Solid Self-Nanoemulsifying Drug Delivery Systems of Furosemide: In Vivo Proof of Concept for Enhanced Predictable Therapeutic Response.

Liquid self-nano emulsifying drug delivery systems (SNEDDS) of furosemide (FSM) have been explored as a potential solution for enhancing solubility and permeability but are associated with rapid emulsification, spontaneous drug release, and poor in vivo correlation. To overcome the shortcoming, this study aimed to develop liquid and solid self-emulsifying drug delivery systems for FSM, compare formulation dynamics, continue in vivo therapeutic efficacy, and investigate the advantages of solidification. For this purpose, liquid SNEDDS (L-SEDDS-FSM) were formed using oleic acid as an oil, chremophore EL, Tween 80, Tween 20 as a surfactant, and PEG 400 as a co-surfactant containing 53 mg/mL FSM. At the same time, solid SNEDDS (S-SEDDS-FSM) was developed by adsorbing liquid SNEDDS onto microcrystalline cellulose in a 1:1 ratio. Both formulations were evaluated for size, zeta potential, lipase degradation, and drug release. Moreover, in vivo diuretic studies regarding urine volume were carried out in mice to investigate the therapeutic responses of liquid and solid SNEDDS formulations. After dilution, L-SEDDS-FSM showed a mean droplet size of 115 ± 4.5 nm, while S-SEDDS-FSM depicted 116 ± 2.6 nm and zeta potentials of -5.4 ± 0.55 and -6.22 ± 1.2, respectively. S-SEDDS-FSM showed 1.8-fold reduced degradation by lipase enzymes in comparison to L-SEDDS-FSM. S-SEDDS-FSM demonstrated a sustained drug release pattern, releasing 63% of the drug over 180 min, in contrast to L-SEDDS-FSM, exhibiting 90% spontaneous drug release within 30 min. L-SEDDS-FSM exhibited a rapid upsurge in urine output (1550 ± 56 µL) compared to S-SEDDS-FSM, showing gradual urine output (969 ± 29 µL) till the 4th h of the study, providing sustained urine output yet a predictable therapeutic response. The solidification of SNEDDS effectively addresses challenges associated with spontaneous drug release and precipitation observed in liquid SNEDDS, highlighting the potential benefits of solid SNEDDS in improving the therapeutic response of furosemide.

Synthesis, characterization, pharmacological and computational evaluation of hyaluronic acid modified chebulinic acid encapsulated chitosan nanocomposite for cancer therapy.

The purpose of this study was to produce hyaluronic acid customized nanoparticles with chitosan for the delivery of chebulinic acid (CLA) to enhance its anticancer potential against breast cancer. A significant portion of CLA was encapsulated (89.72 ± 4.38 %) and loaded (43.15 ± 5.61 %) within hybrid nanoparticles. The colloidal hybrid nanoparticles demonstrated a polydispersity index (PDI) of about 0.379 ± 0.112, with zeta capacitance of 32.69 ± 5.12 (mV), and an average size of 115 ± 8 (nm). It was found that CLA-CT-HA-NPs had stronger anticancer effects on MCF-7 cells (IC50 = 8.18 ± 3.02 µM) than pure CLA (IC50 = 17.15 ± 5.11 µM). The initial cytotoxicity findings were supported by additional investigations based on comet assay and flow cytometry analysis. Tumor remission and survival were evaluated in five separate groups of mice. When juxtaposed with pure CLA (3.17 ± 0.419 %), CLA-CT-HA-NPs improved survival rates and reduced tumor burden by 3.76 ± 0.811(%). Furthermore, in-silico molecular docking investigations revealed that various biodegradable polymers had several levels of compatibility with CLA. The outcomes of this study might potentially served as an effective strategy for delivering drugs in the context of breast cancer therapy.

Sulconazole-Loaded Solid Lipid Nanoparticles for Enhanced Antifungal Activity: In Vitro and In Vivo Approach.

