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Kligfield P.,New York Medical College | Green C.L.,Duke University | Mortara J.,Mortara Instrument | Sager P.,Francisco Partners | And 7 more authors.
American Heart Journal | Year: 2010

This document examines the formation, structure, and principles guiding the use of electrocardiogram (ECG) data sets obtained during thorough QT studies that have been derived from the ECG Warehouse of the Cardiac Safety Research Consortium (CSRC). These principles are designed to preserve the fairness and public interest of access to these data, commensurate with the mission of the CSRC. The data sets comprise anonymized XML formatted digitized ECGs and descriptive variables from placebo and positive control arms of individual studies previously submitted on a proprietary basis to the US Food and Drug Administration by pharmaceutical sponsors. Sponsors permit the release of these studies into the public domain through the CSRC on behalf of the Food and Drug Administration's Critical Path Initiative and public health interest. For algorithm research protocols submitted to and approved by CSRC, unblinded "training" ECG data sets are provided for algorithm development and for initial evaluation, whereas separate blinded "testing" data sets are used for formal algorithm evaluation in cooperation with the CSRC according to methods detailed in this document. © 2010 Mosby, Inc.


Schilling S.U.,University of Texas at Austin | Schilling S.U.,Merck KGaA | Lirola H.L.,University of Texas at Austin | Shah N.H.,Hoffmann LaRoche Inc | And 2 more authors.
Journal of Microencapsulation | Year: 2010

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit® S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20 level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present. © 2010 Informa UK Ltd All rights reserved.


Schilling S.U.,University of Texas at Austin | Shah N.H.,Hoffmann LaRoche Inc | Waseem Malick A.,Hoffmann LaRoche Inc | McGinity J.W.,University of Texas at Austin
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2010

The objective of this study was to investigate the properties of enteric matrix pellets that were prepared by hot-melt extrusion in a one-step, continuous process. Five polymers (Eudragit® L100-55, L100 and S100, Aqoat® grades LF and HF) were investigated as possible matrix formers, and pellets prepared with Eudragit® S100 demonstrated superior gastric protection and acceptable processibility. Extruded pellets containing Eudragit® S100 and up to 40% theophylline released less than 10% drug over 2 h in acid, however, the processibility and yields were compromised by the high amounts of the non-melting drug material in the formulation. Efficient plasticization of Eudragit® S100 was necessary to reduce the polymer's glass transition temperature and melt viscosity. Five compounds including triethyl citrate, methylparaben, polyethylene glycol 8000, citric acid monohydrate and acetyltributyl citrate were investigated in terms of plasticization efficiency and preservation of the delayed drug release properties. The aqueous solubility of the plasticizer and its plasticization efficiency impacted the drug release rate from the matrix pellets. The use of water-soluble plasticizers resulted in a loss of gastric protection, whereas low drug release rates in acid were found for pellets containing insoluble plasticizers or no plasticizer, independent of the extent of Eudragit® S100 plasticization. The release rate of theophylline in buffer pH 7.4 was faster for pellets that were prepared with efficient plasticizers. The microstructure and solid-state properties of plasticized pellets were further investigated by scanning electron microscopy and powder X-ray diffraction. Pellets prepared with efficient plasticizers (TEC, methylparaben, PEG 8000) exhibited matrices of low porosity, and the drug was homogeneously dispersed in its original polymorphic form. Pellets containing ATBC or citric acid monohydrate had to be extruded at elevated temperature and showed physical instabilities in the form of recrystallization at room temperature. Enteric matrix pellets with a diameter below 1 mm and containing 30% theophylline could be successfully prepared by hot-melt extrusion when Eudragit® S100 plasticized with either TEC or methylparaben was employed as the matrix material. © 2009 Elsevier B.V. All rights reserved.

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