive agents are required to manage hypertension; therefore, we synthesised a novel antihypertensive drug from captopril and quercetin (cap-que) and explored its antihypertensive potential in a niosomal formulation via molecular hybridisation. The cap-que hybrid was synthesised, and its structure was characterised via NMR, FTIR, and HRMS. Niosomes were then loaded with cap-que using the thin-film hydration method. The particle size, polydispersity index, surface charge and drug entrapment efficiency (EE%) of the formulation were 418.8 ± 4.21 nm, 0.393 ± 0.063, 16.25 ± 0.21 mV, and 87.74 ± 2.82%, respectively. The drug release profile showed a sustained release of the active compound (43 ± 0.09%) from the niosomal formulation, compared to the parent drug (80.7 ± 4.68%), over 24 h. The cell viability study confirmed the biosafety of the formulation. The in vivo study in a rat model showed enhanced antihypertensive activity of the hybrid molecule and niosomal formulation which reduced systolic and diastolic pressure when compared to the individual, bare drugs. The findings of this study concluded that the antihypertensive potential of captopril can be enhanced by its hybridisation with quercetin, followed by niosomal nano drug delivery.

A transferosome-loaded bigel for enhanced transdermal delivery and antibacterial activity of vancomycin hydrochloride.

Transdermal drug delivery is an attractive route of administration relative to other routes as it offers enhanced therapeutic efficacy. However, due to poor skin permeability of certain drugs, their application in transdermal delivery is limited. The ultra-deformable nature of transferosomes makes them suitable vehicles for transdermal delivery of drugs that have high molecular weights and hydrophilicity. However, their low viscosity, which leads to low contact time on the surface of the skin, has restricted their application in transdermal delivery. Therefore, this study aimed to deliver transferosomes loaded with a highly water-soluble and high molecular weight vancomycin hydrochloride (VCM-HCl) via a bigel for systemic delivery and treatment of microbial infections. VCM-HCl-loaded transferosomal formulations (TNFs) were prepared using a reverse-phase evaporation method and then loaded into a bigel. Both the TNFs and TNFs-loaded bigel (TNF-L-B) were characterized by a range of in vitro and ex vivo techniques. TNFs and TNF-L-B were tested for biosafety via the MTT assay and found to be biosafe. Prepared TNFs had sizes, zeta potential and entrapment efficiency of 63.02 ± 5.34 nm, -20.93 ± 6.13 mV and 84.48 ± 1.22% respectively. VCM-HCl release from TNF-L-B showed a prolonged release profile with 39.76 ± 1.6% after 24hrs when compared to bare VCM-HCl loaded in the bigel (74.81 ± 8.84%). Ex-vivo permeation of prepared TNF-L-B showed a higher permeation flux of 0.56 µg/cm2/h compared to the bare VCM-HCl-loaded bigel of 0.23 µg/cm2/h, indicating superior permeation and bioavailability of the drug. Additionally, the prepared TNF-L-B demonstrated improved antimicrobial activity. The TNF-L-B showed minimum inhibitory concentrations (MIC) of 0.97 µg/ml against Staphylococcus aureus (SA) and 1.95 µg/ml against methicillin-resistant SA (MRSA), which were 2-fold lower MIC values than the bare drug. The time-kill assay showed that both TNFs and TNF-L-B systems caused a 5.6-log reduction (100%) in MRSA compared to bare VCM-HCl after 24 hrs of incubation. Furthermore, as opposed to the bare VCM-HCl solution, the degree of biofilm reduction caused by TNFs (55.72%) and TNF-L-B (34.58%) suggests their dominance in eradicating MRSA biofilm. These findings indicate that TNF-L-B is a promising system for transdermal delivery of hydrophilic and high molecular weight drugs.

Novel formulation of antimicrobial peptides enhances antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA).

