Folate decorated chitosan-chondroitin sulfate nanoparticles loaded hydrogel for targeting macrophages against rheumatoid arthritis.

Inflammatory cell infiltration, particularly macrophages, plays a major contribution to the pathogenesis of Rheumatoid Arthritis (RA). Exploiting the overexpression of folate receptors (FR-ß) on these recruited macrophages has gained significant attraction for ligand-targeted delivery. Leflunomide (LEF), being an immunomodulatory agent is considered the cornerstone of the therapy, however, its oral efficacy is impeded by low solubility and escalating adverse effects profile. Therefore, in the present work, we developed Folate-conjugated chitosan-chondroitin sulfate nanoparticles encapsulating LEF for selective targeting at inflammatory sites in RA. For this purpose, the folate group was first conjugated with the chitosan polymer. After which, Folate Leflunomide Nanoparticles (FA-LEF-NPs) were synthesized through the ionotropic gelation method by employing FA-CHI and CHS. The polymers CHI and CHS were also presented with innate anti-inflammatory and anti-rheumatic attributes that were helpful in provision of synergistic effects to the formulation. These nanoparticles were further fabricated into a hydrogel, employing almond oil (A.O) as a permeation enhancer. The in vivo studies justified the preferential accumulation of FA-conjugated nanoparticles at inflamed joints more than any other organ in comparison to the free LEF and LEF-NPs formulation. The FA-LEF-NPs loaded hydrogel also ascertained a minimal adverse effect profile with an improvement of inflammatory cytokines expression.

Recent Developments in Oral Delivery of Vaccines Using Nanocarriers.

As oral administration of vaccines is the preferred route due to its high patient compliance and ability to stimulate both cellular and humoral immune responses, it is also associated with several challenges that include denaturation of vaccine components in the acidic environment of the stomach, degradation from proteolytic enzymes, and poor absorption through the intestinal membrane. To achieve effective delivery of such biomolecules, there is a need to investigate novel strategies of formulation development that can overcome the barriers associated with conventional vaccine delivery systems. Nanoparticles are advanced drug delivery carriers that provide target-oriented delivery by encapsulating vaccine components within them, thus making them stable against unfavorable conditions. This review provides a detailed overview of the different types of nanocarriers and various approaches that can enhance oral vaccine delivery.

Exploiting Recent Trends in the Treatment of Androgenic Alopecia through Topical Nanocarriers of Minoxidil.

Androgenic alopecia, a polygenetic disorder, is characterized by well-defined hair loss that progresses gradually. The disease affects both males and females and exerts a drastic impact on a person's psychological well-being. Minoxidil (MIN) is the commonly prescribed FDA-approved agent for the treatment of disease. It is conventionally administered as a topical solution but is allied with several adverse reactions, such as erythema and dermatitis, resulting in decreased patient compliance. To overcome these side effects, researchers developed various nanocarriers of MIN. Encapsulation of MIN in various nanocarriers enhances the entry of the drug into hair follicles and results in the formation of reservoirs for controlled delivery of the drug. It also increases the therapeutic outcomes in comparison to conventional formulations. The present review discusses the composition and physicochemical properties of different nanocarrier systems of MIN. Although successful encapsulation of MIN has been observed in these nanocarriers, there is still scarce data regarding their loading in a final dosage form. This allows researchers to conduct more in vivo studies and focus on their clinical applications. HIGHLIGHTS: • Androgenic alopecia is a polygenetic disorder with gradual loss of hair that progresses with age. • Minoxidil An FDA-approved drug for the treatment of androgenic alopecia. • Is allied with several adverse reactions, having decreased therapeutic efficacy. • Several nanocarriers including polymeric lipid-based and inorganic nanoparticles have been developed to improve their therapeutic efficacy. • Utilization of these nanocarriers results in increased retention of MIN within the hair follicles and utilizes low concentrations of solvents. • Modifications of different physicochemical properties of these carriers I.e. Particle size Zeta potential and entrapment efficiency are important to attain the above objectives.

Hydrogel Containing Solid Lipid Nanoparticles Loaded with Argan Oil and Simvastatin: Preparation, In Vitro and Ex Vivo Assessment.

Transdermal hydrogels have the potential to improve therapeutic outcomes via enhancing bioavailability and reducing toxicity associated with oral delivery. The goal of the present study was to formulate and optimise argan oil loaded transdermal hydrogel containing lipid nanoparticles. The high pressure homogenization (HPH) method was utilised to fabricate Simvastatin loaded solid lipid nanoparticles (SIM-SLNs) with precirol ATO 5 as a lipid core and Poloxamer 407 (P407) to stabilise the core. The optimised nanoformulation was characterised for its particle diameter, zeta potential, surface morphology, entrapment efficiency, crystallinity and molecular interaction. Furthermore, transdermal hydrogel was characterised for physical appearance, rheology, pH, bio adhesion, extrudability, spreadability and safety profile. In vitro and ex vivo assays were executed to gauge the potential of SLNs and argan oil for transdermal delivery. The mean particle size, zeta potential and polydispersity index (PDI) of the optimised nanoparticles were 205 nm, -16.6 mV and 0.127, respectively. Crystallinity studies and Fourier transform infrared (FTIR) analysis revealed no molecular interaction. The in vitro release model explains anomalous non-Fickian release of drug from matrix system. Ex vivo skin penetration studies conducted through a fluorescence microscope confirmed penetration of the formulation across the stratum corneum. Hydrogel plays a crucial role in controlling the burst release and imparting the effect of argan oil as hypolipidemic agent and permeation enhancer.