Solid lipid nanoparticles (SLNs) have the advantages of a cell-specific delivery and sustained release of hydrophobic drugs that can be exploited against infectious diseases. The topical delivery of hydrophobic drugs needs pharmaceutical strategies to enhance drug permeation, which is a challenge faced by conventional formulations containing a drug suspended in gel, creams or ointments. We report the fabrication and optimization of SLNs with sulconazole (SCZ) as a model hydrophobic drug and then a formulation of an SLN-based topical gel against fungal infections. The SLNs were optimized through excipients of glyceryl monostearate and Phospholipon® 90 H as lipids and tween 20 as a surfactant for its size, drug entrapment and sustained release and resistance against aggregation. The SCZ-SLNs were physically characterized for their particle size (89.81 ± 2.64), polydispersity index (0.311 ± 0.07), zeta potential (-26.98 ± 1.19) and encapsulation efficiency (86.52 ± 0.53). The SCZ-SLNs showed sustained release of 85.29% drug at the 12 h timepoint. The TEM results demonstrated spherical morphology, while DSC, XRD and FTIR showed the compatibility of the drug inside SLNs. SCZ-SLNs were incorporated into a gel using carbopol and were further optimized for their rheological behavior, pH, homogeneity and spreadability on the skin. The antifungal activity against Candida albicans and Trichophyton rubrum was increased in comparison to a SCZ carbopol-based gel. In vivo antifungal activity in rabbits presented faster healing of skin fungal infections. The histopathological examination of the treated skin from rabbits presented restoration of the dermal architecture. In summary, the approach of formulating SLNs into a topical gel presented an advantageous drug delivery system against mycosis.

Itraconazole Loaded Biosurfactin Micelles with Enhanced Antifungal Activity: Fabrication, Evaluation and Molecular Simulation.

Itraconazole (ITZ) is a broad-spectrum antifungal for superficial subcutaneous and systemic fungal infections. This study aimed to enhance the antifungal activity of ITZ using surfactin A (SA), a cyclic lipopeptide produced by the SA-producing Bacillus strain NH-100, possessing strong antifungal activity. SA was extracted, and ITZ-loaded SA micelles formulations were prepared via a single-pot rinsing method and characterized by particle size, zeta potential, and infrared spectroscopy. In vitro dissolution at pH 1.2, as well as hemolysis studies, was also carried out. The fabricated formulations were stable and non-spherical in shape, with an average size of about 179 nm, and FTIR spectra depicted no chemical interaction among formulation components. ITZ-loaded micelles showed decreased hemolysis activity in comparison to pure ITZ. The drug released followed the Korsmeyer-Peppas model, having R2 0.98 with the diffusion release mechanism. In an acidic buffer, drug release of all prepared formulations was in the range of 73-89% in 2 h. The molecular simulation showed the outstanding binding and stability profile of the ITZ-SA complex. The aromatic ring of the ITZ mediates a π-alkyl contact with a side chain in the SA. It can be concluded that ITZ-loaded micelles, owing to significant enhanced antifungal activity up to 6-fold due to the synergistic effect of SA, can be a promising drug delivery platform for delivery of poorly soluble ITZ.

Tioconazole-Loaded Transethosomal Gel Using Box-Behnken Design for Topical Applications: In Vitro, In Vivo, and Molecular Docking Approaches.

Tioconazole (TCZ) is a broad-spectrum fungicidal BCS class II drug with reported activity against Candida albicans, dermatophytes, and certain Staphylococci bacteria. We report the use of TCZ-loaded transethosomes (TEs) to overcome the skin's barrier function. TCZ-loaded TEs were fabricated by using a cold method with slight modification. Box-Behnken composite design was utilized to investigate the effect of independent variables. The fabricated TEs were assessed with various physicochemical characterizations. The optimized formulation of TCZ-loaded TEs was incorporated into gel and evaluated for pH, conductivity, drug content, spreadability, rheology, in vitro permeation, ex vivo permeation, and in vitro and in vivo antifungal activity. The fabricated TCZ-loaded TEs had a % EE of 60.56 to 86.13, with particle sizes ranging from 219.1 to 757.1 nm. The SEM images showed spherically shaped vesicles. The % drug permeation was between 77.01 and 92.03. The kinetic analysis of all release profiles followed Higuchi's diffusion model. The FTIR, DSC, and XRD analysis showed no significant chemical interactions between the drug and excipients. A significantly higher antifungal activity was observed for TCZ-loaded transethosomal gel in comparison to the control. The in vivo antifungal study on albino rats indicated that TCZ-loaded transethosomal gel showed a comparable therapeutic effect in comparison to the market brand Canesten®. Molecular docking demonstrated that the TCZ in the TE composition was surrounded by hydrophobic excipients with increased overall hydrophobicity and better permeation. Therefore, TCZ in the form of transethosomal gel can serve as an effective drug delivery system, having the ability to penetrate the skin and overcome the stratum corneum barrier with improved efficacy.

