Neuroprotective effect of Berberine Nanoparticles Against Seizures in Pentylenetetrazole Induced Kindling Model of Epileptogenesis: Role of Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Mechanisms.

There is an unmet need to develop alternative therapeutic strategies to not only restrain seizures but also to alleviate the underlying pathologies and sequelae. Berberine (BBR), an isoquinoline alkaloid, has shown promising effect in the kindling model of epileptogenesis, but due to the poor oral bioavailability its clinical application is limited. So, the present study was designed to study the neuroprotective effect of BBR nanoparticles (enhanced bioavailability as compared to BBR) against seizures in pentylenetetrazole (PTZ) induced kindling model of epileptogenesis. Kindling model was established in male Wistar rats by intraperitoneal (i.p.) administration of PTZ (30 mg/kg) on every alternate day till the animal became fully kindled or till 6 weeks. Three doses of BBR (50, 100, and 200 mg/kg) and nano-BBR (25, 50, 100 mg/kg) were studied for seizure score, percentage of animal kindled, histopathological score, oxidative stress, inflammation, and apoptosis in PTZ treated rats by conducting cytokines, gene expression and protein expression analysis. BBR nanoparticles showed significant effect on the seizure score and percentage of animal kindled, histopathological score, neurobehavioral parameters (Forced swim test, Rotarod), oxidative (MDA, SOD, GSH, GPx) and inflammatory (IL-1beta, TNF-alpha) parameters, apoptotic parameters (Bax and iNOS), and gene (Nrf2, NQO1, HO1) and protein expression (Nrf2) as compared to both PTZ and BBR. BBR nanoparticles showed neuroprotective effect in PTZ induced kindling model of epileptogenesis and proves to be a promising antiepileptogenic therapy for the patients who are at high risk of developing seizures.

Preclinical Investigation of Transdermal Route for Enhanced Bio-performance of Duloxetine HCl.

The aim of the study was to develop and optimise drug-in-adhesive (DIA) transdermal patch of duloxetine HCl for enhanced drug delivery. DIA patch so developed reduced the dose and dosing frequency by enhancing bio-performance of the drug. A transdermal DIA patch having Duro-Tak 87-2287 as DIA polymer and Transcutol P as permeation enhancer loaded with 40% drug previously complexed with MeßCD duly characterised (FTIR, DSC, and SEM) was developed for in vivo study. Pharmacokinetic parameters of developed formulation were assessed and compared with oral route of administration. Among various permeation enhancers (PEs), Transcutol P exhibited most enhanced permeation (ER ≈ 1.99) in terms of flux and Q24 compared to control group having. Mean of maximum plasma concentration (Cmax) and area under time-concentration curve (AUC0-72) in Wistar rats (n = 6) for transdermal patch (10 mg/kg) was found to be 70.31 ± 11.2 ng/ml and 2997.29 ± 387.4 ng/ml*h, respectively, and were considerably higher than oral dose of DLX (20 mg/kg and 10 mg/kg). Albeit, T1/2 was higher in case of transdermal delivery, but this was due to sustained behaviour of delivery system. These findings highlight the significance of both inclusion complexation and transdermal delivery of DLX using DIA patch for efficient drug absorption.

Impact of cyclodextrin derivatives on systemic release of duloxetine HCl via buccal route.

Aim: The aim of this work was to develop buccoadhesive tablets for the systemic delivery of duloxetine HCl (DXT) using more soluble derivatives of ß-cyclodextrin, i.e. hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether-ß-cyclodextrin (SBEßCD) and to investigate enhanced cellular uptake of inclusion complexed drug.Materials and methods: Freeze dried and spray dried complexes of both cyclodextrin derivatives with DXT (1:1 molar) were prepared and characterized with DSC, FTIR, and PXRD techniques. C971 and PC, on the basis of swelling behavior, erosion and in vitro residence time, were selected for further study at different levels (-1, 0, +1) to optimize the formulation in terms of enhanced drug release and ex vivo permeation.Results: SBEßCD based complexes show more aqueous solubility of DXT (0.782 and 0.958 mM) and more complexation efficiency compared to HPßCD at 25 °C and 37 °C, respectively. Apparent stability constant was reported to be higher (1109.94 and 1693.25 M-1) for DXT-SBEßCD at 25 °C and 37 °C, respectively, than the corresponding values for DXT-HPßCD systems. Enhanced cellular uptake using fibroblast cells was revealed for complexed drug compared to free drug .Conclusion: Both cyclodextrin derivatives are able to enhance drug release and permeation in vitro and ex vivo.

