A novel synthetic derivative of biaryl guanidine as a potential BACE1 inhibitor, to treat Alzheimer's disease: In-silico, in-vitro and in-vivo evaluation.

BACE1 enzyme has been known a potential target involved in Alzheimer's disease (AD). Present research was focused on the principles of virtually screening, chemical synthesis and protease inhibitory effect of BACE1 enzyme via biaryl guanidine derivatives. In-silico based paradigm (ligand binding interaction within active domain of BACE 1 enzyme i.e., aspartate Asp32 and Asp228) a novel compound was synthesized and subsequently subjected to in-vitro and in-vivo evaluation. 1,3-di(isoquinolin-6-yl) guanidine was synthesized and found potent (IC50 6±0.56 µM) and active to arrest (99 %) ß-secretase enzyme (FRET assay). Furthermore, it was found to improve novel object recognition test (RTI =56.55%) and Morris water maze test (32.26±3.45s) significantly (p<0.05). Enhanced pharmacokinetics and related properties (high iLOGP and Log S =-3.98) along with improved permeation to the blood brain barrier (BBB) (zero Lipinski violation) made it feasible to inhibit BACE1 as a novel therapeutic source to treat AD in future.

Evaluation of different Pakistani medicinal plants for inhibitory potential against Echis carinatus induced Phospholipase A2 toxicity.

Medicinal plants of Pakistan are known for their curative properties against snake bite as rural people have been using natural herbs for such injuries for hundreds to thousands of years. People of rural areas of Pakistan are prone to snakebite, and on the whole death due to snakebite has been increasing worldwide. The objective of this study was to test the neutralizing potential of 17 Pakistani medicinal plant extracts against phospholipase A2 activity in Echis carinatus venom. Plant material was extracted by simple maceration and fractionation of active plant extracts. Venom was collected by manual massage of the venom glands. The PLA2 enzymatic assay was performed to map out the venomous activity of Echis carinatus envenomation. Snake venom released fatty acids at different concentrations (0.1-5 mg/ml) of venom in a dose-dependent manner. Reduction of pH by 01 correlated with 133 µmol of fatty acids released at 5mg/ml of venom. All plants extract inhibited PLA2 activity, however, Curcuma longa, Citrullus colocynthis and Rubia cordifolia inhibited maximum of PLA2 activity (⁓78%) comparable to the standard antidote (p>0.5). Medicinal plants possess secondary metabolites and many active compounds that may have neutralizing or inhibiting properties against the PLA2 activity of Echis venom. Further studies such as compound analysis could provide an alternative against snakebites injuries resulting from Echis carinatus venom.

FORMULATION AND STABILITY EVALUATION OF BAUHINIA VARIEGATA EXTRACT TOPICAL EMULSION.

This study presents the results for the development of water in oil (W/O) emulsion containing 2 % Bauhinia variegata (BV) extract with good antioxidant potential for cosmetic application. Different ratios of surfactant, oil and water were investigated to optimize the ratio of ingredients. It was found that emulsifier and oil4ratio were important in improving the stability of emulsion. The formulation having 2.5% Abil EM90, 12% liquid paraffin, 83.5% distilled water and 2% BV extract was found to be most stable. Stability of the formulation was further evaluated by characterizing for organoleptic, sedimentation, microscopic and rheological properties at a range of storage conditions for a period of 12 weeks. Experimental findings showed stable formulation behavior with respect to color change, liquefaction and phase separation. Centrifugation test was carried out to predict the long term stability..The rheological parameters were evaluated from Power Law and the flow index value less than 1 suggested non-Newtonian behavior of the W/O emulsion. The mean droplet size of the internal phase of freshly prepared formulation was 4.06 ? 1.99 pm that did not change significantly (p > 0.05) during the storage. The newly developed formulation exhibited promising attributes over long term storage and open opportunities for the topical delivery of natural antioxidants for cosmetic and pharmaceutical objectives.

Suitability of Gelucire 50/13 for controlled release formulation of salbutamol sulphate.

