3D QSAR AND DOCKING STUDY OF INDOLE DERIVATIVES AS SELECTIVE COX-2 INHIBITORS

Objective: Non-steroidal anti-inflammatory agents (NSAIDs) continue to be one of the most widely used groups of therapeutic agents. QSAR (quantitative structure-activity relationship) approach is a very useful and widespread technique for drug design. 3D QSAR facilitates evaluation of three-dimensional molecular fields around molecules and generates a relationship of these fields' values with the activity. Methods: 3D QSAR study was performed on selected twenty-four compounds from synthesized indole derivatives using the stepwise variable selection k-nearest neighbor (kNN) molecular field analysis approach for indicating the contribution of the steric and electronic field for activity. The docking study was performed to further confirm the binding affinity of synthesized molecules (ligands) to COX-2 enzyme as well as to study binding nature. Results: Statistically significant model was generated using VLife Molecular Design Suite 3.5 software with cross-validated correlation coefficient q2 of 0.9461 and high predictive correlation coefficient (Pred_r2) of 0.8782 indicating that the model is robust. The results of docking study suggest that the synthesized compounds have a comparable binding affinity with the COX-2 enzyme. Conclusion: The present study may prove to be helpful in the development and optimization of existing indole derivatives as anti-inflammatory agents with selective COX-2 inhibition

In-vitro assessment of CYP3A4 and CYPC29 inhibition potential of Lupeol using human liver microsomes

Background: Lupeol is a dietary triterpene, possesses numerous biological activities. Lupeol is currently under development for chemotherapy and chemoprevention. The aim of present study was to determine the potential inhibitory effect of Lupeol on cytochrome P450 (CYP3A4 and CYP2C9 isozymes) activities in human liver microsomes (HLM). Methods:  The inhibition studies were conducted using testosterone 6β-hydroxylase (CYP3A4), and diclofenac 4’-Hydroxylase (CYP2C9) activity assay using positive control Ketoconazole and Sulphaphenazole, respectively. Inhibition study was performed by incubating lupeol (0 to 20 μM) with human liver microsomes, and the metabolite formation was analyzed by liquid chromatography-Tandem Mass Spectrometry (LC-MS/MS). Results: Luepol did not inhibit CYP3A4 and CYP2C9 isozymes mediated activities in human liver microsomes up to a maximum tested concentration of 20µM based on solubility under tested invitro conditions. Conclusions: Lupeol is not an inhibitor of the CYP3A4 and CYP2C9 isozymes. IC50 is greater than highest tested concentration as well as physiological concentration, where effect was measured with confidence. Therefore, clinically relevant pharmacokinetic herb-drug interactions are unlikely to occur between Lupeol and co-administered substrates of these CYP isozymes. Looking at the spectrum of biological activities and CYP inhibition potential of Lupeol; Lupeol can be used as adjuvant/ chemotherapy agent/ chemopreventive agent in therapy. Keywords: Lupeol, HLM, CYP3A4 and CYP2C9, Inhibition, herb–drug interaction

Development and characterization of biodegradable chitosan nanoparticles loaded with lovastatin using factorial design

The objective of the present work was to formulate chitosan nanoparticles as carriers for the lovastatin, since this drug undergoes extensive first pass extraction in the liver, and bioavailibity is low (< 5 %). Nanoparticles were prepared by modified ionotropic gelation method using 32 full factorial design. From the preliminary trials, the constraints for independent variables X1 (concentration of chitosan) and X2 (concentration of sodium tripolyphosphate) have been fixed and examined to investigate effect on particle size, encapsulation efficiency, zeta potential, % release, SEM, FTIR, XRD and DSC analysis of lovastatin. The diameter of prepared nanoparticles was controlled in the range of 100-800 nm, spherical shape and narrow diameter distribution. The release profiles of all batches were very well fitted by both the zero order model and the anomalous transport. These results indicate that lovastatin nanoparticles could be effective in sustaining drug release for a prolonged period.Colegio de Farmacéuticos de la Provincia de Buenos Aire

