Preparation and evaluation of orally disintegrating tablets containing taste masked microparticles of acetaminophen.

In the present work, taste masked particles of acetaminophen (AAP), a highly soluble bitter tasting drug, were developed and ODT containing the taste masked particles were prepared. Taste masked particles of AAP were prepared using different amounts of tetraglycerol polyricinoleate (TGPR) and Eudragit ®E100. Although the drug content ratio and drug recovery decreased with increasing TGPR, drug release from AAP-CR100 particles containing a large amount of TGPR was mostly suppressed for 2 min. Hence, AAP-CR100 was incorporated into ODT as taste masked particles for AAP. Three major disintegrants were used for ODT, and it was confirmed that the tensile strength of all formulations showed applicable hardness for handling. The AAP-CR100-CP(40) formulation containing crospovidone showed the shortest disintegration time and the drug release from AAP-CR100-CP(40) into pH 6.8 test solution was suppressed compared with commercial AAP tablets. Because the drug release from AAP-CR100-CP(40) into the pH 1.2 test solution was rapid, it was suggested that drug release from AAP-CR100-CP(40) is suppressed in the oral cavity, and the drug is released promptly in the stomach. Thus AAP-CR100-CP(40) may be useful as an ODT in which the dissolution of AAP in the oral cavity is suppressed.

MRI as a promising tool for evaluation of the stability of cosmetic emulsions.

OBJECTIVE: We have recently established a novel method to evaluate the emulsion stability of pharmaceutical skin cream. The key technology of the method is magnetic resonance imaging (MRI). The purpose of this study was to verify the usefulness of the method in the cosmetic industry. METHODS: Milky lotion-type emulsions were employed as test samples. We note that the test samples were prepared by taking account of commercial milky lotions. After the sample preparation, a centrifugation treatment (5000 g for up to 120 min) was implemented to accelerate their destabilization processes. The centrifuged samples were monitored by using T2 relaxation time (T2 ) maps. Furthermore, the histograms generated from the T2 maps were analysed to investigate the destabilization process in more detail. In addition, small fractions of the upper and lower phases were collected from the centrifuged samples, and microscopic observations were conducted. RESULTS: T2 maps successfully visualized the destabilization process accompanying the centrifugation protocol. From the microscopic observations, it was clarified that the main mechanism of the destabilization process was creaming. The sensitivity of the T2 map to creaming was much superior to that of visible observation; the T2 map can detect a slight creaming that is not visible to the naked eye. In addition, the T2 map also enables the detection of slight reversible creaming-dispersion changes accompanied by a repeated centrifugation-vortexing treatment. By using the parameters derived from the histogram analysis, the creaming behaviour can be evaluated more precisely and more objectively. This study prepared emulsions containing different thickener contents and then compared their creaming behaviours. As a consequence of the analysis, we could fully evaluate the effect of thickener on the emulsion stability by the evaluation method. CONCLUSION: MRI is a promising tool for evaluation of the stability of cosmetic emulsions.

Role of valence fluctuations in the superconductivity of Ce122 compounds.

Pressure dependence of the Ce valence in CeCu(2)Ge(2) has been measured up to 24 GPa at 300 K and to 17 GPa at 18-20 K using x-ray absorption spectroscopy in the partial fluorescence yield. A smooth increase of the Ce valence with pressure is observed across the two superconducting (SC) regions without any noticeable irregularity. The chemical pressure dependence of the Ce valence was also measured in Ce(Cu(1-x)Ni(x))(2)Si(2) at 20 K. A very weak, monotonic increase of the valence with x was observed, without any significant change in the two SC regions. Within experimental uncertainties, our results show no evidence for the valence transition with an abrupt change in the valence state near the SC II region, challenging the valence-fluctuation mediated superconductivity model in these compounds at high pressure and low temperature.

Twofold spontaneous symmetry breaking in the heavy-fermion superconductor UPt3.

The field-orientation dependent thermal conductivity of the heavy-fermion superconductor UPt3 was measured down to very low temperatures and under magnetic fields throughout the distinct superconducting phases: B and C phases. In the C phase, a striking twofold oscillation of the thermal conductivity within the basal plane is resolved reflecting the superconducting gap structure with a line of node along the a axis. Moreover, we find an abrupt vanishing of the oscillation across a transition to the B phase, as a clear indication of a change of gap symmetries. We also identify extra two line nodes below and above the equator in both B and C phases. From these results together with the symmetry consideration, the gap function of UPt3 is determined as a E(1u) representation characterized by a combination of two line nodes at the tropics and point nodes at the poles.

Possibility of valence-fluctuatsion-mediated superconductivity in Cd-doped CeIrIn(5) probed by In NQR.

