Explorations of novel pyridine-pyrimidine hybrid phosphonate derivatives as aurora kinase inhibitors.

For developing novel therapeutic agents with good anticancer activities, a series of novel pyridine-pyrimidine hybrid phosphonate derivatives4(a-q) were synthesized by the Kabachnik-Fields method using CAN as catalyst. The compound 4o exhibited the most potent anticancer activity with an IC50 value of 13.62 µM, 17.49 µM, 5.81 µM, 1.59 µM and 2.11 µM against selected cancer cell lines A549, Hep-G2, HeLa, MCF-7, and HL-60, respectively. Compound 4o displayed seven times more selectivity towards Hep-G2 cancer cell lines compared to the human normal hepatocyte cell line LO2 (IC50 value 95.33 µM). Structure-Activity Relationship (SAR) studies were conducted on the variation in the aromatic ring (five-membered heterocyclic ring, six-membered heterocyclic ring) and the variation of substituents on the phenyl ring (electron donating groups, electron withdrawing groups). Furthermore, the mechanism of anticancer activity was clarified by further explorations in bioactivity by using in vitro aurora kinase inhibitory activity and molecular docking studies. The results showed that the compound 4o at IC50concentrationdemonstrated distinctive morphological changes such as cell detachment, cell wall deformation, cell shrinkage and reduced number of viable cells in cancer cell lines. Compound 4o induced early apoptosis and late apoptosis of 27.7% and 6.1% respectively.

Helicobacter pylori and cardiovascular complications: a mechanism based review on role of Helicobacter pylori in cardiovascular diseases.

Heart disease comprises a wide class of cardiovascular abnormalities, including ischemic heart disease, myocardial infarction, atherosclerosis, and coronary artery disease. It is the leading cause of death all over the world. Several traditional and novel risk factors, such as infectious and noninfectious agents, have been associated with heart disease. Out of these, Helicobacter pylori has been recently introduced as an important etiological factor for heart disease. Numerous seroepidemiological findings observed H. pylori antibodies in the blood of a patient with cardiovascular complications. The bacteria survive in the epithelial cells of gastric organs and cause digestive complications. Excess inflammatory pathogenesis and prognosis stimulate an immune response that further causes significant disturbances in various factors like cytokines, fibrinogen, triglycerides, high density lipoprotein, C-reactive protein, heat shock protein, and white blood cell count, and provoke a number of problems such as atherosclerosis and prothrombic state, and cross-reactivity which eventually leads to heart diseases. H. pylori releases toxigenic nutrients, chiefly vacuolating cytotoxin gen A (Vac A) and cytotoxin associated gene A (Cag A), of which Cag A is more virulent and involved in the formation of cholesterol patches in arteries, induction of autoimmune disorder, and release of immune mediated response. Although numerous mechanisms have been correlated with H. pylori and heart disease, the exact role of bacteria is still ambiguous.

Fabrication of fenofibrate nanocrystals by probe sonication method for enhancement of dissolution rate and oral bioavailability.

Fenofibrate (FBT) is lipophillic drug used in hypercholesterolemia and hypertriglyceridemia having logP 5.375, low solubility (practically insoluble in water) and low oral bioavailability (36%). The purpose of work was to develop FBT nanocrystals for the enhancement of solubility and oral bioavailability. Fenofibrate nanosuspension was prepared using probe sonicator and transformed into dry powder using freeze drying and characterized by DSC, FTIR, XRPD, SEM, particle size, polydispersity index (PDI), zeta potential, solubility, in vitro dissolution, in vivo bioavailability and stability studies. Formulation FNS3 and pure drug exhibited the in vitro dissolution about 73.89% and 8.53% in 1% sodium lauryl sulfate (SLS) media, respectively. When the particle size reduced from 80,000±923nm to 460±20nm, saturation solubility was significantly increased. The saturation solubility of formulation FNS3 in 0.5% and 1% of SLS media found to be 67.51±1.5µg/mL and 107±1.9µg/mL, respectively. While, the saturation solubility of pure drug in 0.5% and 1% of SLS was found to be 6.02±1.51µg/ml and 23.54±1.54µg/ml, respectively. The pharmacokinetic study of optimized nanocrystals (FNS3) conducted in New Zealand white rabbits showed 4.73-fold increase in relative bioavailability than that of pure drug. Long term stability studies showed that there was no significant change in the mean particle size and PDI at 5°C±3°C after 180 days. This enhanced dissolution and bioavailability of fenofibrate nanocrystals could be the promising approach for oral delivery.

