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The purpose of the present study was to prepare Orodispersible films (ODFs) loaded with ketoprofen nanoparticles (KT-NP). The Box-Behnken design was constructed in developing and optimizing the KTF-NP-ODFs. The effect of independent variables: Soluplus® concentration (X 1 , stabilizer), Tween 80 concentration (X 2 , surfactant), and KTF concentration (X 3 , drug) were studied on the dependent variables: particle size (PS, Y 1), zeta potential (ZP, Y 2), and the polydispersity index (PDI, Y 3) of the NPs, as well as on the tensile strength (TS, Y 4) and permeability coefficient (PC, Y 5) of the KTF-NP-ODFs. Hydroxypropyl methylcellulose (HPMC E15) and polyethylene glycol (PEG 400) were used as the film former polymer and plasticizer, respectively, and their concentrations were kept constant for all formulations. KTF-NPs were prepared by antisolvent precipitation technology. This was followed by the addition of HPMC E15 and PEG 400 to prepare the ODFs using the solvent-casting method. The PS, PDI, and ZP for all the formulations were found in the range of 94 nm to 350 nm, 0.09 to 0.438, and -21.83 mV to -8.03 mV, respectively. The TS and PC of the prepared KTF-NP-ODFs were found between 1.21 MPa to 3.93 MPa and 3.12 × 10−4 cm/h to 34.23 × 10−4 cm/h, respectively. The amorphous nature of the KTF-NP in the ODFs was confirmed by the absence of characteristic crystalline peaks and endothermic events of KTF in X-ray diffraction (XRD) and modulated differential scanning calorimetry (mDSC), respectively. The optimized formulation showed ̴ 4 times higher permeability as compared to the pure KTF. In addition, the dissolution of pure KTF and the optimized KTF-NP-ODF in pH 1.2 at the end of 60 min was found to be ̴ 30% and ̴ 95%, respectively. Conclusively, KTF-NP-ODFs can be a promising drug delivery system to counter the issues related to dysphagia and bypass the common side effects, such as the gastric irritation associated with NSAIDs like KTF. [ABSTRACT FROM AUTHOR]

Abstract Lilly Laboratories cell porcine kidney 1 (LLC-PK1) cells transfected with human P-glycoprotein (LLC-PK1-P-gp) are widely used in transport assays to identify drug candidates that function as substrates of this efflux transporter. Endogenous transporters expressed in LLC-PK1 cells may complicate the interpretation of findings from P-gp-mediated transport assays. We investigated the impact of porcine breast cancer resistance protein (Bcrp) in P-gp-mediated transport assays in LLC-PK1 cells. Porcine Bcrp mRNA was detected in both LLC-PK1 wildtype (WT) and LLC-PK1-P-gp cells by quantitative RT-PCR. To investigate the activity and impact of porcine Bcrp, we conducted transport assays using 6 typical BCRP substrates in LLC-PK1 cells. Efflux ratios (ER) of the 6 BCRP substrates in LLC-PK1 WT cells were >2, and were reduced in the presence of the BCRP inhibitor Ko143. The efflux activities of the 6 BCRP substrates were confirmed using MDCKII cells transfected with human BCRP. Net ERs of prazosin and fluvastatin, dual substrates of P-gp and BCRP, determined by dividing ERs in LLC-PK1-P-gp cells by those in LLC-PK1 WT cells, were <2, but increased to >2 in the presence of Ko143. These results indicated that endogenous Bcrp in LLC-PK1 cells was involved in the transport of BCRP substrates and may interfere with the identification of P-gp substrates. [ABSTRACT FROM AUTHOR]

Abstract Caco-2 cell line is frequently used as a simplified in vitro model of intestinal absorption. In this study, a database of 1366 Caco-2 permeability coefficients (P e) for 768 diverse drugs and drug-like compounds was compiled from public sources. The collected data represent permeation rates measured at varying experimental conditions (pH from 4.0 to 8.0, and stirring rates from 0 to >1000 rpm) that presumably account for passive diffusion across mucosal epithelium. These data were subjected to multistep nonlinear regression analysis using a minimal set of physicochemical descriptors (octanol-water log D , pKa, hydrogen bonding potential, and molecular size). The model was constructed in a mechanistic manner incorporating the following components: (i) a hydrodynamic equation of size- and charge-specific along with nonspecific diffusion across the paracellular pathway; (ii) transcellular diffusion represented by thermodynamic membrane/water partitioning ratio; (iii) stirring-dependent limit of maximum achievable permeability due to the presence of unstirred water layer. The obtained model demonstrates good accuracy of log P e predictions with a residual mean square error <0.5 log units for all training and validation sets. Given its robust performance and straightforward interpretation in terms of simple physicochemical properties, the proposed model may serve as a valuable tool to guide drug discovery efforts toward readily absorbable compounds. [ABSTRACT FROM AUTHOR]

The ex vivo permeation of diclofenac was studied using four different salts (sodium, potassium, diethylamine, and epolamine) dissolved in four different solvents (water, propylene glycol (PG), Transcutol®, and oleic acid (OA)) as donor phases through a human skin membrane. The four salts show different solubility values and different behavior in the four solvents, which are also permeation enhancers and this fact further is connected to the permeation results. The same order of magnitude of fluxes through the membrane as those previously reported for acidic diclofenac released from buffer solutions of pH >7 were found, taking into account differences originated by different membranes and other parameters tested in the experiments. Saturation concentration for the four salts in different solvents, necessary to calculate permeation coefficients, was critically evaluated; a short discussion made it possible to explain that corrections in the solubility values must be considered, related to the complex behavior in solution of these salts. Statistical processing of the experimental data suggests that differences between the four salts in promoting absorption of the drug is unproven; while differences are evident between the solvents, water is the most effective enhancing vehicle. Aqueous formulations containing diclofenac salt with an organic base appear to be the best combination to promote permeation in topical applications. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 814–823, 2007 [ABSTRACT FROM AUTHOR]

New dermal penetration data have been measured in both “infinite” and finite dose experiments on a range of compounds of varying lipophilicities. The data are analyzed, using parameter fitting, to determine the values of parameters governing the overall skin absorption processes. Two one-dimensional diffusion models are used. The first is novel, and well suited to the modeling of dermal uptake in occupational exposure scenarios. The second is an implementation of a model taken from the literature. The models are compared in a variety of exposure scenarios, and exhibit good mutual agreement. Both successfully reproduce expected features of the absorption process. Penetration parameters are determined by analyzing both infinite and finite dose data. Prediction of dermal absorption with finite dose scenarios is carried out and compared with experimental data obtained under these conditions. Parameters determined may also have an important role in improving the reliability of predictive QSARs used to estimate the extent of penetration of untested molecules. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [ABSTRACT FROM AUTHOR]