Antimicrobial peptides (AMPs) have the ability to penetrate as well as transport cargo across bacterial cell membranes, and they have been labeled as exceptional candidates to function in drug delivery. The aim of this study was to investigate the effectiveness of novel formulation of AMPs for enhanced MRSA activity. The strategy was carried out through the formulation of liposomes by thin-layer film hydration methodology, containing phosphatidylcholine, cholesterol, oleic acid, the novel AMP, as well as vancomycin (VCM). Characterization of the AMPs and liposomes included HPLC and LCMS for peptide purity and mass determination; DLS (size, polydispersity, zeta potential), TEM (surface morphology), dialysis (drug release), broth dilution, and flow cytometry (antibacterial activity); MTT assay, haemolysis and intracellular antibacterial studies. The size, PDI, and zeta potential of the drug-loaded AMP2-Lipo-1 were 102.6 ± 1.81 nm, 0.157 ± 0.01, and - 9.81 ± 1.69 mV, respectively, while for AMP3-Lipo-2 drug-loaded formulation, it was 146.4 ± 1.90 nm, 0.412 ± 0.05, and - 4.27 ± 1.25 mV respectively at pH 7.4. However, in acidic pH for both formulations, we observed an increase in size, PDI, and a switch to positive zeta potential, which indicated the pH responsiveness of our liposomal systems. The in vitro drug release studies demonstrated that liposomal formulations released VCM-HCl at a faster rate at pH 6.0 compared to pH 7.4. In vitro antibacterial activity against S. aureus and MRSA revealed that liposomes had enhanced activity at pH 6 compared to pH 7.4. The study revealed that the formulation can potentially be used to enhance activity and penetration of AMPs, thereby improving the treatment of bacterial infections.

pH-Responsive Lipid-Dendrimer Hybrid Nanoparticles: An Approach To Target and Eliminate Intracellular Pathogens.

pH-responsive drug delivery systems are yielding opportunities to directly deliver antibiotics to the site of infection. Therefore, this study aimed to develop and evaluate novel pH-responsive lipid-dendrimer hybrid nanoparticles (LDH-NPs) for the delivery of vancomycin (VCM) to the site of infection, by intracellular bacterial pathogens. The LDH-NPs were formulated using the emulsification solvent evaporation method and were characterized by various in vitro and molecular dynamic (MD) simulation techniques. LDH-NPs were 124.4 ± 2.01 nm in size, with a zeta-potential of -7.15 ± 2.98 mV and drug entrapment efficiency of 82.70 ± 4.09%, which exhibited pH-responsive behavior by shifting the surface charge from negative at physiological pH to positive in acidic pHs, with a size increase from 124.4 ± 2.01 to 173.9 ± 13.38 nm, and 252.7 ± 3.98 nm at pHs of 7.4, 6.0, and 4.5, respectively. Results indicated that the in vitro drug release of VCM from LDH-NPs occurred faster at pH 6.0 than at pH 7.4. The antibacterial activity of LDH-NPs against methicillin-resistance Staphylococcus aureus (MRSA) showed 8-fold lower MICs at pH 6.0 and 7.4, compared to treatment with VCM only. A bacterial cell viability study showed LDH-NPs had an 84.19% killing of MRSA, compared to VCM (49.26%) at the same MIC, further confirming its efficacy. Cell uptake studies showed that LDH-NPs intracellularly accumulated in HEK 293 cells, confirming significant clearance (p < 0.0001) of intracellular bacteria. MD simulation showed that interaction between the dendrimer and oleylamine was predominantly governed by van der Waals (VdW) interactions; whereas the interaction between the dendrimer and VCM was governed by both VdW and electrostatic interactions. Therefore, this study concludes that the pH-responsive release of VCM enhanced antibacterial efficacy against MRSA and intracellular delivery of an antibiotic. Thus, LDH-NPs is a promising nanocarrier system for antibiotics with the potential to improve the treatment outcomes of bacterial infections in patients with antibiotic resistant strains.

Variation of Pharmacokinetic Profiles of Some Antidiabetic Drugs from Nanostructured Formulations Administered Through Pulmonary Route.