Development of Chitosan-Based Hydrogel Containing Antibiofilm Agents for the Treatment of Staphylococcus aureus-Infected Burn Wound in Mice.

Methicillin-resistant Staphylococcus aureus (MRSA) is considered a common colonizer of burn wound and accounts for high morbidity and mortality all across the globe. Systemic antibiotic therapy which is generally prescribed for these patients has a number of limitations. These include high drug dose, toxicity, and chances of development of drug resistance. However, local delivery of drug not only addresses these limitations but also provides better efficacy at the site of infection. In the present study, hydrogel preparations were developed for the topical delivery of moxifloxacin for the treatment of S. aureus-infected burn wound. Moxifloxacin was characterized by UV, FTIR, DSC, hot-stage microscopy, NMR, and HPLC and loaded into conventional and Boswellia-containing novel gels. Gels were characterized by visual examination, pH, UV spectroscopy, and release assays. In vivo studies showed that both gels were effective in eradicating the bacteria completely from the wound site when treatment was started during the early stage of infection. On the contrary, delayed treatment of planktonic and biofilm cells with novel gel showed better efficacy as compared with conventional gel in S. aureus-infected burn wound. Histopathological analysis also showed better skin healing efficacy of novel gel than conventional gel. Our results show that moxifloxacin can be efficiently used topically in the management of burn wound infections along with other antibacterial agents. Since biofilm-mediated infections are on the rise especially in chronic bacterial disease, therefore, a preparation containing antibiofilm agent-like Boswellia as one of the excipients would be more meaningful.

Lipid Nanocarrier: an Efficient Approach Towards Ocular Delivery of Hydrophilic Drug (Valacyclovir).

This research focuses on the fabrication and evaluation of solid lipid nanoparticles (SLNs) for improved ocular delivery of valacyclovir (VAC). Stearic acid and tristearin were selected as the lipid carrier while Poloxamer 188 and sodium taurocholate were used as surfactant and co-surfactant, respectively. The physiochemical properties of the optimized batch (SLN-6) fulfil the prerequisites needed for an ideal ocular formulation like submicron size (202.5 ± 2.56 nm), narrow PDI (0.252 ± 0.06), high zeta potential (-34.4 ± 3.04 mV) and good entrapment efficiency (58.82 ± 2.45%). The in vitro release study of SLN-6 exhibited a sustained release profile (>60% in 12 h). The ex vivo studies performed on excised cornea exhibited enhanced drug permeation of SLNs (22.17 ± 1.41 µg/cm2 h) in comparison to the drug solution (3.78 ± 1.34 µg/cm2 h). Apart, the corneal hydration studies, histopathology and Hen's Egg Test Chorio Allantoic Membrane (HETCAM) assay, confirmed the non-irritancy of SLNs. The in vivo study confirmed improved ocular bioavailability of VAC from SLN-6 (AUC0-12: 856.47 ± 7.86 µg h/mL) in contrast to the drug solution (AUC0-12: 470.75 ± 8.91 µg h/mL). Hence, the overall studies suggested the potential of SLNs in efficient ocular delivery of a hydrophilic molecule like VAC.

Preparation and evaluation of floating tablets of pregabalin.