Gelucire 50/13 (G50/13) was assessed to develop controlled release formulation of salbutamol sulphate (SBL) a highly water soluble drug by semisolid matrix filling capsule technique. Drug release profiles of SBL release by using G50/13 and its blends with other hydrophilic or hydrophobic materials were investigated. Lipid matrix formulations prepared with increasing amount of polymer showed a substantial decrease in release rate of the drug while increasing drug amount in fixed polymer concentration did not significantly affect the release profile. Polyethylene glycol 6000 caused an increased water uptake resulting in fast erosion of the matrix whereas cetostearyl alcohol and stearic acid caused retardation in drug release. These findings confirm that a considerable amount of Gelucire is required alone or in combination with hydrophobic substances in order to sustain the release profiles of water soluble drugs. More linear profile was obtained by using matrix comprising Gelucire/stearic acid blend in more than 85% that was comparable to standard, Ventolin SR tablet. The test formulation showed a significant decrease at pH 1.0 and the drug release rate increased at high stirring speed. Moreover, short term stability of controlled release test formulation indicated slight increase in dissolution rate at high temperature.

Chitosan/guar gum-based thermoreversible hydrogels loaded with pullulan nanoparticles for enhanced nose-to-brain drug delivery.

The biopolymers-based two-fold system could provide a sustained release platform for drug delivery to the brain resisting the mucociliary clearance, enzymatic degradation, bypassing the first-pass hepatic metabolism, and BBB thus providing superior bioavailability through intranasal administration. In this study, poloxamers PF-127/PF-68 grafted chitosan HCl-co-guar gum-based thermoresponsive hydrogel loaded with eletriptan hydrobromide laden pullulan nanoparticles was synthesized and subjected to dynamic light scattering, Fourier transform infrared spectroscopy, thermal analysis, x-ray diffraction, scanning electron microscopy, stability studies, mucoadhesive strength and time, gel strength, cloud point assessment, rheological assessment, ex-vivo permeation, cell viability assay, histology studies, and in-vivo Pharmacokinetics studies, etc. It is quite evident that CSG-EH-NPs T-Hgel has an enhanced sustained release drug profile where approximately 86 % and 84 % of drug released in phosphate buffer saline and simulated nasal fluid respectively throughout 48 h compared to EH-NPs where 99.44 % and 97.53 % of the drug was released in PBS and SNF for 8 h. In-vivo PKa parameters i.e., mean residence time (MRT) of 11.9 ± 0.83 compared to EH-NPs MRT of 10.2 ± 0.92 and area under the curve (AUCtot) of 42,540.5 ± 5314.14 comparing to AUCtot of EH-NPs 38,026 ± 6343.1 also establish the superiority of CSG-EH-NPs T-Hgel.

Chitosan based thermosensitive injectable hydrogels for controlled delivery of loxoprofen: development, characterization and in-vivo evaluation.

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.

Naproxen release from sustained release matrix system and effect of cellulose derivatives.

The present study was conducted to investigate the low viscosity grades of hydroxypropylmethyl cellulose (HPMC) and ethyl cellulose (EC) in sustaining the release of water insoluble drug, naproxen from the matrix tablets. Both HPMC and EC were incorporated in the matrix system separately or in combinations by wet granulation technique. In vitro dissolution studies indicated that EC significantly reduced the rate of drug release compared to HPMC in 12 hour testing time. But, no significant difference was observed in the release profiles of matrix tablets made by higher percentages of EC. The tablets prepared with various combinations of HPMC and EC also failed to produce produce the desired release profiles. However, comparatively linear and desirable sustained release was obtained from EC-based matrix tablets prepared by slightly modifying the granulation method. Moreover, two different compression forces used in tableting had no remarkable effect on the release profile of naproxen.

Ethyl cellulose-based solid matrix system for sustaining release of naproxen.

The present study was conducted to develop sustained release matrix tablets of naproxen with the help of a hydrophobic polymer, Ethyl Cellulose (EC). Matrix tablets were prepared by incorporating various proportions of EC in the matrix system using wet granulation technique. The rate of drug release from the matrix tablets was found to be very slow and could not produce the desired release profiles in 12 h testing time. However, the tablets prepared by slightly modifying the wet granulation method exhibited comparatively linear and desirable release rate. No significant difference in the release profiles of naproxen matrix tablets was observed at different stirring speeds and storage conditions.