BACKGROUND: Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. WHO projects that diabetes death will be doubled between 2005 and 2030, where 347 million people worldwide had diabetes as per the report of 2013. The increase in the prevalence of diabetes is due to three influences - lifestyle, ethnicity, and age. METHODS: The present review summarizes the pharmacokinetic parameters and challenges in the field of nanoparticles and nanoliposomes of insulin and other antidiabetic drugs given through pulmonary route to treat diabetes effectively. RESULTS: Current challenges in diabetes management include optimizing the use of the already available therapies to ensure adequate glycemic condition, blood pressure, lipid control and to reduce complications. At present, several pieces of research have been focusing on new management options for diabetes. Among these options, the use of nanomedicine is becoming an eye catching and most promising one. Currently, nanoparticles and nanoliposomes are thrust areas of research to treat any deadly disease like diabetes. These drug delivery systems ultimately result in longer circulation half-lives, improved drug pharmacokinetics, and reduced side effects of therapeutically active substances that may be insulin and non-insulin. CONCLUSIONS: Thus, the pulmonary route is the most promising alternative route of drug delivery since it is non-invasive and lungs have a large surface area, richly supplied by the capillary network, for absorption of drugs.

Development of Linker-Conjugated Nanosize Lipid Vesicles: A Strategy for Cell Selective Treatment in Breast Cancer.

Among the various drug delivery devices, nanoliposome is an emerging formulation in the treatment of cancer. Here we have developed tamoxifen citrate (TC) loaded nanoliposome conjugated with phosphoethanolamine (PE) by thin film hydration method. Various physicochemical and biopharmaceutical characterization studies such as drug-excipients interaction, surface morphology, energy dispersive X-ray analysis, zeta potential, in vitro drug release, cellular uptake, in vitro cytotoxicity assay and in vivo pharmacokinetic profiles were conducted. TC-loaded nanoliposome (TNL1) and PE-conjugated TC-loaded nanoliposome (TNL-PE) showed 3.23±0.26% and 3.07±0.05% drug loading values, respectively. Average diameters (z-average) of the nanoliposomes were within 100 nm, with negative zeta potentials and cumulative percentages of drug release were 75.77±12.21% and 61.04±10.53% at 30 h for TNL1 and TNL-PE respectively. Predominant uptake of both the types of nanoliposomes was visualized in MCF-7 breast cancer cells. TNL1 and TNL-PE decreased the cell viability from 95.95±0.37 to 12.22±0.64% and from 96.51±0.24 to 13.49±0.08% respectively. In vivo pharmacokinetic study showed that AUC 0-∞, AUMC0-∞, MRT, and t1/2 value of TNL-PE increased (22%, 100%, 2.66 fold and 60% respectively) as compared to the free drug. Administration of TNL-PE decreased the renal clearance value (about 38%) as compared to the free drug. TNL1 and TNL-PE released the drug in a sustained manner. Further, TNL-PE may be used for active targeting for breast cancer cells when it is tagged with specific antibodies to PE, a linker molecule.

Toxicological Concerns of Engineered Nanosize Drug Delivery Systems.

Matters when converted into nanosize provide some unique surface properties, which are different from those of the bulk materials. Nanomaterials show some extraordinary behavioral patterns because of those properties, such as supermagnetism, quantum confinement, etc. A great deal of implication of nanomaterials in nanomedicine has already been realized. Utility of nanomaterials as drug nanocarrier projects many potential advantages of them in drug delivery. Despite many such advantages, the potential risk of health and environmental hazards related to them cannot be ignored. Here various physicochemical factors, such as chemical nature, degradability, surface properties, surface charge, particle size, and shape, have been shown to play a crucial role in toxicity related to drug nanocarriers. Evidence-based findings of some drug nanocarriers have been incorporated to provide distinct knowledge to the readers in the field. A glimpse of current regulatory controls and measures required to combat the challenges of toxicological aspects of drug nanocarriers have been described.

Nanoscale Formulations and Diagnostics With Their Recent Trends: A Major Focus of Future Nanotechnology.