Floating tablets of pregabalin were prepared using different concentrations of the gums (xanthan gum and guar gum), Carbopol 974P NF and HPMC K100. Optimized formulations were studied for physical tests, floating time, swelling behavior, in vitro release studies and stability studies. In vitro drug release was higher for tablet batches containing guar and xanthan gum as compared to the batches containing Carbopol 974P NF. Tablet batches were subjected to stability studies and evaluated by different parameters (drug release, drug content, FTIR and DSC studies). The optimized tablet batch was selected for in vivo pharmacodynamic studies (PTZ induced seizures). The results obtained showed that the onset of jerks and clonus were delayed and extensor phase was abolished with time in treated groups. A significant difference (p > 0.05) was observed in control and treated group behavior indicating an excellent activity of the formulation for a longer period (>12 h).

Forging Ahead the Repositioning of Multitargeted Drug Ivermectin.

With the advent of ivermectin, tremendous improvement in public health has been observed, especially in the treatment of onchocerciasis and lymphatic filariasis that created chaos mostly in rural, sub-Saharan Africa and Latin American countries. The discovery of ivermectin became a boon to millions of people that had suffered in the pandemic and still holds its pharmacological potential. Ivermectin continued to surprise scientists because of its notable role in the treatment of various other tropical diseases (Chagas, leishmaniasis, worm infections, etc.) and is viewed as the safest drug with the least toxic effects. The current review highlights its role in unexplored avenues towards forging ahead of the repositioning of this multitargeted drug in cancer, viral (the evaluation of the efficacy of ivermectin against SARS-Cov-2 is under investigation) and bacterial infection and malaria. This article also provides a glimpse of regulatory considerations of drug repurposing and current formulation strategies. Due to its broad-spectrum activity, multitargeted nature and promising efforts are put towards the repurposing of this drug throughout the field of medicine. This single drug originated from a microbe, changed the face of global health by proving its unmatched success and progressive efforts continue in maintaining its bequestnin the management of global health by decreasing the burden of various diseases worldwide.

In silico predicative studies for cytotoxic potential of NSAIDs using self-organizing molecular field analysis.

Antiproliferative potential of nonsteroidal anti-inflammatory drugs (NSAIDs) has generated an immense interest among the scientific fraternity to assess its broader role in the chemoprevention of colon cancer. Due to serious adverse events associated with the chemotherapy, NSAIDs have been exploited as adjuvants to synergize the cytotoxic potential of conventional chemotherapeutic agents at low-dose regimens. The present investigation has been focused on in silico model generation for in vitro cytotoxicity activity of the clinically active NSAIDs using self-organizing molecular field analysis (SOMFA) studies. A statistically validated robust model for a diverse group of NSAIDs having flexibility in structure and cytotoxicity activity was obtained using SOMFA. The statistical measures having good cross-validated correlation coefficient r (2) (cv) (.8291), noncross-validated correlation coefficient r (2) values (.8686), and high F test value (41.8722) proved significance in the generated model. Analysis of 3-dimensional quantitative structure activity relationship (3D-QSAR) models through electrostatic and shape grids provided additional valuable information regarding shape and electrostatic potential influence on in vitro cytotoxicity profile. The analysis of SOMFA results provided a better insight about the generation of molecular architecture of novel NSAIDs yet to be synthesized, with optimum in vitro cytotoxicity activity and improved therapeutic profile.

Pharmaceutical strategies for the treatment of bacterial biofilms in chronic wounds.

Biofilms are sessile communities of microorganisms, mainly bacteria, that grow on biotic and abiotic surfaces. These microorganisms are embedded within an extracellular polymeric substance that provides enhanced protection from antimicrobials. Chronic wounds provide an ideal habitat for biofilm formation. Bacteria can easily attach to wound debris and can infect the wound due to an impaired host immune response. This review highlights the mechanism of biofilm formation and the role of biofilms in the pathophysiology of chronic wounds. Our major focus is on various formulation strategies and delivery systems that are employed to eradicate or disperse biofilms, thereby effectively managing acute and chronic wounds. We also discuss clinical research that has studied or is studying the treatment of biofilm-infected chronic wounds.