DESIGN AND DEVELOPMENT OF FLOATING PULSATILE DRUG DELIVERY OF LOSARTAN POTASSIUM

Objective: The objective of the present investigation was to the development of floating pulsatile drug delivery system of Losartan potassium (LP) tablets for obtaining no drug release during floating followed by pulsed, rapid drug release to achieve chronotherapeutic release. In hypertension, the risk of getting heart attacks early in the morning is high and therefore, there was need to develop drug delivery, which will release drugs at morning hours and provide efficacious therapy. LP is a short biological half-life (1.5-2.5h) and readily absorbed from the stomach and upper gastrointestinal tract. Methods: Tablet formulation was prepared by press coating of rapid release core tablets and core tablets were further top coated with a buoyant layer of HPMC K4M and sodium bicarbonate. Various grades of HPMC polymer (E5/E15/E50) were used for the pulsatile coating layer. The developed formulations were characterized for physical characteristics, floating lag time, floating time, release lag time, drug content, swelling index, in vitro dissolution studies, DSC and XRD. Results: The FTIR and DSC studies predicted that there was no chemical interaction between drug and excipients. The core tablet coated with HPMC E50 showed a high swelling index and release the drug 97.60±1.2% at 6h. Buoyant layer with 80 mg HPMC K4M and 25 mg sodium bicarbonate gave satisfactory floating lag time. Conclusion: The system showed an excellent lag phase followed by burst release in the distal small intestine, which gives site and time-specific delivery of LP acting as per chronotherapy for treatment of hypertension

Vacuum foam dried sugar-phosphate amorphous mixtures for stabilization of doxorubicin hydrochloride

The objective of the present study was to stabilize doxorubicin hydrochloride in sugar-phosphate amorphous mixtures at ambient temperature by drying it with vacuum foam drying. Finished products were evaluated for foam characteristic, residual moisture content, reconstitution time, percent drug recovery and drug-excipient interactions. FTIR studies revealed existence of physical interaction of drug with sugar. Light microscopy showed formation of amorphous glass which was supported by the observations of XRPD analyses. The optimized composition in vacuum foam drying was processed by lyophilization and their stability was compared. Storage at ambient temperature for 6 months showed that stability of vacuum foam dried product was better than lyophilized products. The amount of residual moisture affected the stability of drug. The detailed study revealed lactose and sodium dihydrogen phosphate is best suited for stabilization of doxorubicin hydrochloride at room temperature.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Research Journal of Pharmaceutical, Biological and Chemical Sciences Development and characterisation of oral fast dissolving tablet of nifedipine using camphor as a subliming material

ABSTRACT Mouth fast dissolving drug delivery system has gained high patient acceptability and popularity in the recent times. The aim of this study was to evaluate the effect of increasing nifedipine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anginal pain and hypertension. Nifedipine undergoes first pass metabolism in liver and gut wall which has oral bioavailability of 43-77%. Sublingual dosage form bypasses the metabolism of the nifedipine in liver and offers a fast relieve from anginal pain and hypertension. An attempt has been made to prepare fast dissolving tablets of nifedipine were prepared by wet granulation technique using camphor as subliming agent and sodium starch glycolate together with crosscarmellose sodium as superdisintegrants, flavor and sweetner impart the taste to the formulation. The porous granules were compressed in to tablets by single punch tablet machine. Camphor was sublimed from the tablet by exposing to vacuum drier at 60°c for 12 hrs. All the formulations were evaluated for weight variation, hardness, friability, content uniformity, wetting time, disintegration time and dissolution rate. Among the formulations, (NEF6) one containing to be the best acceptable in terms of palatability, fast dissolving tablet having adequate strength. The disintegration time was found to be 58.0 ± 0.4 seconds, hardness of 3.4 ± 0.41 kg/cm2, wetting time of 39.3 ± 1.80 sec and drug release of 99.96% in 10 mins. All the formulations showed low weight variation. The present study demonstrated potentials for rapid absorption, improved bioavailability, effective therapy and patient compliance

COMPARATIVE IN-VITRO ANTIBACTERIAL AND ANTIFUNGAL ATTRIBUTES OF DIFFERENT SOLVENT EXTRACTS FROM LEAF, BARK, ROOT AND INFLORESCENCE OF MEMECYLON UMBELLATUM BURM.

This paper describes the antibacterial and antifungal activities and Minimum Inhibitory Concentration (MIC) of different solvent (pet. ether, chloroform, ethyl acetate, acetone, methanol and water) extracts of leaves, bark, root and inflorescence of Memecylon umbellatum burm. The percent yields from leaves, bark, root and inflorescence was found to be 0.2062 to 2.836, 0.0601 to 0.5142, 0.050 to 1.425, 0.0210 to 0.717 respectively. Overall, acetone extract produced from the leaves exhibited significantly (P &lt; 0.05) higher antibacterial activity along with superior antifungal activity. MIC for acetone and ethyl acetate extract of leaf was found to be 0.5 mg for the entire organisms compared to 3-15 mg for other extracts. Such study will explore pharmacological activity of the tested parts of Memecylon umbellatum burm especially, the leaves which might be valuable for therapeutic applications

Colorimetric method for simultaneous estimation of amlodipine besylate from plasma