Nanomedicine is an emerging and rapidly growing field, possibly exploring for high expectation to healthcare. Nanoformulations have been designed to overcome challenges due to the development and fabrication of nanostructures. Unique size-dependent properties of nanoformulations make them superior and indispensable in many areas of human activity. Nano drug delivery systems are formulated and engineered to carry and deliver a number of substances in a targeted and controlled way. The vision of nanocarriers can be designed that will serve a dual purpose, allowing both treatment and diagnosis to be contained in an 'all-in-one' package. Nanoscale drugdelivery systems efficiently regulate the release, pharmacokinetics, pharmacodynamics, solubility, immunocompatibility, cellular uptake and biodistribution of chemical entities (drug). Their cellular uptake takes place by various mechanisms such as micropinocytosis, phagocytosis and receptor mediated endocytosis. These phenomena cause longer retention in blood circulation resulting in the release of the encapsulated materials in a sustained manner thus minimize the plasma fluctuations and toxic side effects. In this manner, the therapeutic index of conventional pharmaceuticals is efficiently increased. They can be used to deliver both micro and macro biomolecules such as peptides, proteins, plasmid DNA and synthetic oligodeoxynucleotides. In this present review, several recent developing and modifying nano-products for the detection, analysis, and treatment of diseases with their US and world patents along with various diagnostic kits have been discussed.

Preparation and characterization of Tamoxifen citrate loaded nanoparticles for breast cancer therapy.

BACKGROUND: Four formulations of Tamoxifen citrate loaded polylactide-co-glycolide (PLGA) based nanoparticles (TNPs) were developed and characterized. Their internalization by Michigan Cancer Foundation-7 (MCF-7) breast cancer cells was also investigated. METHODS: Nanoparticles were prepared by a multiple emulsion solvent evaporation method. Then the following studies were carried out: drug-excipients interaction using Fourier transform infrared spectroscopy (FTIR), surface morphology by field emission scanning electron microscopy (FESEM), zeta potential and size distribution using a Zetasizer Nano ZS90 and particle size analyzer, and in vitro drug release. In vitro cellular uptake of nanoparticles was assessed by confocal microscopy and their cell viability (%) was studied. RESULTS: No chemical interaction was observed between the drug and the selected excipients. TNPs had a smooth surface, and a nanosize range (250-380 nm) with a negative surface charge. Drug loadings of the prepared particles were 1.5%±0.02% weight/weight (w/w), 2.68%±0.5% w/w, 4.09%±0.2% w/w, 27.16%±2.08% w/w for NP1-NP4, respectively. A sustained drug release pattern from the nanoparticles was observed for the entire period of study, ie, up to 60 days. Further, nanoparticles were internalized well by the MCF-7 breast cancer cells on a concentration dependent manner and were present in the cytoplasm. The nucleus was free from nanoparticle entry. Drug loaded nanoparticles were found to be more cytotoxic than the free drug. CONCLUSION: TNPs (NP4) showed the highest drug loading, released the drug in a sustained manner for a prolonged period of time and were taken up well by the MCF-7 breast cancer cell line in vitro. Thus the formulation may be suitable for breast cancer treatment due to the good permeation of the formulation into the breast cancer cells.

Gastroretentive hydrodynamically balanced systems of ofloxacin: In vitro evaluation.

Hydrodynamically balanced systems (HBSs) of ofloxacin were prepared using lactose, HPMC K4M, PVP K 30, and liquid paraffin, which may increase the mean residence time in the gastrointestinal tract, and may be able to provide maximum drug at the site of absorption to improve oral bioavailability. All these formulated HBS capsules were floated well over 6 h with no floating lag time. They also showed sustained drug release over 6 h. Time for 50% release of ofloxacin was within the range, 2.47 ± 0.02 to 3.07 ± 0.08 h. The in vitro drug release from these HBS capsules was dependent on HPMC K4M, PVP K 30, and liquid paraffin content. The drug release pattern of these HBS capsules containing ofloxacin followed the Higuchi model with the anomalous transport mechanism.

Potentials and challenges of active targeting at the tumor cells by engineered polymeric nanoparticles.