We report on a pressure-induced evolution of exotic superconductivity and spin correlations in CeIr(In(1-x)Cd(x))(5) by means of in-nuclear-quadrupole-resonance (NQR) studies. Measurements of an NQR spectrum and nuclear-spin-lattice-relaxation rate 1/T(1) have revealed that antiferromagnetism induced by Cd doping emerges locally around Cd dopants, but superconductivity is suddenly induced at T(c)=0.7 and 0.9 K at 2.34 and 2.75 GPa, respectively. The unique superconducting characteristics with a large fraction of the residual density of state at the Fermi level which increases with T(c) differ from those for anisotropic superconductivity mediated by antiferromagnetic correlations. By incorporating the pressure dependence of the NQR frequency pointing to the valence change of Ce, we suggest that unconventional superconductivity in the CeIr(In(1-x)Cd(x))(5) system may be mediated by valence fluctuations.

Cyclotron resonance in the hidden-order phase of URu2Si2.

We report the first observation of cyclotron resonance in the hidden-order phase of ultraclean URu2Si2 crystals, which allows the full determination of angle-dependent electron-mass structure of the main Fermi-surface sheets. We find an anomalous splitting of the sharpest resonance line under in-plane magnetic-field rotation. This is most naturally explained by the domain formation, which breaks the fourfold rotational symmetry of the underlying tetragonal lattice. The results reveal the emergence of an in-plane mass anisotropy with hot spots along the [110] direction, which can account for the anisotropic in-plane magnetic susceptibility reported recently. This is consistent with the "nematic" Fermi liquid state, in which itinerant electrons have unidirectional correlations.

Sign reversal of field-angle resolved heat capacity oscillations in a heavy Fermion superconductor CeCoIn5 and d{x{2}-y{2}} pairing symmetry.

To identify the superconducting gap symmetry in CeCoIn5 (T{c}=2.3 K), we measured the angle-resolved specific heat (C{phi}) in a field rotated around the c axis down to a very low temperature, 0.05T{c}, and made detailed theoretical calculations. In a field of 1 T, a sign reversal of the fourfold angular oscillation in C{phi} was observed at T approximately 0.1T{c} upon entering a quasiclassical regime where the maximum of C{phi} corresponds to the antinodal direction, coinciding with the angle-resolved density of states (ADOS) calculation. The C{phi} behavior, which exhibits minima along the [110] directions, unambiguously allows us to conclude d{x{2}-y{2}} symmetry of this system. The ADOS-quasiclassical region is confined to a narrow T and H domain within T/T{c} approximately 0.1 and 1.5 T (0.13H{c2}).

Spin susceptibility of noncentrosymmetric heavy-fermion superconductor CeIrSi3 under pressure: 29Si Knight-shift study on single crystal.

We report 29Si NMR study on a single crystal of the heavy-fermion superconductor CeIrSi3 without an inversion symmetry along the c axis. The 29Si Knight-shift measurements under pressure have revealed that the spin susceptibility for the ab plane decreases slightly below T(c), whereas along the c axis it does not change at all. The result can be accounted for by the spin susceptibility in the superconducting state being dominated by the strong antisymmetric (Rashba-type) spin-orbit interaction that originates from the absence of an inversion center along the c axis and it being much larger than superconducting condensation energy. This is the first observation which exhibits an anisotropy of the spin susceptibility below T(c) in the noncentrosymmetric superconductor dominated by strong Rashba-type spin-orbit interaction.

Evolution of the Fermi surface of BaFe2(As1-xPx){2} on entering the superconducting dome.

Using the de Haas-van Alphen effect we have measured the evolution of the Fermi surface of BaFe2(As1-xPx){2} as a function of isoelectric substitution (As/P) for 0.41

Probing bulk states of correlated electron systems by high-resolution resonance photoemission

Electron correlations are known to play an important role in determining the unusual physical properties of a variety of compounds. Such properties include high-temperature superconductivity, heavy fermion behaviour and metal-to-insulator transitions. High-resolution photoelectron spectroscopy (PES) provides a means of directly probing the electronic states (particularly those near the Fermi level) in these materials, but the short photoelectron mean free paths (< or = 5 A) associated with the low excitation energies conventionally used (< or = 120 eV) make this a surface-sensitive technique. Now that high-resolution PES is possible at much higher energies, with mean free paths as long as 15 A (ref. 6), it should become feasible to probe the bulk electronic states in these materials. Here we demonstrate the power of this technique by applying it to the cerium compounds CeRu2Si2 and CeRu2. Previous PES studies of these compounds revealed very similar spectra for the Ce 4f electronic states, yet it is expected that such states should be different owing to their differing degrees of hybridization with other valence bands. Our determination of the bulk Ce 4f electronic states of these compounds resolves these differences.

Chromosome lesions produced with an argon laser microbeam without dye sensitization.