Fabrication and Evaluation of Anticancer Potential of Eugenol Incorporated Chitosan-Silver Nanocomposites: In Vitro, In Vivo, and In Silico Studies.

The expanding global cancer burden necessitates a comprehensive strategy to promote possible therapeutic interventions. Nanomedicine is a cutting-edge approach for treating cancer with minimal adverse effects. In the present study, chitosan-silver nanoparticles (ChAgNPs) containing Eugenol (EGN) were synthesized and evaluated for their anticancer activity against breast cancer cells (MCF-7). The physical, pharmacological, and molecular docking studies were used to characterize these nanoparticles. EGN had been effectively entrapped into hybrid NPs (84 ± 7%). The EGN-ChAgNPs had a diameter of 128 ± 14 nm, a PDI of 0.472 ± 0.118, and a zeta potential of 30.58 ± 6.92 mV. Anticancer activity was measured in vitro using an SRB assay, and the findings revealed that EGN-ChAgNPs demonstrated stronger anticancer activity against MCF-7 cells (IC50 = 14.87 ± 5.34 µg/ml) than pure EGN (30.72 ± 4.91 µg/ml). To support initial cytotoxicity findings, advanced procedures such as cell cycle analysis and genotoxicity were performed. Tumor weight reduction and survival rate were determined using different groups of mice. Both survival rates and tumor weight reduction were higher in the EGN-ChAgNPs (12.5 mg/kg) treated group than in the pure EGN treated group. Based on protein-ligand interactions, it might be proposed that eugenol had a favorable interaction with Aurora Kinase A. It was observed that C9 had the highest HYDE score of any sample, measuring at -6.8 kJ/mol. These results, in conjunction with physical and pharmacological evaluations, implies that EGN-ChAgNPs may be a suitable drug delivery method for treating breast cancer in a safe and efficient way.

A Novel Intronic Deletion in PDE6B Causes Autosomal Recessive Retinitis Pigmentosa by Interfering with RNA Splicing.

INTRODUCTION: Retinitis pigmentosa (RP) is a rare degenerative retinal disease caused by mutations in approximately seventy genes. Currently, despite the availability of large-scale DNA sequencing technologies, ∼30-40% of patients still cannot be diagnosed at the molecular level. In this study, we investigated a novel intronic deletion of PDE6B, encoding the beta subunit of phosphodiesterase 6 in association with recessive RP. METHODS: Three unrelated consanguineous families were recruited from the northwestern part of Pakistan. Whole exome sequencing was performed for the proband of each family, and the data were analyzed according to an in-house computer pipeline. Relevant DNA variants in all available members of these families were assessed through Sanger sequencing. A minigene-based splicing assay was also performed. RESULTS: The clinical phenotype for all patients was compatible with rod cone degeneration, with the onset during childhood. Whole exome sequencing revealed a homozygous 18 bp intronic deletion (NM_000283.3:c.1921-20_1921-3del) in PDE6B, which co-segregated with disease in 10 affected individuals. In vitro splicing tests showed that this deletion causes aberrant RNA splicing of the gene, leading to the in-frame deletion of 6 codons and, likely, to disease. CONCLUSION: Our findings further expand the mutational spectrum of the PDE6B gene.

Voriconazole Cyclodextrin Based Polymeric Nanobeads for Enhanced Solubility and Activity: In Vitro/In Vivo and Molecular Simulation Approach.

