This work deals with the formulation of ocular niosomal in-situ gel of Ketorolac tromethamine for improved bioavailability. Ketorolac tromethamine loaded niosomes were prepared by thin film hydration method using cholesterol and different surfactants. Niosomal in-situ gel was prepared using HPMC (K15M) and Carbopol (934P) to maintain the drug localization for extended period of time. The niosomes formulations were characterized for vesicle size, entrapment efficiency and in-vitro release and niosomal in-situ gel were evaluated for visual appearance, clarity, pH measurement, drug content measurement, rheological study, and stability testing. Niosomal vesicles were discrete and spherical in shape, 2.09µm-5.59µm in size, 19.32%-53.06% entrapment efficiency and showed sustained release behavior. The formulation F10 shows the highest entrapment efficiency with 53.06%. Drug loaded niosomal in-situ gel sustained the drug release (71.74%-86.20%) for 24 hours. The mechanism of drug release was non-Fickian diffusion controlled first order kinetics for niosomal in-situ gel formulation. Stability study indicated that the prepared niosomal in- situ gel remained more stable at refrigeration (4-8˚C) and room temperature (25±2˚C) as compared to (45±2˚C) in humidity control oven for 3 months. FT-IR and DSC studies revealed the integrity of the drug in the formulations. Thus, the present study conclusively demonstrates the feasibility of effectively formulating Ketorolac tromethamine niosomal in situ gels which are capable of releasing the drug for extended periods of time.
Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.