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The objective of the present study was to investigate the effect of isopropyl myristate (IPM) on the in vitro permeation of testosterone through human cadaver skin from carbopol gels. Six testosterone gel formulations were prepared using different IPM contents of 0%, 0.4%, 0.7%, 1%, 2%, and 3%. The gels were characterized for drug permeation, matrix morphology, pH, kinetics of ethanol evaporation, and viscosity. Mass balance studies were performed to estimate testosterone distribution among the compartments of diffusion cells. All formulations exhibited pH values of 5.1 and viscosities of 1.25-1.75 Pa.s depending on IPM contents. Under occlusive condition, testosterone flux was found to increase significantly (p < 0.05) by increasing IPM content. Gels containing 2% IPM exhibited 11-fold increase in flux compared with formulation devoid of IPM. Ethanol was found to have a synergistic effect with IPM in enhancing testosterone flux. Mass balance analysis showed that testosterone was in a saturated state in the skin. Conducting permeation experiments under nonocclusive condition was nondiscriminating because of the evaporation of alcohol and consequent precipitation of drugs. Based on demonstrated effect of IPM on product performance, the final IPM concentration should be controlled with minimal variation during manufacturing and shelf life of drug product., (Published by Elsevier Inc.)

The low permeability of the anti-AIDS, tenofovir, limits its antiretroviral clinical potency. The proposed study aimed at assessing the critical biological responses of tenofovir through the development and optimization of its surfactant-based niosomal gels intended for vaginal delivery. Fatty acid chain length of the amphiphile and cholesterol loading were optimized using a 3² full factorial design. Vesicular size, shape and surface charge, drug entrapment efficiency, in vitro release, and skin permeation were used to assess the gels. In addition, their biological performance on Lactobacillus crispatus viability and mucoadhesion to porcine vaginal tissue was also assessed. Within the design space, mucoadhesion percentage ranged from 6.2% to 28.6% and increased nonlinearly by decreasing niosomal vesicular size and linearly by increasing surface charge. Moreover, these gels were not cytotoxic to Lactobacillus crispatus for 48 h. For maximizing tenofovir entrapment, percutaneous permeation, and mucoadhesion while achieving sustained-release features, an optimum formulation was proposed with the shortest length of fatty chain and 0.48 mM cholesterol content. Overall, applying quality by design paradigm to the development of tenofovir niosomal gels not only offered a promising nanomedicine for the vaginal microbicide delivery but also unveiled the critical formulation interactions influencing its biological performance., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The objective of the current study was to evaluate the performance of Raman and near-infrared (NIR) techniques combined with chemometrics in characterizing the critical quality attributes of brompheniramine (BP)-tannate complexes. Seven complexes were prepared and evaluated for chemical interactions, solubilities, dissolutions, and spatial distributions by NIR chemical imaging (CI). Principal component analysis (PCA) was applied before either partial least squares regression (PLSR) or principal component regression (PCR) models were developed. Complexation was confirmed by Fourier transform IR analysis to yield complexes of lower drug solubilities and sustained-release characteristics in alkaline media. PCA results showed better discrimination ability by NIR than by Raman spectroscopy. Compared with PCR, the PLSR predictions errors, calculated from the Raman and NIR data with second-derivative pretreatment, showed lesser values of 2.68, 0.37, 1.79, and 5.60 and 0.58, 0.25, 0.93, and 0.58 for complex solubilities in acidic and alkaline media and percentages dissolved after 1 and 20 h, respectively. In addition, good correlation (>0.95) was obtained for predicting the drug concentration using PLSR score images explaining the validity of the NIR-CI model for spatial quantitation of BP within its tannate complexes. In conclusion, the chemometric analysis of NIR and/or Raman spectra represented an innovative approach to determine the tannate complexation variability., (Copyright © 2011 Wiley Periodicals, Inc.)