Hydroxypropyl ß-cyclodextrin (HPßCD) based polymeric nanobeads containing voriconazole (VRC) were fabricated by free radical polymerization using N, N'-methylene bisacrylamide (MBA) as a cross-linker, 2-acrylamide-2-methylpropane sulfonic acid (AMPS) as monomer and ammonium persulfate (APS) as reaction promoter. Optimized formulation (CDN5) had a particle size of 320 nm with a zeta potential of -35.5 mV and 87% EE. Scanning electron microscopy (SEM) depicted porous and non-spherical shaped beads. No evidence of chemical interaction was evident in FT-IR studies, whereas distinctive high-intensity VRC peaks were found superimposed in XRD. A stable polymeric network formation was evident in DSC studies owing to a lower breakdown in VRC loaded HPßCD in comparison to blank HPßCD. In vitro release studies showed 91 and 92% drug release for optimized formulation at pH 1.2 and 6.8, respectively, with first-order kinetics as the best-fit model and non-Fickian diffusion as the release mechanism. No evidence of toxicity was observed upon oral administration of HPßCD loaded VRC polymeric nanobeads owing to with cellular morphology of vital organs as observed in histopathology. Molecular docking indicates the amalgamation of the compounds highlighting the hydrophobic patching mediated by nanogel formulation. It can be concluded that the development of polymeric nanobeads can be a promising tool to enhance the solubility and efficacy of hydrophobic drugs such as VRC besides decreased toxicity and for effective management of fungal infections.

Natural Polymer-Based Graphene Oxide Bio-nanocomposite Hydrogel Beads: Superstructures with Advanced Potentials for Drug Delivery.

The current study sought to create graphene oxide-based superstructures for gastrointestinal drug delivery. Graphene oxide has a large surface area that can be used to load anti-cancer drugs via non-covalent methods such as surface adsorption and hydrogen bonding. To enhance the bio-applicability of graphene oxide, nano-hybrids were synthesized by encapsulating the graphene oxide into calcium alginate hydrogel beads through the dripping-extrusion technique. These newly developed bio-nanocomposite hybrid hydrogel beads were evaluated in structural analysis, swelling study, drug release parameters, haemolytic assay, and antibacterial activity. Doxorubicin served as a model drug. The drug entrapment efficiency was determined by UV-spectroscopy analysis and was found to be high at ⁓89% in graphene oxide hybrid hydrogel beads. These fabricated hydrogel beads ensure the drug release from a hybrid polymeric matrix in a more controlled and sustained pattern avoiding the problems associated with a non-hybrid polymeric system. The drug release study of 12 h shows about 83% release at pH 6.8. In vitro drug release kinetics proved that drug release was a Fickian mechanism. The cytotoxic effect of graphene oxide hybrid alginate beads was also determined by evaluating the morphology of bacterial cells and red blood cells after incubation. Additionally, it was determined that the sequential encapsulation of graphene oxide in alginate hydrogel beads hides its uneven edges and lessens the graphene oxide's negative impacts. Also, the antibacterial study and biocompatibility of fabricated hydrogel beads made them potential candidates for gastrointestinal delivery.

Phytochemical Profiling, In Vitro Biological Activities, and In-Silico Studies of Ficus vasta Forssk.: An Unexplored Plant.

Ficus vasta Forssk. (Moraceae family) is an important medicinal plant that has not been previously investigated for its phytochemical and biological potential. Phytochemical screening, total bioactive content, and GCMS analysis were used to determine its phytoconstituents profile. Antioxidant, antibacterial, antifungal, anti-viral, cytotoxicity, thrombolytic, and enzyme inhibition activities were examined for biological evaluation. The plant extract exhibited the maximum total phenolic (89.47 ± 3.21 mg GAE/g) and total flavonoid contents (129.2 ± 4.14 mg QE/g), which may be related to the higher antioxidant potential of the extract. The extract showed strong α-amylase (IC50 5 ± 0.21 µg/mL) and α-glucosidase inhibition activity (IC50 5 ± 0.32 µg/mL). Significant results were observed in the case of antibacterial, antifungal, and anti-viral activities. The F. vasta extract inhibited the growth of HepG2 cells in a dose-dependent manner. The GCMS analysis of the extract provided the preliminary identification of 28 phytocompounds. In addition, the compounds identified by GCMS were subjected to in silico molecular docking analysis in order to identify any interactions between the compounds and enzymes (α-amylase and α-glucosidase). After that, the best-docked compounds were subjected to ADMET studies which provide information on pharmacokinetics, drug-likeness, physicochemical properties, and toxicity. The present study highlighted that the ethanol extract of F. vasta has antidiabetic, antimicrobial, anti-viral, and anti-cancer potentials that can be further explored for novel drug development.

