Effect of Different Direct Compaction Grades of Mannitol on the Storage Stability of Tablet Properties Investigated Using a Kohonen Self-Organizing Map and Elastic Net Regression Model.

This study tested 15 direct compaction grades to identify the contribution of different grades of mannitol to the storage stability of the resulting tablets. After preparing the model tablets with different values of hardness, they were stored at 25 °C, 75% relative humidity for 1 week. Then, measurement of the tablet properties was conducted on both pre- and post-storage tablets.

A Precise Prediction Method for the Properties of API-Containing Tablets Based on Data from Placebo Tablets.

We previously reported a novel method for the precise prediction of tablet properties (e.g., tensile strength (TS)) using a small number of experimental data.

Characterization of Powder- and Tablet Properties of Different Direct Compaction Grades of Mannitol Using a Kohonen Self-organizing Map and a Lasso Regression Model.

The purpose of this study was to accumulate enhanced technical knowledge about the powder properties of direct compaction grades of mannitol that could lead to new tablet formulations. Fifteen different commercial direct compaction grades of mannitol were tested. Ten different powder properties representing flowability, particle size, specific surface area and manufacturing properties were measured.

T Relaxation Study to Evaluate the Crystalline State of Indomethacin Containing Solid Dispersions Using Time-Domain NMR.

The aim of this study was to demonstrate the usefulness of T measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. A solid dispersion (SD) and a physical mixture (PM) consisting of indomethacin (IMC) and polyvinylpyrrolidone (PVP) were prepared at different weight ratios as test samples, and then their T relaxation curves were measured by TD-NMR. The T relaxation curve of IMC was quite different from that of PVP by nature.

A Time-Domain NMR Study of the State of Water in Wet Granules with Different Fillers and Its Contribution to the Wet Granulation Process and to the Characteristics of Granules.

The different states of water incorporated in wet granules were studied by a low-field benchtop H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T) was measured using the NMR relaxation technique. The experimental T relaxation curves were analyzed by the two-component curve fitting, and then the individual T relaxation behaviors of solid and water in wet granules were identified.

A Novel Approach to Evaluate Amorphous-to-Crystalline Transformation of Active Pharmaceutical Ingredients in Solid Dispersion Using Time-Domain NMR.

The aim of this study was to demonstrate the usefulness of the time-domain NMR (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing a solid dispersion. In this study, indomethacin (IMC) was used as a model for poorly water-soluble API. Solid dispersions of IMC were prepared with polyvinylpyrrolidone (PVP) at different weight ratios.

H NMR Relaxation Study to Evaluate the Crystalline State of Active Pharmaceutical Ingredients Containing Solid Dosage Forms Using Time Domain NMR.

The aim of this study was to demonstrate the usefulness of the time domain nuclear magnetic resonance (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing solid dosage forms. In this study, carbamazepine and indomethacin are used as models for poorly water-soluble APIs. First, we measured the T and T relaxation behavior of crystalline and amorphous APIs.

Inhibition of Gastric H,K-ATPase Activity in Vitro by Dissolution Media of Original Brand-Name and Generic Tablets of Lansoprazole, a Proton Pump Inhibitor.

To investigate the inhibitory effect of a commercial proton pump inhibitor (lansoprazole) on the gastric proton pump H,K-ATPase in vitro, we used orally disintegrating (OD) tablets including original brand-name and generic tablets. In the course of the development of generic products, dissolution and clinical tests are necessary to ensure their bioequivalence to the original brand-name products; by contrast, there is almost no opportunity to demonstrate their activity in vitro. This study initially compared the similarity of the dissolution of test generic tablets with that of the original brand-name tablets.

Determining the Influence of Granule Size on Simulation Parameters and Residual Shear Stress Distribution in Tablets by Combining the Finite Element Method into the Design of Experiments.

The influence of granule size on simulation parameters and residual shear stress in tablets was determined by combining the finite element method (FEM) into the design of experiments (DoE). Lactose granules were prepared using a wet granulation method with a high-shear mixer and sorted into small and large granules using sieves. To simulate the tableting process using the FEM, parameters simulating each granule were optimized using a DoE and a response surface method (RSM).

Modeling of quantitative relationships between physicochemical properties of active pharmaceutical ingredients and tensile strength of tablets using a boosted tree.

Objectives: The aim of this study was to explore the potential of boosted tree (BT) to develop a correlation model between active pharmaceutical ingredient (API) characteristics and a tensile strength (TS) of tablets as critical quality attributes.

Methods: First, we evaluated 81 kinds of API characteristics, such as particle size distribution, bulk density, tapped density, Hausner ratio, moisture content, elastic recovery, molecular weight, and partition coefficient. Next, we prepared tablets containing 50% API, 49% microcrystalline cellulose, and 1% magnesium stearate using direct compression at 6, 8, and 10 kN, and measured TS.

Relationships between response surfaces for tablet characteristics of placebo and API-containing tablets manufactured by direct compression method.