Advancements in redox-sensitive micelles as nanotheranostics: A new horizon in cancer management.

World Health Organisation (WHO) delineated cancer as one of the foremost reasons for mortality with 10 million deaths in the year 2020. Early diagnosis and effective drug delivery are of utmost importance in cancer management. The entrapment of both bio-imaging dyes and drugs will open novel avenues in the area of tumor theranostics. Elevated levels of reactive oxygen species (ROS) and glutathione (GSH) are the characteristic features of the tumor microenvironment (TME). Researchers have taken advantage of these specific TME features in recent years to develop micelle-based theranostic nanosystems. This review focuses on the advantages of redox-sensitive micelles (RSMs) and supramolecular self-assemblies for tumor theranostics. Key chemical linkers employed for the tumor-specific release of the cargo have been discussed. In vitro characterisation techniques used for the characterization of RSMs have been deliberated. Potential bottlenecks that may present themselves in the bench-to-bedside translation of this technology and the regulatory considerations have been deliberated.

Long Acting Polycaprolactone Based Parenteral Formulation of Aripiprazole Targeting Behavioural and Biochemical Deficit in Schizophrenia.

Schizophrenia is a neurodevelopmental disorder which is expressed in the form of disturbed behaviour and abnormal mental functions. Patient's non-adherence to the medicine is the main cause of failure of drug therapy and increases incidence of relapses. Thus, for successful management of disease long acting parenteral formulations were developed. Aripiprazole was encapsulated in biocompatible polycaprolactone microsphere by o/w emulsion solvent-evaporation method in order to achieve sustained release of the drug for several weeks after single subcutaneous administration. They were optimised on the basis of various parameters such as physical appearance, particle size (49.4 µm-387.1 µm), encapsulation efficiency (70%-95%), percentage yield (33%-75%) and drug loading (25.9%-47.5%). The surface topography and sphericity of the microspheres was determined by scanning electron microscopy which revealed that the microspheres formed were spherical and non-porous in nature. The in vitro releases from the selected formulations were found to be 87% and 95% respectively after 45 days of dissolution. In vivo efficacy of optimised formulation showed significantly (p < 0.05) amelioration of various positive, negative and cognitive symptoms associated with schizophrenia and oxidative stress markers in ketamine-induced schizophrenia model in rats for 30 days.

Transdermal delivery of duloxetine-sulfobutylether-ß-cyclodextrin complex for effective management of depression.

Aim of the study was to reduce the dose and dosing frequency of duloxetine HCl (DXT) by complexation with sulfobutylether-ß-cyclodextrin (SBEßCD), an anionic cyclodextrin through permeation enhancement for more effective management of depression. Spray dried inclusion complexes of drug with SBEßCD were prepared and incorporated in medicated patches followed by their ex vivo permeation and skin retention studies. Then, in vivo efficacy and absorption of the drug from developed optimised patch was determined in Wistar rats by administering drug through oral route (free drug) and transdermal route (complexed drug). Swimming, immobility and climbing parameters in FST while ambulation and rearings parameters in LAT test were assessed. Addition of permeation enhancer (PE) increased drug permeation and the enhancement ratio (ER) was 3.05 and 1.67 for the patch having complexed DXT and spray dried sample of DXT in comparison to free DXT respectively. The amount of drug retained in skin and in optimized medicated patch after 72 h was relatively lower compared to the formulation having free DXT. Enhanced antidepressive activity was observed for complexed drug compared to free drug. We believe that spray dried complexation based transdermal patch can serve as potential innovative drug delivery system for DXT.

Development of mirtazapine loaded solid lipid nanoparticles for topical delivery: Optimization, characterization and cytotoxicity evaluation.