In vitro and in vivo consideration of novel environmentally responsive ophthalmic drug delivery system.

In the present study, novel environmentally responsive ophthalmic drug delivery system composed of two gelling polymers with different phase transition mechanisms was developed in order to obtain sustained drug release in ocular cavity. Combination of polyacrylic acid (carbopol 934P) and xanthan gum was investigated as ophthalmic vehicle and assessed for its in vitro and in vivo performance. Different ratios of these polymers were used to prepare environmentally responsive ophthalmic drug delivery system by simple mixing procedure. Developed formulation was assessed for physical tests such as appearance/clarity, pH, gelation; and performance characteristics such as drug content, rheological measurement, in vitro release, antimicrobial efficiency, in vivo studies for eye irritation, residence time estimation. Prepared formulation showed agreeable appearance/clarity, acceptable pH and good gelation property. In vitro and in vivo studies demonstrated adequate drug content, desired rheological behavior and reasonable in vitro and in vivo drug release property. In conclusion, the optimum concentration of polymers results in increased residence time and sustained drug release. On the basis of these findings, environmentally responsive system based on combination of carbopol and xanthan gum may be considered as a promising tool for ophthalmic delivery.

Microwave-generated bionanocomposites for solubility and dissolution enhancement of poorly water-soluble drug glipizide: in-vitro and in-vivo studies.

OBJECTIVES: In oral absorption of a drug, the drug first dissolves and then is absorbed by diffusion through gastrointestinal membranes. The gastrointestinal environment is aqueous in nature and it is well-known that one-third of the drug population is water insoluble. Hence, there is a need for enhancement of the solubility and dissolution of such drugs. In this work, enhancement of the solubility and dissolution of the practically insoluble drug glipizide was achieved by formation of bionanocomposites (BNCs) using microwave-induced diffusion (MIND), which ultimately leads to bioavailability enhancement. METHODS: BNCs were formed by using natural carriers such as gelatin, acacia, cassia and ghatti gum, with the help of microwaves. Selection of carriers was based on their surfactant and wetting properties. Solubility studies were carried out to establish the solubility-enhancing property of the BNCs. To support solubility analysis results, dissolution studies (i.e. powder dissolution and in-vitro dissolution) were carried out. The BNCs were characterized by Fourier transform infra-red spectroscopy, differential scanning calorimetry, X-ray diffraction studies, scanning electron microscopy and transmission electron microscopy. In-vivo performance of the optimised formulation was assessed by glucose-induced hyperglycaemia test in male albino Wistar rats. KEY FINDINGS: It was found that as the concentration of polymer in the composite increased the solubility and dissolution of glipizide were enhanced. The optimised ratio (drug : polymer) for all the composites was found to be 1:9. In the glucose-induced hyperglycemia test in rats, the optimized formulation demonstrated a significant reduction in hyperglycemia compared with a marketed formulation, Glynase. CONCLUSIONS: The novelty of this work is the green and cost-effective way of forming drug nanocomposites with the help of microwave, which can be scaled up to an industrial level. The method gives an immaculate means of solubilisation by generating drug dispersion at the micro and nanoscale level in natural biodegradable stabilising media. Hence, this study demonstrates the use of BNCs in solubility and dissolution enhancement.

Formulation and evaluation of bilayer tablets of metoclopramide hydrochloride and diclofenac sodium.