Chemical Profiling, Formulation Development, In Vitro Evaluation and Molecular Docking of Piper nigrum Seeds Extract Loaded Emulgel for Anti-Aging.

Emulgel is a new innovatory technique for drug development permitting controlled release of active ingredients for topical administration. We report a stable emulgel of 4% Piper nigrum extract (PNE) prepared using 80% ethanol. The PNE-loaded formulation had an antioxidant activity of 84% and tyrosinase inhibition was 82%. Prepared formulation rendered spherical-shaped globules with high zeta potential (-45.5 mV) indicative of a stable system. Total phenolic contents were 58.01 mg GAE/g of dry extract whereas total flavonoid content was 52.63 mg QE/g of dry extract. Sun protection factor for PNE-loaded emulgel was 7.512 and formulation was stable without any evidence of physical and chemical changes following 90 days of storage. Gas chromatography-mass spectroscopy (GC-MS) revealed seventeen bioactive compounds in the PNE including monoterpenoids, triterpenoids, a tertiary alcohol, fatty acid esters, and phytosterols. In silico studies of GC-MS identified compounds show higher binding affinity in comparison to standard kojic acid indicating tyrosinase inhibition. It can be concluded that PNE-loaded emulgel had prominent antioxidant and tyrosinase inhibition and can be utilized as a promising topical system for anti-aging skin formulation.

Fabrication and Evaluation of Voriconazole Loaded Transethosomal Gel for Enhanced Antifungal and Antileishmanial Activity.

Voriconazole (VRC) is a broad-spectrum antifungal agent belonging to BCS class II (biopharmaceutical classification system). Despite many efforts to enhance its solubility, this primary issue still remains challenging for formulation scientists. Transethosomes (TELs) are one of the potential innovative nano-carriers for improving the solubility and permeation of poorly soluble and permeable drugs. We herein report voriconazole-loaded transethosomes (VRCT) fabricated by the cold method and followed by their incorporation into carbopol 940 as a gel. The prepared VRCT were evaluated for % yield, % entrapment efficiency (EE), surface morphology, possible chemical interaction, particle size, zeta potential, and polydispersity index (PDI). The optimized formulation had a particle size of 228.2 nm, a zeta potential of -26.5 mV, and a PDI of 0.45 with enhanced % EE. Rheology, spreadability, extrudability, in vitro release, skin permeation, molecular docking, antifungal, and antileishmanial activity were also assessed for VRCT and VRC loaded transethosomal gel (VTEG). Ex-vivo permeation using rat skin depicted a transdermal flux of 22.8 µg/cm2/h with enhanced efficiency up to 4-fold. A two-fold reduction in inhibitory as well as fungicidal concentration was observed against various fungal strains by VRCT and VTEG besides similar results against L-donovani. The development of transethosomal formulation can serve as an efficient drug delivery system through a topical route with enhanced efficacy and better patient compliance.

Controlled release floating drug delivery system for proton pump inhibitors lansoprazole: In-vitro, In-vivo floating and pharmacokinetic evaluation.

Lansoprazole (LPZ) show poor bioavailability because of first pass effect and absorption factors. The floating delivery systems could reduce fluctuations in plasma drug concentration through maintaining desirable plasma drug concentration. The objective of present study was to enhance bioavailability despite first pass effect through continuous availability of drug from floating system. Gum tragacanth (GT) and itaconic acid (IA) based floating hydrogels (FH) were synthesized. Parameters optimized were; microwave radiation exposure time, pH, GT:IA ratio and concentration of the glutaraldehyde. Optimized FH were evaluated for entrapment efficiency (% EE), in-vitro release, FTIR, SEM, and in- vitro and in-vivo floating study. Finally, pharmacokinetic was evaluated in ulcer-induced SD rats. Grafting percentage, swelling ratio and %EE of LPZ was 115%, Ì´250% and 90%, respectively. Microwave radiation exposure time, pH of reaction medium, GT:IA ratios and cross linker concentration were 2 min, pH 5, ratios 2:1 and 0.02%, respectively. The optimized FH showed acceptable floating behavior. The X-ray images revealed that hydrogels remained floated over gastric contents up to 24 hours. The in-vitro release and pharmacokinetics revealed availability of LPZ upto to 24h in-vitro and in ulcer-induced SD rats, respectively. The present hydrogels based floating system of lansoprazole is capable to extend the gastric residence time upto 24 hours.