Flurbiprofen was formulated as a proniosomal transdermal gel with high drug loading (55.4%, w/w), using a series of nonionic surfactant and cholesterol. A two-factor, three-level randomized full factorial strategy was developed to optimize simultaneously the effect of surfactant fatty acid side chain length and the amount of cholesterol on the properties of the proniosomes, namely drug permeation characteristics such as steady-state transdermal flux (SSTF), permeability coefficient (PC), and drug entrapment efficiency. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation variables that showed significant effects on the selected responses. Polynomial equations fitted to the data were used to predict the responses in the optimal region. For maximizing the selected responses using a generalized desirability function, an optimum formulation was found to have a maximum side chain length and minimum cholesterol content. Optimized formulation showed highest entrapment of 39.45%, percentages drug permeated through cellulose ester membrane of 3.1 and 28.93 after 0.5 and 8 h, respectively, and SSTF and PC of 152 μg/cm(2) h and 0.263 cm/h, respectively, through rabbit skin. These results demonstrated the efficacy of statistical experimental design to unveil the critical formulation interactions and variability affecting the performance of proniosomal formulations., (Copyright © 2011 Wiley-Liss, Inc.)

The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess drug contents in poly(dl-lactide-co-glycolide) (PLGA) based nanoparticles of a model protein, cyclosporine A (CyA). A 6-factors 12-runs designed set of experiments with Plackett-Burman (PB) screening was applied in order to examine the effects of drug loading (X(1)), polymer loading (X(2)), emulsifier concentration (X(3)), stirring rate (X(4)), type of organic solvent (X(5)), and ratio of organic to aqueous phases' volumes (X(6)), on drug entrapment efficiency (EFF). After omitting the factors with nonsignificant influences on EFF, a reduced mathematical relationship, EFF = 48.34 + 7.3X(1) - 29.95X(3), was obtained to explain the effect of the significant factors on EFF. Using two different sets for calibration and validation, the developed NIR calibration model was able to assess CyA contents within the 12 PB formulations. NIR spectral imaging was capable of clearly distinguishing the 12 formulations, both qualitatively and quantitatively. A good correlation with a coefficient of 0.9727 was obtained for constructing a quantile-quantile plot for the actual drug loading percentage and the % standard deviation obtained for the drug loading prediction using the hyperspectral images., (2009 Wiley-Liss, Inc. and the American Pharmacists Association)

The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess phospholipid compartment within its solid dispersion with cyclosporine A (CyA). By varying dimyristoyl phosphatidylcholine (DMPC) to CyA weight ratio, five batches were prepared by the kneading technique and characterized by DSC and FTIR. A drug/DMPC ratio of 50:1 provided an enhanced dissolution of CyA. FTIR spectra and DSC thermograms revealed a significant interaction between the drug and DMPC which suggested incorporation of CyA within the formed DMPC liposomes. The developed NIR calibration model was able to assess DMPC concentrations within the kneaded products. The calibration and prediction linear plots showed slopes of 0.9711 and 0.9915, offsets of 0.1247 and 0.1080, correlation coefficients of 0.9854 and 0.9889 and root mean square standard errors of 0.43% and 0.42%, respectively. In contrast, NIR spectral imaging was capable of clearly distinguishing the kneaded products, both qualitatively and quantitatively. NIR imaging revealed the poor powder blending efficiency of the method used to prepare physical mixture compared to the efficient distribution of the kneaded products. In conclusion, NIR spectral imaging system provides a rapid approach for acquiring high-resolution spatial and spectral information on solid dispersions.

The objective of this work was to understand the product variability due to size and other characteristics of the SNEDDS by utilizing near infrared (NIR) and chemometric analysis, as well as several other well-known procedures. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region using CyA solutions in sweet orange oil (oily phase), Emulphor EL-620 (surfactant), and Capmul MCM-C8 (cosurfactant). The formulated SNEDDS were characterized by droplet size, turbidity, zeta potential, and Fourier transform infrared (FTIR) analysis. Drug release studies were performed by dissolution in conjunction with turbidimetry. Permeability studies were performed in a Franz diffusion cell assembly. The results indicated an optimum surfactant to cosurfactant ratio of 2:1. Above this ratio, the resultant nanoemulsions had a particle size of 10 nm and turbidity of 10 nephlometric units (NTU). All the prepared systems were positively charged. The FTIR spectra and the DSC thermograms obtained showed no incompatibility between the SNEDDS ingredients. Turbidity time profiles revealed three distinctive regions: lag phase, plateau, and pseudolinear phase. Emulsification rate was obtained from the corrected slope of the pseudolinear phase of the profile. Permeability data indicated that the product variability is more with smaller droplet size. The size of the droplets showed good correlation with NIR spectral data by partial least square (PLS) regression plots. In conclusion, this study demonstrated the ability to understand the impact of nanodroplets size on the SNEDDS variability by different product analyzing tools., ((c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.)