The main objective of the present research work was to develop a bilayer tablet of metoclopramide hydrochloride (MTH) and diclofenac sodium (DS) in separate layers to avoid incompatibility and thus to maximize the efficacy of both drugs in combination for the effective treatment of migraine headaches. MTH and DS were formulated as immediate and sustained release layers respectively. In vitro dissolution kinetic studies of an optimized (D10) batch of DS in both sustained release layer and bilayer tablet forms show good linearity of regression coefficient 0.9773 (first order equation). The results reveal that an optimized immediate release layer (M5) of MTH and a sustained release layer (D10) of DS might be suitable for the treatment of migraine by sequential release of the two drugs in a bilayer tablet. LAY ABSTRACT: Migraine is a type of recurring headache of moderate to severe intensity associated with gastrointestinal, neurological, and autonomic symptoms. In migraine, a combination of pretreatment with antiemetics is required for symptomatic treatment, when nausea and vomiting are severe. In our present research, we have selected the metoclopramide hydrochloride (MTH) active ingredient for study because it has an antiemetic effect and is a prokinetic agent. MTH is more effective to counteract gastric stasis associated with migraine, and it enhances the rate of absorption of non-steroidal anti-inflammatory drugs (NSAIDs). In the present investigation we combine MTH and a second active ingredient, diclofenac sodium, as a formulated bilayer tablet to prevent degradation of MTH.

Identification and development of 2,5-disubstituted oxadiazole as potential candidate for treatment of XDR and MDR tuberculosis.

Tuberculosis, the infection on the verge of eradication once, is now a great threat to mankind. Emergence of MDR and XDR-TB synergised with HIV and other immune-compressive diseases have increased the life threatening capacities of the disease. A small molecule has been identified here, which showed potent anti-tubercular activity. The identified hit compound has also been proved active against nearly 25 clinical isolates comparable with isoniazid.

A novel hydrogel plug of Sterculia urens for pulsatile delivery: in vitro and in vivo evaluation.

The objective of this study was to investigate a novel hydrogel plug using isolated root mucilage of Sterculia urens to obtain a desired lag time for an oral chronotherapeutic colon-specific pulsatile drug delivery of indomethacin. Pulsatile drug delivery was developed using chemically treated hard gelatin capsule bodies filled with eudragit multiparticulates of indomethacin, and sealed with different hydrogel plugs (root mucilage of S. urens, xanthan gum, guar gum, HPMC K4M and combination of maltodextrin with guar gum). Indomethacin multiparticulates were prepared using extrusion spheronization, spray drying and solvent evaporation techniques with Eudragit® L-100 and S-100 (1:2) by varying drug-to-polymer ratio. After oral administration, the water-soluble cap of capsule dissolved in the intestinal fluid and the hydrogel plug swells. After a controlled time, the swollen plug subsequently ejected from the dosage form, releases the contents of the capsule. The formulation factors affecting the drug release were concentration and types of hydrogel plug used. In vivo gamma scintigraphy study in healthy rabbits proved the capability of the system to release drug in lower parts of the gastrointestinal tract after a programmed lag time. This study demonstrates that the indomethacin multiparticulates could be successfully colon-targeted by the design of time and pH-dependent modified chronopharmaceutical formulation. In conclusion, the investigated novel hydrogel plug could be a valuable tool for achieving desired lag time.

Enhancement of oral bioavailability of atorvastatin calcium by self-emulsifying drug delivery systems (SEDDS).

The aim of the present study was to formulate a self-emulsifying drug delivery system of atorvastatin calcium and its characterization including in vitro and in vivo potential. The solubility of atorvastatin calcium was determined in various vehicles such as Captex 355, Captex 355 EP/NF, Ethyl oleate, Capmul MCM, Capmul PG-8, Gelucire 44/14, Tween 80, Tween 20, and PEG 400. Pseudoternary phase diagrams were plotted on the basis of solubility data of drug in various components to evaluate the microemulsification region. Formulation development and screening was carried out based on results obtained from phase diagrams and characteristics of resultant microemulsion. Prepared formulations were tested for microemulsifying properties and evaluated for clarity, precipitation, viscosity determination, drug content and in vitro dissolution. The optimized formulation further evaluated for particle size distribution, zeta potential, stability studies and in vivo potential. In vivo performance of the optimized formulation was evaluated using a Triton-induced hypercholesterolemia model in male Albino Wistar rats. The formulation significantly reduced serum lipid levels as compared with atorvastatin calcium. Thus studies illustrated the potential use for the delivery of hydrophobic drug such as atorvastatin calcium by oral route.

Development of colon targeted multiparticulate pulsatile drug delivery system for treating nocturnal asthma.