Preparation, Characterization, and Pharmacological Investigation of Withaferin-A Loaded Nanosponges for Cancer Therapy; In Vitro, In Vivo and Molecular Docking Studies.

The rapidly growing global burden of cancer poses a major challenge to public health and demands a robust approach to access promising anticancer therapeutics. In parallel, nanotechnology approaches with various pharmacological properties offer efficacious clinical outcomes. The use of new artificial variants of nanosponges (NS) as a transporter of chemotherapeutic drugs to target cells has emerged as a very promising tool. Therefore, in this research, ethylcellulose (EC) NS were prepared using the ultrasonication assisted-emulsion solvent evaporation technique. Withaferin-A (WFA), an active ingredient in Withania somnifera, has been implanted into the nanospongic framework with enhanced anticancer properties. Inside the polymeric structure, WFA was efficiently entrapped (85 ± 11%). The drug (WFA) was found to be stable within polymeric nanosponges, as demonstrated by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies. The WFA-NS had a diameter of 117 ± 4 nm and zeta potential of -39.02 ± 5.71 mV with a polydispersity index (PDI) of 0.419 ± 0.073. In addition, scanning electron microscopy (SEM) revealed the porous surface texture of WFA-NS. In vitro anticancer activity (SRB assay) results showed that WFA-NS exhibited almost twice the anticancer efficacy against MCF-7 cells (IC50 = 1.57 ± 0.091 µM), as quantified by flow cytometry and comet tests. Moreover, fluorescence microscopy with DAPI staining and analysis of DNA fragmentation revealed apoptosis as a mechanism of cancer cell death. The anticancer activity of WFA-NS was further determined in vivo and results were compared to cisplatin. The anticancer activity of WFA-NS was further investigated in vivo, and the data were consistent to those obtained with cisplatin. At Day 10, WFA-NS (10 mg/kg) significantly reduced tumour volume to 72 ± 6%, which was comparable to cisplatin (10 mg/kg), which reduced tumour volume to 78 ± 8%. Finally, the outcomes of molecular modeling (in silico) also suggested that WFA established a stable connection with nanosponges, generating persistent hydrophobic contacts (polar and nonpolar) and helping with the attractive delayed-release features of the formulation. Collectively, all the findings support the use of WFA in nanosponges as a prototype for cancer treatment, and opened up new avenues for increasing the efficacy of natural product-derived medications.

Fabrication and Biological Assessment of Antidiabetic α-Mangostin Loaded Nanosponges: In Vitro, In Vivo, and In Silico Studies.

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic ß-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively.

Formulation and optimization of dimenhydrinate emulgels for topical delivery using response surface methodology.

Development of dimenhydrinate (DMN) emulgel formulation has been described in this work with enhanced permeation for transdermal delivery of DMN for effective management of motion sickness. Various DMN emulgel formulations were prepared using central composite design in response surface methodology. Propylene glycol and olive oil were used in varying ratios as permeation enhancers along-with carbopol-934 as gelling agent. Prepared formulations were evaluated by physico-chemical properties, stability and Fourier transform infrared spectroscopy (FTIR) studies. In-vitro drug release was studied using cellophane membrane. Formulation F2 showed maximum drug permeation following diffusion-based release mechanism and was used in further studies. Rat skin was used in Franz cell for ex-vivo studies to determine various permeation kinetic parameters. FTIR studies provided no evidence of chemical interaction between DMN and polymers used, whereas molecular docking revealed formation of a stable complex in the presence of aqueous environment with stable intermolecular binding and the complex was well hydrated. No evidence of skin irritation was observed in human volunteers following application of the optimized formulation. Histopathology data of the rat skin showed a decreased proliferation of the lymphocytes whereas monocytes were induced. In conclusion, combination of propylene glycol and olive oil was successfully employed for delivery of DMN through transdermal route with good permeability and prolonged release time that can be highly beneficial in treating motion sickness in unusual circumstances.

Statistically optimized pentazocine loaded microsphere for the sustained delivery application: Formulation and characterization.