Tumor targeted therapy has brought a new hope to the cancer patients. With the recent advances in nanotechnology and growing knowledge on unique cancer biomarkers, it is now possible to manipulate the surface architecture of polymeric nanoscale delivery systems with targeting moieties, such as antibodies, antibody fragments, specific molecules, small peptides, RNA aptamers etc. to target specific receptors and antigens present exclusively or overexpressed on the tumor cell surface or on the tumor endothelial cell surface. These modified polymeric nanoparticles deliver the loaded chemotherapeutics preferentially to the tumor tissue and not to the healthy tissue. This ensures highly targeted treatment without severe side effects which are normally experienced by the cancer patients in case of conventional chemotherapy. Such specifically constructed polymeric nanocarriers with improved tumor targeting profile are now regarded as engineered polymeric nanoparticles, which have become one of the prime areas of drug delivery research in recent times. This review describes specific approaches used in recent years to construct engineered polymeric nanoparticles, their emerging potential for cancer therapy and recent advances in tumor targeting. An equal attention has been devoted to the fundamental problems encountered in practical fields which limit their clinical use and industrial production.

Colloidal gold-loaded, biodegradable, polymer-based stavudine nanoparticle uptake by macrophages: an in vitro study.

OBJECTIVE: We describe the development, evaluation, and comparison of colloidal gold-loaded, poly(d,l-lactic-co-glycolic acid)-based nanoparticles containing anti-acquired immunodeficiency syndrome drug stavudine and uptake of these nanoparticles by macrophages in vitro. METHODS: WE USED THE FOLLOWING METHODS IN THIS STUDY: drug-excipient interaction by Fourier transform infrared spectroscopy, morphology of nanoparticles by field-emission scanning electron microscopy, particle size by a particle size analyzer, and zeta potential and polydispersity index by a zetasizer. Drug loading and in vitro release were evaluated for formulations. The best formulation was incorporated with fluorescein isothiocyanate. Macrophage uptake of fluorescein isothiocyanate nanoparticles was studied in vitro. RESULTS: Variations in process parameters, such as speed of homogenization and amount of excipients, affected drug loading and the polydispersity index. We found that the drug was released for a prolonged period (over 63 days) from the nanoparticles, and observed cellular uptake of stavudine nanoparticles by macrophages. CONCLUSION: Experimental nanoparticles represent an interesting carrier system for the transport of stavudine to macrophages, providing reduced required drug dose and improved drug delivery to macrophages over an extended period. The presence of colloidal gold in the particles decreased the drug content and resulted in comparatively faster drug release.

Calcium alginate/gum Arabic beads containing glibenclamide: development and in vitro characterization.

This work investigates the development, optimization and in vitro characterization of calcium alginate/gum Arabic beads by an ionotropic gelation method for prolonged sustained release of glibenclamide. The effects of amount of sodium alginate and gum Arabic as independent process variables on the drug encapsulation efficiency and drug release were optimized and analyzed based on central composite design and response surface methodology. Increment in drug encapsulation efficiency and decrease in drug release were found with the increase of both the amounts of sodium alginate and gum Arabic, used as polymer-blend. These optimized beads showed high drug encapsulation efficiency (86.02±2.97%), and suitable sustained drug release pattern over prolonged period (cumulative drug release after 7 h of 35.68±1.38%). The average size of these formulated dried beads containing glibenclamide ranged from 1.15±0.11 to 1.55±0.19 mm. The in vitro dissolution of these beads showed prolonged sustained release of glibenclamide over 7 h, which followed first-order model (R(2)=0.9886-0.9985) with anomalous (non-Fickian) diffusion mechanism (release exponent, n=0.72-0.81). The swelling and degradation of the optimized beads were influenced by pH of test mediums. These beads were also characterized by SEM and FTIR spectroscopy for surface morphology and excipients-drug interaction analysis, respectively. These developed calcium alginate/gum Arabic beads containing glibenclamide could possibly be advantageous in terms of advanced patient compliance with reduced dosing interval.