The aim of the present study was to develop theophylline fast release enteric-coated pellets as a pulsatile drug delivery to the colon. The novelty of this work is the combination of pH and time-dependant enteric polymers as a single coating for the development of multiparticulate formulation. Theophylline pellets were optimized by applying a 2-factors 3-levels full factorial design. Continuous dissolution studies were carried out in simulated gastric, intestinal, and colonic fluid with pH 1.2 (0.1 N HCl), pH 7.4 and pH 6.8 (phosphate buffer), respectively. The lag time prior to the drug release was highly affected by combination of two factors, i.e. the percentage of Eudragit RL100 in polymer mixture and coating level. The formulation containing Eudragit RL100 and Eudragit S100 with a ratio of 4:1 and coating level of 12%w/w was found to be optimum. The results of serum study in New Zealand rabbits showed that the developed formulation provided a significant lag phase of 5 h. The present study demonstrates that the theophylline enteric-coated pellets could be successfully colon targeted by the design of pH- and time-dependant modified chronopharmaceutical formulation. In conclusion, pulsatile drug release over a period of 3-12 h is consistent with the requirements for chronopharmaceutical drug delivery.

Development and evaluation of a pulsatile drug delivery system using novel polymer. Part II: in vivo radio imaging study.

The objective of the present study was to correlate the results of the in vitro release of a previously reported pulsatile drug delivery system with the in vivo radio imaging study. The formulated drug delivery system containing pellets of barium sulphate was administered to rabbits after overnight fast. Formulated dosage form, previously evaluated for in vitro drug release study, showed drug release after 6-10 h of lag time depending on the hardness as well as the thickness of the plug. Radio imaging study also showed that the plug in the capsule drug delivery system remains intact for the period of 6 h. Thus, the formulated drug delivery system is capable of delaying release in vitro as well as in rabbits for 6 hours.

Formulation and evaluation of a pulsatile drug delivery system using time- and pH-dependant polymers.

The aim of the present study was to develop fast-release enteric-coated tablets for pulsatile drug delivery to the colon. The novelty of this work is a combination of pH- and time-dependant enteric polymers as a single coating. Eudragit S100 was used as a pH-dependant polymer and eudragit RL100 was used as a time-dependant polymer. Theophylline was taken as a model drug. Dissolution studies of enteric-coated tablets were performed with different media having a pH of 1.2, 7.4, and 6.8. Results of the dissolution data show that drug release in the colon could be controlled by using eudragit RL100 eudragit S100. The lag time prior to the drug release was highly affected by a combination of two factors: The percentage of eudragit RL100 and coating level. The optimum formulation was found to be one containing eudragit RL100 and eudragit S100 with a ratio of 60:40 of polymer and coating level of 4.66% w/w. The present study demonstrates that the theophylline enteric-coated tablets could be successfully formulated as a pulsatile drug delivery by the design of a time- and pH-dependant modified chronopharmaceutical formulation. In conclusion, pulsatile drug release over a period of 2-12 hours, consistent with the requirements for chronopharmaceutical drug delivery, can be achieved by using time- and pH-dependant polymers.

Nasal administration of ondansetron using a novel microspheres delivery system Part II: ex vivo and in vivo studies.

Gellan gum-based mucoadhesive microspheres of ondansetron hydrochloride for intranasal systemic delivery were prepared to avoid first pass effect, an alternative route of administration to injection and to enhance systemic bioavailability of ondansetron hydrochloride. The microspheres were prepared using spray method. The evaluation results of microspheres were reported in our previous study. The aim of this work was to study the in vivo performance of mucoadhesive microspheres in comparison with oral and intravenous preparations of ondansetron hydrochloride. The nasal delivery system gave increased AUC(0-240) and C(max) as compared to those of oral delivery. In conclusion, the gellan gum-based microsphere formulation of ondansetron hydrochloride with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.

Formulation and evaluation of nasal mucoadhesive microspheres of sumatriptan succinate.