Improvements in the argon laser microbeam have made it possible to cause damage to chromosomes of tissue culture cells without prior treatment of the cells with a photosensitizing agent. These results have been confirmed independently in two laboratories.

Point-contact spectroscopy of the heavy-fermion superconductor CePt(3)Si.

Differential resistance spectra (dV/dI-V characteristics) have been measured for point contacts between the heavy-fermion superconductor (HFS) CePt(3)Si and a normal metal. Some contacts show a peak at V = 0 that is characteristic of HFS coexisting with a magnetic order such as UPd(2)Al(3), UNi(2)Al(3) and URu(2)Si(2). The evolution of the peak occurs well above the antiferromagnetic transition temperature T(N)∼2.2 K, so that the direct relationship with the magnetic transition is questionable. The half-width of the peak seems to reflect the crystal field splitting or the spin-wave gap as observed for the above-mentioned HFSs, possibly suggesting that some common scattering process induces the zero-bias peaks in these materials.

Unconventional superconductivity of NpPd(5)Al(2).

The high quality single crystals of NpPd(5)Al(2) with the body-centered tetragonal structure were grown by the Pb flux method. NpPd(5)Al(2) was found to be the first Np-based heavy fermion superconductor with the relatively high critical temperature T(sc) = 4.9 K. The upper critical field H(c2) is large and highly anisotropic. Corresponding to the heavy electronic state, the initial slope of H(c2) is large, but H(c2) at low temperatures is suppressed by the magnetic field, indicating a strong Pauli paramagnetic effect and the first-order transition at H(c2). These results imply that NpPd(5)Al(2) is located at the proximity of the antiferromagnetic ordering, which might be hidden by the superconductivity. The d-wave superconductivity with a spin singlet state is most likely realized in NpPd(5)Al(2).

Prediction of permeability of FD-4 through porous poly (2-hydroxyethyl methacrylate) membrane by multiple linear regression and artificial neural network.

The aim of this study was to predict the permeability through porous poly (2-hydroxyethyl methacrylate) (pHEMA) membranes of fluorescein isothiocyanate-labeled dextran molecular weight 4400 (FD-4) as a model of peptide and protein drug movement. Homogeneous standard membranes were prepared by redox polymerization. Permeability data were predicted by an artificial neural network (ANN) as a function of polymerization factors, and the accuracy was compared with that of conventional multiple linear regression (MLR). Good linearity was observed with each model, with the correlation coefficient of a leave-one-out cross-validation (Rcross) being 0.857 for the MLR model and 0.876 for the ANN model. The mean bias and mean accuracy for the ANN were somewhat smaller than those of the MLR. The ANN method provides an accurate quantitative approximation of the permeability coefficient of FD-4, as judged by conventional MLR, and could be applied to prediction of the non-linear relation between polymerization factors and the permeability of FD-4.

Factors affecting release rate of diltiazem hydrochloride from poly (2-hydroxyethyl methacrylate) matrices.

Sustained release diltiazem hydrochloride (DIL) formulation is widely used over 110 countries worldwide, and is among the drugs recommended as a first-line therapy in the major guidelines for the management of hypertension. In search for a most suitable controlled release formulation of DIL, we investigated poly (2-hydroxyethyl methacrylate) matrix (pHEMA matrix) synthesized by photopolymerization. Factors affecting the release rate of DIL from pHEMA matrices were investigated, focusing on the internal structure of the matrices. The effects of the porosity (epsilon), the fractal dimensions (Df) and the microscopic viscosity (eta matrix) of the matrices on the release rate of DIL were investigated on the basis of the linear least square equation as well as the Higuchi's equation. A relation between the actual value and predicted value based on the linear least square equation exhibited a fairly good linearity (r=0.979). Furthermore, the release rate of DIL was represented based on the Higuchi's equation including the values of epsilon, Df and eta matrix. It is likely that the release rate of DIL from pHEMA matrices is mainly controlled by epsilon and Df, but eta matrix was less effective.

Comparison of the effect of monopolar and bipolar cauterization on skeletonized, dissected internal thoracic arteries.