Aim: The present work was to develop the method of analysis which can estimate drug in combined form without prior separation. Materials and method: By using UV spectroscopy colorimetric method was used for determination of Amlodipine besylate (AML) from plasma. Result and conclusion: This method is based on the formation of green colour in reaction between AML and 0.4 % Ferric chloride (FC) and 0.2 % Potassium ferricyanide (PF).The absorbance was measured at 775 nm. Result of tablet analysis showed % S.D. values in the range of 098.22 to 100,63%. Standard deviation value for tablet analysis by using methanol ranging from 98.01 to 101,13 % which proves the ability of the method to remain unaffected by small but deliberate change in reaction conditions and this method is used for estimation of AML from biological samples.Objetivo. El objetivo del presente estudio era desarrollar un método de análisis que permitiera estimar la cantidad de fármaco en forma combinada sin separación previa. Material y Método. Se utilizó espectroscopía colorimétrica UV para la determinación de Amlodipino Besilato (AML) plasmático Resultados. El presente método está basado en la formación de color verde en la reacción entre Amlodipino Besilato (AML) y cloruro férrico 0,4% y ferrocianuro potásico 0,2%. La medida de la absorbancia se realizó a 775nm. El resultado del análisis de los comprimidos mostró unos valores de DE comprendidos entre 098,22 y 100,63%. El valor de la DE utilizando metanol oscilan entre 98,01 y 101,13% lo que demuestra la capacidad del método de permanecer inalterado por pequeños pero intencionados cambios en las condiciones de la reacción, este método es usado para la estimación de Amlodipino Besilato (AML) en muestras biológicas

Phytochemical screening and In Vitro Antioxidant potential of Memecylon umbellatum Burm leaf extracts

Objective: Different dry extracts of Memecylon umbellatum Burm leaf obtained by various solvents such as petroleum ether, chloroform, ethyl acetate, acetone, methanol and chloroform water (IP) was screened to reap the benefits of its antioxidant and free radical scavenging properties using ascorbic acid as standard antioxidants. Methods: The in vitro free radical scavenging activity was evaluated using diphenyl picryl hydrazyl (DPPH) radical method using various concentrations of dry extract in distilled water (1, 2, 4, 8, 16, 20 μg/ml) against blank with ascorbic acid as a standard in same concentrations. Results: Among the all extracts, Methanol leaf extract has showed higher Antioxidant activity (84.65 ± 0.064 %) having IC50 Value 11.81 ± 0.033 μg/ml at 20 μg/ml. While, IC50 value for ascorbic acid was found to be 8.91 ± 0.084 μg/ml. Conclusion: The results clearly indicate that Methanol leaf extract of Memecylon umbellatum is effective in free radical scavenging. So in future, this may emerge as promising natural herbal source of powerful antioxidant. Keywords: Memecylon umbellatum, DPPH reagent, Antioxidant activity, Ascorbic acid, IC50

A NOVEL RP-HPLC GRADIENT ELUTION TECHNIQUE FOR BIOANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR ESTIMATING GALLIC ACID IN WISTAR RAT PLASMA

Objective: Present study aimed to develop and validate a novel, unique, simple, quick, cost-effective, sensitive, specific, accurate, precise, rugged, and robust bioanalytical method for the quantification of gallic acid in rat plasma by reverse phase high performance liquid chromatography (RP-HPLC) using gradient elution technique. Methods: The stationary phase was a Zorbax SB C18 5 µ (4.6*150) mm column, with the mobile phase being water with 0.1 percent formic acid (A): acetonitrile (ACN) with 0.08 percent formic acid (B). Gradient chromatographic method was used throughout this experiment from the point of view of estimation of gallic acid from herbal formulations when present along with other phytoconstituents. So at gradient method all the present phytoconstituents has cleared off from the column and no any strongly adsorption of phytoconstituents occurred. The experiment was carried out at a flow rate of 1.0 ml/min at 30°C utilising PDA detectors at 271 nm. The proposed method was validated for different parameters.  Results: The approach was found to be linear in the concentration range of 0.5-100 µg/ml, with a r2 of 0.9998. There was not observed any interference of co-eluting peaks of endogenous compounds from biological matrix at the same retention time (Rt) of gallic acid. The RSD (%) of intra and interday precision was found to be within acceptable limit. The overall % mean recovery was found to be 99.97%. LOD and LLOQ were found to be 0.1 and 0.5 μg/ml, respectively. In terms of fluctuation in essential parameters and operating settings, the devised bioanalytical approach was shown to be rugged and resilient. Short-term, long-term, auto sampler, bench-top, and freeze-thaw stability experiments revealed that gallic acid is stable. Conclusion: The developed method described in this report was found to be well within an acceptable range. Hence, in the future, this method can be used successfully for the estimation of gallic acid alone or in combination with another analyte or marker present in bulk or an extract containing various phytoconstituents in pharmacokinetic, bioequivalence, and therapeutic drug monitoring studies in clinical laboratories