In this study, we evaluated the correlation between the response surfaces for the tablet characteristics of placebo and active pharmaceutical ingredient (API)-containing tablets. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Ten tablet formulations were prepared.

Palmitoylation of LAT contributes to its subcellular localization and stability.

Palmitoylation is a protein modification for trafficking to lipid raft. Without palmitoylation, linker for activation of T cells (LAT), an adaptor molecule mediating T cell receptor signaling, is unable to localize in lipid rafts and to mediate T cell activation. We here show a novel role for palmitoylation in LAT trafficking to the plasma membrane and in the stability of the LAT protein.

Structure and function of lipid rafts in human activated T cells.

Lipid rafts, specialized membrane microdomains enriched in sphingolipids and cholesterol, have been shown to function as signaling platforms in T cells. Surface raft expression is known to be increased in human T cells upon activation, and this increased raft expression may account for efficient signaling capability and decreased dependency for co-stimulation in effector and/or activated T cells. However, raft-mediated signaling ability in activated T cells remains to be clarified.

Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling.

Toll-like receptor 4 (TLR4) and MD-2 recognize lipid A, the active moiety of microbial lipopolysaccharide (LPS). Little is known about mechanisms for LPS recognition by TLR4/MD-2. We here showed, by using in vitro transfectants, ligand-induced TLR4-oligomerization, which required both membrane CD14 and MD-2.

Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice.

Lung fibrosis is a common feature of interstitial lung diseases, and apoptosis and fibrinogenesis play critical roles in its formation and progression. Hepatocyte growth factor (HGF) is one of the ideal therapeutic agents for prevention of lung fibrosis because of its antiapoptotic and fibrinolytic effects. The aim of this study is to establish nonviral HGF gene therapy of bleomycin-induced lung fibrosis avoiding the viral vector-related side effects.

Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization.

Toll-like receptor 4 (TLR4) and MD-2 recognizes lipid A, the active moiety of microbial lipopolysaccharide (LPS). Little is known about mechanisms for LPS recognition by TLR4-MD-2. Here we show ligand-induced TLR4 oligomerization, homotypic interaction of TLR4, which directly leads to TLR4 signaling.

Nonviral gene gun mediated transfer into the beating heart.

Several techniques for gene transfer into the heart have been developed, including direct injection of naked plasmid DNA into the myocardium and coronary infusion of various viral vectors. However, complications and side effects with those methods have been reported. In this study, to resolve these problems, the authors investigated the feasibility of nonviral gene transfer into the beating heart with the hand held gene gun.

Essential role for ERK2 mitogen-activated protein kinase in placental development.

Background: Extracellular signal-regulated kinase 2 (ERK2) has been implicated in cell proliferation, differentiation, and survival. However, its role in vivo remains to be determined.

Results: Here we show that the targeted disruption of the mouse ERK2 gene results in embryonic lethality by E11.

Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14.

Toll-like receptors (TLRs) are innate recognition molecules for microbial products, but their direct interactions with corresponding ligands remain unclarified. LPS, a membrane constituent of gram-negative bacteria, is the best-studied TLR ligand and is recognized by TLR4 and MD-2, a molecule associated with the extracellular domain of TLR4. Although TLR4-MD-2 recognizes LPS, little is known about the physical interaction between LPS and TLR4-MD-2.

Reduction of glycosphingolipid levels in lipid rafts affects the expression state and function of glycosylphosphatidylinositol-anchored proteins but does not impair signal transduction via the T cell receptor.

Lipid rafts are highly enriched in cholesterol and sphingolipids. In contrast to many reports that verify the importance of cholesterol among raft lipid components, studies that address the role of sphingolipids in raft organization and function are scarce. Here, we investigate the role of glycosphingolipids (GSLs) in raft structure and raft-mediated signal transduction in T lymphocytes by the usage of a specific GSL synthesis inhibitor, d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP).

Interaction of SAP-1, a transmembrane-type protein-tyrosine phosphatase, with the tyrosine kinase Lck. Roles in regulation of T cell function.

SAP-1 is a transmembrane-type protein-tyrosine phosphatase that is expressed in most tissues but whose physiological functions remain unknown. The cytoplasmic region of SAP-1 has now been shown to bind directly the tyrosine kinase Lck. Overexpression of wild-type SAP-1, but not that of a catalytically inactive mutant of SAP-1, inhibited both the basal and the T cell antigen receptor (TCR)-stimulated activity of Lck in human Jurkat T cell lines.

Analysis of the mobility of signaling molecules in lymphocytes using fluorescence photobleaching techniques.

The earliest biochemical events at the plasma membrane that lead to gene activation appear to depend not only on the local concentration of signaling molecules, but also on the mobility of these molecules at the site of signaling. To elucidate the process of signal transduction after receptor engagement in the immune system, it is important to analyze the mobility of signaling molecules in living lymphocytes. Current knowledge of the changes in intracellular localization and dynamic movements of signaling molecules during lymphocyte activation is limited.