Mirtazapine, an antidepressant drug has been proved to exert antipruritic effect upon oral administration in numerous clinical trial studies. The objective of the current study was to develop mirtazapine loaded solid lipid nanoparticles (SLNs) and evaluate its potential as a topical drug delivery system for management of pruritus. Mirtazapine loaded SLNs were successfully developed and optimized applying Box-Behnken design. The optimized mirtazapine loaded SLNs were characterized for physicochemical parameters and morphology. The in vitro cytotoxicity and cellular uptake studies of optimized SLNs were performed in human epithelial A-431 cell line. Further, the optimized mirtazapine loaded SLNs dispersion was incorporated into gel and characterized for rheology and texture analysis. The particle size and PDI of optimized mirtazapine loaded was found to be 180.3 nm and 0.209 respectively. The cytotoxicity studies revealed the safety of mirtazapine loaded SLNs on topical administration. The developed gel showed pseudoplastic flow behavior and good textural profile. The in vitro drug release studies showed that the developed mirtazapine loaded SLNs dispersion and its gel followed Korsmeyer-Peppas model (R2 = 0.905) and Higuchi model (R2 = 0.928) respectively. The ex vivo drug permeation studies showed higher values for mean cumulative amount of drug released (548.25 ± 29.29 µg/cm2), permeation flux (45.10 ± 0.78 µg/cm2/h) and skin retention (11.33 ± 0.85%) of SLNs gel in comparison to pure drug gel. The stability studies indicate the stability of SLNs gel for three months at refrigerated and ambient temperatures. Therefore, abovementioned findings suggest that mirtazapine loaded SLNs could be a potential system for topical management of pruritus.

Stress degradation studies on duloxetine hydrochloride and development of an RP-HPLC method for its determination in capsule formulation.

Duloxetine hydrochloride (HCl) is an antidepressant drug prescribed for major depressive disorders, pain related to diabetic peripheral neuropathy, and stress urinary incontinence. In the present study, degradation behavior of duloxetine HCl was studied by subjecting the drug to various International Conference on Harmonization-recommended stress conditions. Also, a stability-indicating high-performance liquid chromatography method was established for analysis of the drug in the presence of various degradation products. An acceptable separation of the drug and its degradation products was achieved on a C-8 column at 40 degrees C using a mobile phase comprised of phosphate buffer (pH 2.5)-methanol-tetrahydrofuran in the ratio of 50:40:10 at a flow rate of 1 mL/min. The detection wavelength was 232 nm. The method was validated for linearity, precision, accuracy, selectivity, specificity, and robustness. The method was found to be linear over a concentration range of 1-100 microg/mL (n = 6). The value of slope was found to be 85.735 mV/s ppm with correlation coefficient of 0.9994 and relative standard deviation (RSD) of 0.87%. RSD values ranged from 0.20% to 0.82% in the case of intra-day precision studies, whereas the values ranged from 0.63% to 1.57% in the case of inter-day precision. The drug was found to be stable on exposure of 30% H(2)O(2) for 48 h. It was found to be highly unstable in acidic conditions, as 41.35% degradation was observed in 0.01N HCl at 40 degrees C after 8 h. Degradation was also observed in alkaline and neutral conditions (2.83% and 42.75%, respectively) on refluxing the drug for 1 h. The drug was stable under photolytic and thermal stress on exposure in solid form but showed considerable degradation in solution form.

Polycaprolactone-based neurotherapeutic delivery of rasagiline targeting behavioral and biochemical deficits in Parkinson's disease.