The internal thoracic artery is preferable to the saphenous vein for use as a conduit for coronary artery bypass. More extensive use is possible if this artery is mobilized in a skeletonized form to provide greater length. Internal thoracic arteries are usually mobilized with cauterization. This study compared the effectiveness and effects on neighboring areas of division of the branches of the canine internal thoracic artery with bipolar cauterization and monopolar cauterization. Branch closure was significantly more secure in the bipolar cauterization group, with bleeding in 25 (9%) of 279 branches of 15 internal thoracic arteries treated with monopolar cauterization, in contrast to bleeding in 4 (1.3%) of 306 branches in the 15 internal thoracic arteries treated with bipolar cauterization, which were paired with the group treated with monopolar cauterization. The group of internal thoracic arteries treated with monopolar cauterization had a significantly higher prevalence of leakage when luminal pressure was increased from 120 to 160 mm Hg. Scanning electron microscopy demonstrated partial loss of endothelial cells on the flow surface of internal thoracic arteries treated with bipolar cauterization, compared with almost complete loss of endothelial cells around the orificial areas after monopolar cauterization. Secondary bipolar cauterization treatment caused only slightly more damage than primary treatment, but secondary monopolar cauterization was much more severe and extensive than primary treatment. These data suggest that bipolar cauterization is preferable to monopolar cauterization for skeletonized dissection of the internal thoracic artery.

Effect of altered blood flow on the caliber and morphology of the internal thoracic artery in the dog.

OBJECTIVE: The purpose of this study was to evaluate in dogs the effect of blood flow alteration on caliber and morphology of in situ internal thoracic arteries. METHODS: Six dogs underwent creation of a unilateral distal arteriovenous fistula between the internal thoracic artery and vein at the sixth rib to create high flow, and in six others the internal thoracic artery was unilaterally skeletonized and dissected. For both groups the contralateral internal thoracic artery served as the control; sides were alternated among cases. Blood flow was measured for shear stress calculation before and after surgical alteration. After 2 months, internal thoracic arteries were harvested with the entire anterior chest plate, which was dynamically inflated and fixed with 10% formalin at a controlled pressure of 120 mm Hg after angiography had been done at the same pressure. The luminal diameters were then measured at eight levels on the angiograms. Arterial tissue samples were taken at three levels and embedded, sectioned, and treated with hematoxylin-eosin and Verhoeff-van Gieson stains. Digital imaging analysis was used for quantitative morphometric studies. RESULTS: All fistulas remained patent. In comparison with control arteries, high-flow internal thoracic arteries dilated and low-flow internal thoracic arteries narrowed, which was associated with significant change in shear stress for both groups. There were no substantial structural changes in the walls of either group. CONCLUSION: In the dog, the luminal diameter of the internal thoracic artery responds to altered blood flow without intimal thickening or other undesirable wall changes.

Magnetic order in the heavy fermion compound CeCu6 at mK temperatures

We have measured the ac magnetic susceptibility in various fields and thermal expansion of single crystals of the heavy fermion compound CeCu6 at temperatures down to 250 &mgr;K. The susceptibility of CeCu6 shows a peak at about 2 mK and has a large anisotropy. We also detected an anomaly of thermal expansion at the same temperature. The observed behaviors of the susceptibility and the thermal expansion in CeCu6 indicate the occurrence of an antiferromagnetic order.

Synthesis and diuretic activity of bicyclic fused heterocycles containing oxime-O-sulfonic acid moiety.

In order to investigate the origin of the loop-type diuretic activity of M17055 (1), several variants (3-9) were designed and synthesized by modifying the quinolinone skeleton, and their diuretic activities were compared with the lead 1 and furosemide in dogs. It was found that the negative charge distribution pattern afforded by the dispositional arrangement of the 4-oxime-O-sulfonic acid and 1-N-acyl carbonyl moiety attached to the tetrahydropyridine ring system is inevitable for the development of the activity, which strongly supports the previously proposed model for the active site of the Na(+)-K(+)-2Cl(-) cotransporter. Also reported is the first synthesis of the dihydrothieno[3,2-b]pyridine-7(4H)-one ring system required in the synthesis of compound 9.

In vivo effects of highly purified docosahexaenoic acid on rectal insulin absorption.

The purpose of this study was to evaluate the effectiveness and the toxicity of polyunsaturated fatty acid, such as oleic acid, eicosapentaenoic acid (DHA), as potential absorption enhancer for rectal delivery of insulin, using a water-in-oil-in water (W/O/W) multiple emulsion. In a single administration study, rectal insulin absorption was enhanced markedly, and marked hypoglycemia was induced by the emulsion incorporating various fatty acids in an insulin dose-related fashion. The pharmacological availability of the emulsion incorporating 2% oleic acid, EPA and DHA was approximately 7.7, 11.0 and 25.4%, respectively. The insulin absorption enhancement effect was not increased in proportion to the amount of DHA in the emulsion, the mean T(max) value of the serum glucose-time curve could be extended to twice that of the emulsion without PF 127. In a multiple administration study, the mean AUC(glucose) values of the emulsion incorporating DHA showed almost the same value on the first and the tenth day. From the morphological appearance of the mucosal surface, the emulsion incorporating DHA induced no or little mucosal damage. Our findings demonstrated that DHA has a strong insulin permeability enhancement effect and little toxicity. Thus, DHA is an attractive candidate as an absorption enhancer for intestinal delivery of insulin.