Pentazocine (PTZ) is a narcotic analgesic used to manage moderate to severe, acute and chronic pains. In this study, PTZ loaded Ethyl cellulose microsphere has been formulated for sustained release and improved bioavailability of PTZ. These microspheres were fabricated by oil in water emulsion solvent evaporation technique. A three factorial, three levels Box-Behnken design was applied to investigate the influence of different formulation components and process variables on the formulation response using the numeric approach through the design expert® software. All the formulations were characterized for the morphology, different physicochemical properties and the results were supported with the ANOVA analysis, three dimensional contour graphs and regression equations. The maximum percentage yield was 98.67% with 98% entrapment of PTZ. The mean particle size of the formulations ranges from 50-148µm, which directly relates to the concentration of polymer and inversely proportional to the stirring speed. SEM revealed the spherical shape of PTZ microspheres with porous structures. These are physically, chemically and thermally stable as confirmed through Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD) and thermal gravimetric (TG) analysis respectively. The microspheres provided a sustained release of the PTZ for more than 12 hours, following zero order with fickian and non fickian diffusion. The results indicate that prepared microspheres can be a potential drug delivery system (DDS) for the delivery of PTZ in the management of pains.

Antidiarrheal and Cardio-Depressant Effects of Himalaiella heteromalla (D.Don) Raab-Straube: In Vitro, In Vivo, and In Silico Studies.

Himalaiella heteromalla (D.Don) Raab-Straube is a commonly used remedy against various diseases. Crude extract and fractions of H. heteromalla were investigated for a gastrointestinal, bronchodilator, cardiovascular, and anti-inflammatory activities. H. heteromalla crude extract (Hh.Cr) relaxed spontaneous contractions and K+ (80 mM)-induced contraction in jejunum tissue dose-dependently. The relaxation of K+ (80 mM) indicates the presence of Ca++ channel blocking (CCB) effect, which was further confirmed by constructing calcium response curves (CRCs) as they caused rightward parallel shift of CRCs in a manner comparable to verapamil, so the spasmolytic effect of Hh.Cr was due to its CCB activity. Application of Hh.Cr on CCh (1 µM) and K+ (80 mM)-induced contraction in tracheal preparation resulted in complete relaxation, showing its bronchodilator effect mediated through Ca++ channels and cholinergic antagonist activity. Application of Hh.Cr on aortic preparations exhibited vasorelaxant activity through angiotensin and α-adrenergic receptors blockage. It also showed the cardio suppressant effect with negative chronotropic and inotropic response in paired atrium preparation. Similar effects were observed in in vivo models, i.e., decreased propulsive movement, wet feces, and inhibition of edema formation.

Biodistribution and histopathology studies of amphotericin B sodium deoxycholate sulfate formulation following intratracheal instillation in rat models.

Aerosol inhalation of amphotericin B (AmB) can be a clinically compliant way to administer the drug directly to the pulmonary route for treatment as well as prophylaxis of invasive pulmonary aspergillosis (IPA). We report aerosol formulation of AmB using sodium deoxycholate sulfate (SDCS), a lipid carrier synthesized in-house using natural precursor deoxycholic acid. In vitro toxicity was determined by MTT assay. Biodistribution and histopathology in rats were evaluated in targeted organs including the lungs, kidneys, spleen, and liver. No toxicity was observed when lung and kidney cells treated with AmB-SDCS formulations up to 8 µg/mL and minimal toxicity at higher concentration 16 µg/mL, while the Fungizone®-like formulation induced toxicity to lung and kidney cells with viability decreasing from 86 to 41% and 100 to 49%, respectively, when compared with an equivalent concentration of AmB-SDCS. Renal and hepatic markers were raised for Fungizone®-like formulation-treated rats but not for AmB-SDCS formulations following 7 days of regular dosing by intratracheal instillation. AmB concentrations were highest in the lungs (5.4-8.3 µg/g) which were well above minimum inhibitory concentration (MIC) of all Aspergillus species. Plasma concentration was also above MIC (> 2 µg/mL) for all AmB-SDCS formulations in comparison with Fungizone®-like formulation. No evidence of abnormal histopathology was observed in the lungs, liver, spleen, and kidneys for all AmB-SDCS formulations but was observed for the group treated with Fungizone®-like formulation. It is concluded that AmB-SDCS formulations can be efficiently administered via intratracheal instillation with no evidence of toxicity and may find great value in the treatment as well as prophylaxis of IPA through inhalation route.