Major Depressive Disorder: Existing Hypotheses about Pathophysiological Mechanisms and New Genetic Findings.

Major depressive disorder (MDD) is a common mental disorder generally characterized by symptoms associated with mood, pleasure and effectiveness in daily life activities. MDD is ranked as a major contributor to worldwide disability. The complex pathogenesis of MDD is not yet understood, and this is a major cause of failure to develop new therapies and MDD recurrence. Here we summarize the literature on existing hypotheses about the pathophysiological mechanisms of MDD. We describe the different approaches undertaken to understand the molecular mechanism of MDD using genetic data. Hundreds of loci have now been identified by large genome-wide association studies (GWAS). We describe these studies and how they have provided information on the biological processes, cell types, tissues and druggable targets that are enriched for MDD risk genes. We detail our understanding of the genetic correlations and causal relationships between MDD and many psychiatric and non-psychiatric disorders and traits. We highlight the challenges associated with genetic studies, including the complexity of MDD genetics in diverse populations and the need for a study of rare variants and new studies of gene-environment interactions.

Development of novel biopolymer-based nanoparticles loaded cream for potential treatment of topical fungal infections.

OBJECTIVE: Biodegradable polymers are extensively used due to their efficient safety profiles. The aim of the current study was to fabricate, evaluate, and characterize biodegradable, biocompatible fluconazole (FLZ) loaded chitosan (CHS) chondroitin sulfate (CS) nanoparticles (NPs) for topical delivery. Polymers utilized in the formulation not only served as a carrier system but also aided in fighting with complex etiology of the disease due to their innate antifungal activities. METHODS: NPs were prepared by the complex coacervation method, then were optimized for various parameters and subsequently loaded into a cream. RESULTS: Scanning electron microscopic (SEM) analysis showed spherical morphology of the NPs. Prepared NPs showed an average particle size in the range of 350-450 nm and an encapsulation efficiency (EE) of 86%. The polydispersity index (PDI) was found to be 0.148 that showed a uniform distribution of NPs. Fourier transform infrared (FTIR) spectroscopy confirmed the absence of any electrostatic interaction between ingredients. In vitro drug release analyses exhibited a sustained release of the drug and higher antifungal activity than free FLZ. Ex vivo permeability and drug distribution in different skin layers ensured a site-specific delivery of the FLZ-NPs. As compared with free FLZ and other control groups, the prepared NPs also exhibited significantly higher antifungal activity against Candida albicans (p < .01). CONCLUSION: It was concluded from the results that the FLZ-NPs laden cream could be a potential candidate for topical and site-specific delivery of the drug cargo for the potential treatment of fungal infections.

Audit of antibiotic prophylaxis and adherence of surgeons to standard guidelines in common abdominal surgical procedures.

BACKGROUND: Prophylactic use of antibiotics before surgery is evidence-based practice for prevention of surgical site infections (SSIs). AIMS: To investigate adherence to and surgeons' perception of antibiotic prophylaxis guidelines. METHODS: A two-phase, cross-sectional prospective study conducted in two teaching hospitals. Phase 1: 6-month audit of prescriptions to investigate adherence rate to evidence-based guidelines. The important information was collected from medical charts through a predesigned proforma. Phase 2: self-administration questionnaire was used to investigate the surgeons' perception. Descriptive statistics, independent-sample Kruskal-Wallis test and multivariate linear regression analysis were performed using SPSS version 21.0. RESULTS: A total of 866 eligible surgical cases (acute appendectomy; n = 418; 48.2%), laparoscopic cholecystectomy (n = 278; 32.1%) and inguinal hernia (n = 170; 19.7%) were investigated. Surgical antibiotic prophylaxis was prescribed in 97.5% of procedures. Out of these, 9.5% adhered to guidelines with respect to correct choice, 40% for timing, and 100% for dose and route (optimal value 100%). Most patients received ceftriaxone (n = 503; 59.5%) as prophylactic antibiotic. The questionnaire (good internal consistency; α ≥ 0.7) was filled out by 200 surgeons. More than half (69%) of participants thought that antibiotics were overused. Most surgeons perceive that poor adherence to treatment guidelines is due to poor awareness, underestimation of infection, lack of consensus, and disagreement with guidelines recommendations. CONCLUSIONS: Surgeons have positive perception that antibiotics should be used according to guidelines recommendations. However, we found poor treatment adherence to antibiotic prophylaxis guidelines.

Proniosomes as a Carrier System for Transdermal Delivery of Clozapine.

