Design and Comparative Evaluation of In-vitro Drug Release, Pharmacokinetics and Gamma Scintigraphic Analysis of Controlled Release Tablets Using Novel pH Sensitive Starch and Modified Starch- acrylate Graft Copolymer Matrices.

The present investigation deals with the development of controlled release tablets of salbutamol sulphate using graft copolymers (St-g-PMMA and Ast-g-PMMA) of starch and acetylated starch. Drug excipient compatibility was spectroscopically analyzed via FT-IR, which confirmed no interaction between drug and other excipients. Formulations were evaluated for physical characteristics like hardness, friability, weight variations, drug release and drug content analysis which satisfies all the pharmacopoeial requirement of tablet dosage form. Release rate of a model drug from formulated matrix tablets were studied at two different pH namely 1.2 and 6.8, spectrophotometrically. Drug release from the tablets of graft copolymer matrices is profoundly pH-dependent and showed a reduced release rate under acidic conditions as compared to the alkaline conditions. Study of release mechanism by Korsmeyer's model with n values between 0.61-0.67, proved that release was governed by both diffusion and erosion. In comparison to starch and acetylated starch matrix formulations, pharmacokinetic parameters of graft copolymers matrix formulations showed a significant decrease in Cmax with an increase in tmax, indicating the effect of dosage form would last for longer duration. The gastro intestinal transit behavior of the formulation was determined by gamma scintigraphy, using (99m)Tc as a marker in healthy rabbits. The amount of radioactive tracer released from the labelled tablets was minimal when the tablets were in the stomach, whereas it increased as tablets reached to intestine. Thus, in-vitro and in-vivo drug release studies of starch-acrylate graft copolymers proved their controlled release behavior with preferential delivery into alkaline pH environment.

Preparation and characterization of pH-sensitive methyl methacrylate-g-starch/hydroxypropylated starch hydrogels: in vitro and in vivo study on release of esomeprazole magnesium.

In the present study, novel hydrogels were prepared through graft copolymerization of methyl methacrylate onto starch and hydroxypropylated starch for intestinal drug delivery. The successful grafting has been confirmed by FTIR, NMR spectroscopy, and elemental analysis. Morphological examination of copolymeric hydrogels by scanning electron microscopy (SEM) confirms the macroporous nature of the copolymers. The high decomposition temperature was observed in thermograms indicating the thermal stability of the hydrogels. To attain a hydrogel with maximum percent graft yield, the impact of reaction variables like concentration of ceric ammonium nitrate as initiator and methyl methacrylate as monomer were consistently optimized. X-ray powder diffraction and differential scanning calorimetric analysis supported the successful entrapment of the drug moiety (esomeprazole magnesium; proton pump inhibitor) within the hydrogel network. Drug encapsulation efficiency of optimized hydrogels was found to be >78%. Furthermore, swelling capacity of copolymeric hydrogels exhibited a pH-responsive behavior which makes the synthesized hydrogels potential candidates for controlled delivery of medicinal agents. In vitro drug release was found to be sustained up to 14 h with 80-90% drug release in pH 6.8 solution; however, the cumulative release was 40-45% in pH 1.2. The gastrointestinal transit behavior of optimized hydrogel was determined by gamma scintigraphy, using (99m)Tc as marker. The amount of radioactive tracer released from the labeled hydrogel was minimal when the hydrogel was in the stomach, whereas it increased as hydrogel reached in intestine. Well-correlated results of in vitro and in vivo analysis proved their controlled release behavior with preferential delivery into alkaline pH environment.

Synthesis, cytotoxic evaluation, docking and in silico pharmacokinetic prediction of 4-arylideneamino/cycloalkylidineamino 1, 2-naphthoquinone thiosemicarbazones.

In an attempt to develop potent anticancer agents, a series of 4-arylideneamino/cycloalkylidineamino-1, 2-naphthoquinone thiosemicarbazones were synthesized and characterized using FT-IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis. The compounds were screened for antiproliferative activity against three human cancer cell lines (Hep-G2, MG-63 and MCF-7) using the MTT assay. Significant anticancer activity was observed for several members of the series. The compounds 4-(3, 4, 5-trimethoxybenzylidene amino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS10) and 4-(4-hydroxy-3-methoxy benzylideneamino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS13) were active cytotoxic agents in all three cancer cell lines, with IC50 values in the range of 3.5-6.4 µM. Further evaluation of some of these potent cytotoxic compounds demonstrated their good safety profile in a normal cell line (MCF-12A). Docking experiments showed a good correlation between the predicted glide scores and the IC50 values of these compounds. In silico ADME studies revealed that these compounds can be used for second generation development.

Synthesis, characterization, biological evaluation and docking of coumarin coupled thiazolidinedione derivatives and its bioisosteres as PPARγ agonists.

Thiazolidinedione (TZD) derivatives are the novel class of oral antidiabetic drugs which are selective agonist for the nuclear PPAR γ that enhances the transcription of several insulin responsive genes but TZDs are known to cause weight gain, hepatotoxicity and fluid retention. So a new series of coumarin coupled thiazolidinedione derivatives and its bioisosters (oxazolidinedione and imidazolidinedione) were synthesized by Knoevenagel condensation of 4-((7-hydroxy-2-oxo-2H-chromen-4-yl) methoxy) benzaldehyde with 2,4 thiazolidinedione and its bioisosteres. The structures of these compounds were established by means of FT IR, 1H-NMR, elemental analysis and mass spectroscopy. All the compounds were screened for antidiabetic activity in streptozotocin induced diabetic wistar male rats. Most of the compounds revealed significant antidiabetic activity when compared with the standard drug rosiglitazone. Compounds 5 & 6 containing oxazolidinedione ring system were found to be more active than compounds having thiazolidinedione and imidazolidinedione nucleus. Molecular docking was performed on 2 PRG protein by using the software Glide (Schrödinger, LLC, USA). The QikProp program was used to obtain the pharmacokinetic properties of analogues.

Synthesis, Molecular docking and Biological evaluation of 4-Cycloalkylidineamino 1, 2-Naphthoquinone Semicarbazones as Anticancer agents

Objective: In an effort to etablish new candidates with improved antineoplastic activity, 4-cycloalkylidineamino 1,2-naphthoquinone semicarbazones were synthesized, characterized and evaluated for anticancer activity. Method: The desired compounds were synthesized by condensation of 4- amino1, 2-naphthoquinone with cyclic ketones and further subsequent reaction of this product with semicarbazide hydrochloride. Compounds were characterized by FT-IR, 1H NMR, 13C NMR, elemental analysis and screened for antiproliferative activity against three human cancer cell lines (HepG2, MG-63 and MCF-7) by MTT assay using doxorubicin as standard. Docking was performed by using the Glide 5.7 integrated with Maestro 9.2 (Schr?dinger, LLC, 2011) to understand the binding preference of synthesized compounds with target enzyme topoisomerase-II. Results: 4-(cyclohexylideneamino) [1, 2] naphthoquinone 2-semicarbazone was found to be most active cytotoxic agent against all cancer cell lines with IC50 values in the range of 5.58–6.31 μM. Results of molecular docking were also well correlated in vitro cytotoxicity assay. Insilico ADME studies revealed the drug likeliness of compounds. Conclusions: The synthesized compounds were found to have significant anticancer activity and able to enter in higher phases of the drug development process due to favorable pharmacokinetic properties.