The purpose of present research work was to develop mucoadhesive microspheres for nasal delivery with the aim to avoid hepatic first-pass metabolism, improve therapeutic efficacy and enhance residence time. For the treatment of migraine, hydroxypropyl methylcellulose (HPMC) K4M and K15M based microspheres containing sumatriptan succinate (SS) were prepared by spray-drying technique. The microspheres were evaluated with respect to the yield, particle size, incorporation efficiency, swelling property, in vitro mucoadhesion, in vitro drug release, histological study and stability. Microspheres were characterized by differential scanning calorimetry, scanning electron microscopy and X-ray diffraction study. It was found that the particle size, swelling ability and incorporation efficiency of microspheres increases with increasing drug-to-polymer ratio. HPMC-based microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. On the basis of these results, SS microspheres based on HPMC may be considered as a promising nasal delivery system.

Nasal administration of ondansetron using a novel microspheres delivery system.

Gellan gum microspheres of ondansetron hydrochloride, for intranasal delivery, were prepared to avoid the first pass metabolism as an alternative therapy to parentral, and to improve therapeutic efficiency in treatment of nausea and vomiting. The microspheres were prepared using conventional spray-drying method. The microspheres were evaluated for characteristics like particle size, incorporation efficiency, swelling ability, zeta potential, in-vitro mucoadhesion, thermal analysis, XRD study and in-vitro drug release. Treatment of in-vitro data to different kinetic equations indicated diffusion controlled drug delivery from gellan gum microspheres. The results of DSC and XRD studies revealed molecular amorphous dispersion of ondansetron into the gellan gum microspheres.

Chitosan-chondroitin sulfate based matrix tablets for colon specific delivery of indomethacin.

The different approaches for targeting orally administered drugs to the colon include coating with pH-dependent polymers, design of time-release dosage forms, and the utilization of carriers that are degraded exclusively by colonic bacteria. The aim of the present study was to develop a single unit, site-specific drug formulation allowing targeted drug release in the colon. Matrix tablets were prepared by wet granulation using cross-linked chitosan (ChI) and chondroitin sulfate (ChS) polysaccharides as binder and carrier. ChS was used to form polyelectrolyte complexes (PEC) with ChI, and its potential as a colon-targeted drug carrier was investigated. Indomethacin was used as a model drug. The ChI and ChS PEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction studies (XRD). The matrix tablets were tested in vitro for their suitability as colon-specific drug delivery systems. FTIR demonstrated that the PEC forms through an electrostatic interaction between the protonated amine (NH(3)(+) group of ChI with the free carboxylate (COO(-)) group and sulfate (SO(4)(2-)) group of ChS. DSC and XRD indicated that the PEC has different thermal characteristics from ChI or ChS. The dissolution data demonstrates that the dissolution rate of the tablet is dependent upon the concentration of polysaccharide used as binder and matrix and time of cross-linking. The study confirmed that selective delivery of indomethacin to the colon can be achieved using cross-linked ChI and ChS polysaccharides.

Development and evaluation of pulsatile drug delivery system using novel polymer.

The aim of the present investigation was to develop a pulsatile drug delivery system based on an insoluble capsule body filled with theophylline microspheres and sealed with a swellable novel polymer plug isolated from the endosperm of seeds of higher plant Delonix regia family-Fabaceae. Theophylline microspheres were prepared by solvent evaporation method using Eudragit S 100. The swellable plugs of varying thickness and hardness were prepared by direct compression, which were then placed in the capsule opening. The drug delivery system was designed to deliver the drug at such a time when it was needed most to offer convenience to the chronic patients of asthma. Formulated dosage forms were evaluated for an in vitro drug release study, which showed that the release might be consistent with a release time expected to deliver the drug to the colon depending on the thickness and hardness of the hydrogel plug. Thus, thickness and hardness of the novel polymeric plug plays an important role in controlling the drug release from the formulated drug delivery system.

Formulation and evaluation of in situ gelling system of dimenhydrinate for nasal administration.

Nasal drug delivery has a variety of advantages. Drugs can be rapidly absorbed through the nasal mucosa, giving rapid onset of action, and avoiding presystemic metabolism. In present study; the nasal mucoadhesive in situ gels of anti-emetic drug Dimenhydrinate were formulated using Gellan gum and Carbopol 934P. The in situ gels so prepared were characterized for gelation, viscosity, gel strength, mucoadhesion, drug content, drug diffusion, ex vivo permeation and histopathological studies. The optimized formulation passing from above tests was further subjected to accelerated stability study. It retained the good stability over the period of 90 days. From the overall performance this in situ gel seems to be an effective delivery system for the nasal route.