The current study aimed to formulate the clozapine (CLZ) loaded proniosomal gel (PN) and evaluate it's in vitro release, ex vivo permeation and gel properties. CLZ is a BCS class II drug with low bioavailability of 27% and severe adverse drug reactions (ADRs) due to frequent dosing. Proniosomes offer a versatile pro-vesicular approach with potential in transdermal drug delivery. PN-CLZ gel was prepared by the coacervation phase separation method utilizing span-60, cholesterol and lecithin. Optimization of PN gel was done by hit & trial method and the formulations were characterized for particle size, entrapment efficiency (EE), polydispersity index (PDI) and zeta potential (ZP). The optimized formulation had the highest entrapment efficiency of 90% and the average particle size of approx. 325 nm. PDI reflected homogeneity in the formulation. ZP was -59.76 mV, high enough to indicate a stable formulation. The in vitro release studies manifested a sustained release behavior of clozapine from the proniosomal gel. The ex vivo permeation showed noteworthy permeation of the drug through stratum corneum with a steady state flux of 18.26 ug/cm2/hr. The optimized gel was analyzed for pH, spreadability, bioadhesion and rheology. The results suggested that clozapine could be effectively loaded into proniosomal gel for administration through skin.

Development and Evaluation of Optimized Thiolated Chitosan Proniosomal Gel Containing Duloxetine for Intranasal Delivery.

Proniosomes offer excellent potential for improved drug delivery, through versatile routes, by overcoming the permeation barriers faced by several drugs. The study was aimed to develop a thiomer gel containing duloxetine proniosomes for the intranasal delivery, improving its bioavailability and brain delivery through olfactory system. Duloxetine-loaded proniosomes were optimized through Design-Expert Software, prepared by coacervation phase separation method and then characterized in vitro for different vesicle features, and permeation enhancement potential using various techniques. The formulation F2, out of all the trials, fulfilled the maximum requisite of highest entrapment efficiency (76.21 ± 1.24%) and minimum vesicle size (223.91 ± 11.07 nm). The F2 was embedded in thiolated chitosan gel rendering it mucoadhesive and further characterized. The in vitro release showed a sustained drug release from the mucoadhesive proniosomal gel with only 54% drug release as compared to that of 71% from proniosome over 8 h, following Higuchi drug release model. Ex vivo permeation studies showed the enhancement ratio for the mucoadhesive proniosomal gel to be 1.86-fold greater than proniosomes, indicating a significant improvement in transmucosal permeation. The results suggest that incorporation of proniosomes into thiolated gel can significantly improve its mucoadhesion and retention time in the nasal cavity for providing a sustained drug release. Thus, gel formulation could be considered as a promising approach for efficient intranasal drug delivery of duloxetine. Graphical Abstract.

Development of novel pH-sensitive nanoparticles loaded hydrogel for transdermal drug delivery.

OBJECTIVE: Difference of pH that exists between the skin surface and blood circulation can be exploited for transdermal delivery of drug molecules by loading drug into pH-sensitive polymer. Eudragit S100 (ES100), a pH-sensitive polymer having dissolution profile above pH 7.4, is used in oral, ocular, vaginal and topical delivery of drug molecules. However, pH-sensitive potential of this polymer has not been explored for transdermal delivery. The aim of this research work was to exploit the pH-sensitive potential of ES100 as a nanocarrier for transdermal delivery of model drug, that is, Piroxicam. METHODS: Simple nanoprecipitation technique was employed to prepare the nanoparticles and response surface quadratic model was applied to get an optimized formulation. The prepared nanoparticles were characterized and loaded into Carbopol 934 based hydrogel. In vitro release, ex vivo permeation and accelerated stability studies were carried out on the prepared formulation. RESULTS: Particles with an average size of 25-40 nm were obtained with an encapsulation efficiency of 88%. Release studies revealed that nanoparticles remained stable at acidic pH while sustained release with no initial burst effect was observed at pH 7.4 from the hydrogel. Permeation of these nanocarriers from hydrogel matrix showed significant permeation of Piroxicam through mice skin. CONCLUSION: It can be concluded that ES100 based pH-sensitive nanoparticles have potential to be delivered through transdermal route.

Nanotechnology: from In Vivo Imaging System to Controlled Drug Delivery.

Science and technology have always been the vitals of human's struggle, utilized exclusively for the development of novel tools and products, ranging from micro- to nanosize. Nanotechnology has gained significant attention due to its extensive applications in biomedicine, particularly related to bio imaging and drug delivery. Various nanodevices and nanomaterials have been developed for the diagnosis and treatment of different diseases. Herein, we have described two primary aspects of the nanomedicine, i.e., in vivo imaging and drug delivery, highlighting the recent advancements and future explorations. Tremendous advancements in the nanotechnology tools for the imaging, particularly of the cancer cells, have recently been observed. Nanoparticles offer a suitable medium to carryout molecular level modifications including the site-specific imaging and targeting. Invention of radionuclides, quantum dots, magnetic nanoparticles, and carbon nanotubes and use of gold nanoparticles in biosensors have revolutionized the field of imaging, resulting in easy understanding of the pathophysiology of disease, improved ability to diagnose and enhanced therapeutic delivery. This high specificity and selectivity of the nanomedicine is important, and thus, the recent advancements in this field need to be understood for a better today and a more prosperous future.