Rasagiline mesylate is an irreversible MAO-B inhibitor which requires daily oral administration for treatment of Parkinson's disease due to its short half-life. Patients with Parkinson's disease also develop dysphagia, i.e., difficulty in swallowing. Encapsulating rasagiline in polycaprolactone microspheres can alleviate the problem of daily oral administration by prolonging drug release from polymeric microspheres for 1 month by single subcutaneous administration. Polycaprolactone shows absence of any acidic environment generation during its degradation in body which is its advantage over poly (lactic-co-glycolic) acid. Exploiting pH-based solubility of rasagiline mesylate pH changes during microencapsulation process was performed to fabricate rasagiline mesylate-loaded polycaprolactone microspheres. Particle size analysis of microspheres showed mean particle size range of 24.18-47.87 µm. Scanning electron micrographs revealed spherical non-porous particles with small pits and depressions on the surface. In vitro release studies of formulations were performed to get an idea about in vivo behavior of prepared formulations. Stereotaxic rotenone model was used to study in vivo efficacy of formulation in rats. Selected formulation significantly (p < 0.05) improved various behavioral (locomotor activity, grip strength, etc.) and biochemical (lipid peroxidation, reduced glutathione, etc.) changes. Polymeric microspheres showed robust effect on all outcomes assessed with non-significant difference between daily administration of rasagiline mesylate solution and drug-loaded polymeric microspheres administered once in a month. With prepared controlled release injectable once a month, administration is required making it an interesting and convenient approach in treatment of Parkinson's disease with dysphagia. Patient compliant system can be achieved by exploiting this approach for future use.

A simple and sensitive stability-indicating RP-HPLC assay method for the determination of aceclofenac.

The aim of the present study is to develop a stability-indicating assay method for the determination of aceclofenac after being subjected to different International Conference on Harmonization prescribed stress conditions, such as hydrolysis, oxidation, heat, and photolysis. Aceclofenac (2-[2-[2-(2,6-dichlorophenyl)aminophenyl]acetyl]oxyacetic acid) is decomposed under hydrolytic stress (neutral, acidic, and alkaline) and also on exposure to light (in solution form). The compound is stable to oxidative stress, heat, and photolytic stress (in solid form). The major degradation product is diclofenac, which is confirmed through comparison with the standard. Separation of the drug from major and minor degradation products is achieved on a C-18 column using methanol-0.02% of ortho phosphoric acid in a ratio of 70:30. The method is linear over the concentration range of 17-100 microg/mL (r(2) = 0.9988). The detection wavelength is 275 nm. The method is validated for linearity, range, precision, accuracy, specificity, and selectivity.

Antidepressants as antipruritic agents: A review.

Pruritus is a concomitant symptom of various underlying disorders viz. dermatological, systemic and psychiatric disorders that provoke the person to scratch the skin. Many natural as well as, antipruritic therapies are usually practiced in the treatment of pruritus including general preventive measures, topical therapies such as cooling agents, antihistamines, anesthetics, capsaicin, corticosteroids, immunomodulators and; systemic therapies including administration of antihistamines, opioid antagonists/agonists, antiepileptic drugs/neuroleptics (e.g., gabapentin and pregabalin), antidepressants (e.g., doxepin, amitriptyline, paroxetine, fluvoxamine, sertraline, escitalopram and mirtazapine) (Patel and Yosipovitch, 2010; Reich et al., 2011; Martín and Padilla, 2015; Eskeland et al., 2016). Topical therapies are the mainstay of treatment of delicate and localized pruritus while other systemic drug therapies are used to treat stern and generalized pruritus. The reported antipruritic activity of some antidepressant drugs has intrigued this review to focus on the types of pruritus, pruritus mechanism, the antipruritic mechanism of antidepressants and to comprehend the role of antidepressants in the management of pruritus.

Use of thermal and non thermal techniques for assessing compatibility between mirtazapine and solid lipids.

The present investigation was aimed at the evaluation of possible interactions between mirtazapine and selected solid lipids that are commonly used to develop solid lipid nanoparticles (SLNs) and nanostructured lipidic carriers (NLCs). The solids lipids explored were palmitic acid, stearic acid, glycerylmonostearate, cutina CPPH, sterotex NF, gelucire 50/13, hydrogenated castor oil and compritol 888 ATO. The techniques used were Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), Hot Stage Microscopy (HSM) and Isothermal Stress Testing (IST) studies. In some cases, the DSC results indicated the possibility of drug-solid lipid interactions which was further ruled out by performing HSM studies. Moreover, IST studies were also used to further confirm the compatibility between the drug and selected solid lipids. And the findings from these studies indicated compatibility between mirtazapine and solid lipids that can further be used to develop SLNs or NLCs.