An improved vibrating screener is disclosed as including an inlet system which provides for tangential input of the material to be processed by the screener. A spacing frame is provided in connection with the tangential inlet in order to separate materials by disengaging particles from the input material as it spirals down the side of the spacing frame and feed tray. During the spiraling down action, the material decreases in velocity. During the separation process, an external loop is used for by-passed air, thereby providing the full diameter of the machine for the by-pass screen, to avoid by-pass screen blinding. The by-passed air can then be used to pick up the screened powder at the bottom of the unit; or, the by-passed air is reintroduced below the separating screen to flush the machine free of screened product.

Generally, sifters utilized within a dilute phase pneumatic conveying system, include, for instance, a pressurized container with a screen or screens of desired mesh size therein. Commonly, the container is mounted in such a manner that it is vibrated to cause the materials provided at the input of the container to move across the screen and thereby to effect the sifting action.
As shown and described by Krolopp, et al, U.S. Pat. No. 3,796,312, issued Mar. 12, 1974, there are essentially three courses of flowthrough in a typical screener; one for oversized material, a second for undersized or desired material and a third for air flow used to convey the undersized product. As shown by the Krolopp system, air and solid material traverse an inlet pipe at the top center of the container. As air enters into the container, since the container is much larger than the inlet pipe, such air will be reduced in velocity as it travels downward into the container. Nevertheless, the particulate materials moving with the air are still travelling at full velocity, and are thereby impinging the screen at high velocity sufficient to break up some of the unwanted contaminants (bugs, pieces of glass, pieces of trash, etc.) so that they pass through the screen mesh. As to the contaminants that do not pass through the screen, they are forced to the periphery of the screen in the same manner as oversized material.
Another feature shown by the Krolopp structure is the use of a by-pass screen for by-passing the converying air, which because of the design turns out to be very small in area, which allows it to possibly become plugged.


A latching system for latching first and second connectors (120,20) together along a mating axis includes a pair of latch arms (126) spaced a selected distance apart along a common side (124) of a first housing (122) and extending to free ends (127) proximate the mating face (133) thereof, and a pair of embossments (50) spaced along a common side (24) of a second housing (22) includes beams (52) extending outwardly therefrom a second selected distance beyond a mating face (46) to free ends (53). Upon mating the connectors (120, 20), the free ends (53) of the embossments (50) stabilize axial alignment and orientation of the connectors (120, 20) relative to each other during final stages of mating. The embossments (50) pass freely beside the latch arms (126) during initial stages of mating until the connectors (120, 20) are axially aligned whereupon the latch arms (126) latch during final stages of mating.

Various latching systems are known for latching together housings of opposing electrical connectors being mated to engage mating pairs of contact terminals secured therein. When one of the connectors is a right angle connector mounted to a circuit board, the latching system needs to be provided at either the two ends of the connector or along a common side parallel to a circuit board. To minimize real estate on the circuit boards it is more desirable to have a latching system that is on a common side of the housings. U.S. Pat. No. 5,344,335 discloses one such latching system in which one of the connectors includes a latch arm having a spaced apart pair of latches, each being received in latching slots on the other connector near the lateral ends of the connectors. This type of latching system, however, requires additional height beyond the housing envelope of the connector, which may interfere with stacking the connectors close together. In those instances where it is desirable to have an array of connectors in a closely stacked arrangement, such as a card cage, for example, it is desirable to have a latching system that essentially functions within the envelope of the housing walls and one that furthermore provides a clear indication that the housings are in a full mated condition. It is also desirable to provide a latching system that can minimize that possibility of incomplete latching and incomplete mating.


A flexible packaging system containing spiral wound instant pasta noodles along with a system for packing the noodles in flexible envelopes to reduce breakage of the noodles to permit inclusion of noodles longer than the flexible package filling aperture and reducing the incidence of perforation of the package.

1. Field of the Invention
This invention relates to a novel system for reducing perforations in flexible packaging which contains dried pasta noodles by employing selected space-saving shapes of instant pasta noodles as well as methods for preparing both the noodles and the packaged noodles.
2. Description of the Related Art
Generally dry or dehydrated foods are contained in bags or flexible packaging for convenience and ease of opening such as in U.S. Pat. Nos. 5,410,857 and 2,357,585. Dry soups frequently employ noodles or pasta as a major portion of the soup and if the noodles or pasta is cut into small straight pieces prior to drying, the ends of the dried material are relatively sharp and when introduced into the package, can easily perforate the packaging material. One solution to prevent this is to make the packaging from relatively strong flexible material, however, this is needlessly expensive and the use of any such material must be balanced against the overall cost of the product. Cheaper packaging material being clearly more desirable than expensive material. A method of including dried pasta in a flexible package while limiting the perforations of the packaging is thus seen to be desirable.
Accordingly, it is an object of the present invention to provide a system employing a spiral pasta shape for use with a flexible package system which substantially reduces the perforations of the flexible packaging containing the pasta.
Over the years there have been many methods for making farinaceous products and for making such products in various shapes. Some of the pasta is made into nests and skeins and this is mentioned in chapter 10 entitled "Manufacture of Pasta Products", by Dante Baroni, pp. 191-203 in a book by Dr. Charles Hummel entitled Macaroni Products, Manufacture, Processing and Packaging, 1966, London, Food Trade Press Inc. In essence, these noodles are prepared to be cooked in a cooking pot containing boiling water and the like and served.
U.S. Pat. No. 4,323,585 relates to a process for producing pasta products in serving portions in packages. This patent refers to nests and other pasta products packed on the basis of eating portions.
U.S. Pat. No. 3,798,343 relates to a process for preparing frozen rolled lasagna. Generally the process used is one where cheese and meat are applied to one face of the single noodle which is then rolled in a spiral and frozen.
U.S. Pat. No. 4,988,528 relates to preparing instant noodles adapted to be cooked in boiling water or the like and then served. This patent particularly relates to fried noodles.
Although many ways of preparing pasta are known, and although many shapes are available, in the art of preparing noodles for instant dishes which noodles are then contained in flexible packaging, for instance, it is difficult to obtain long noodles which can fit within the package since the package is relatively short. Thus, there is a need for a noodle shape which will allow placement into a package of relatively short dimensions. In addition, perforation of the packages can result from the sharp corners of cut noodles.
Spiral shapes are well known, for example, U.S. Pat. No. 4,882,175 employs a rolled tape of a confectionery such as bubble gum. In addition, in the baking industry several patents deal with preparing dough in a rolled spiral form such as, for example, U.S. Pat. No. 2,352,617. Instant noodles, however, present completely different problems from preparing dough into a cinnamon bun shape or into rolls of bubble gum. This is so principally because the pasta first must be prepared and precooked to a certain degree, then spiral rolled, then packed into relatively flexible packaging and when cooked, it must be capable of unrolling to its original length without sticking together. Thus, simply rolling pasta into a spiral formation would not permit unrolling upon cooking. The noodles would stick together in a disc and not unroll.
Conventional instant noodles are manufactured by preparing a dough which is then formed into a strip by multistage rolls. The strip is steamed to partially cook it, gelatinize it and improve its elasticity. It is then cut in the longitudinal direction and subsequently chopped to the appropriate length, dried, and introduced into an appropriate package either alone or with other materials to constitute instant noodles or for example, instant soup. This method, however, leaves many sharp ends of noodles which can perforate the package.

Method for reducing flexible packaging perforations from dried pasta noodles


A method of producing a glass substrate for a mask blank has the steps of measuring a convex/concave profile of a surface of the glass substrate, controlling a flatness of the surface of the glass substrate to a value not greater than a predetermined reference value by specifying the degree of convexity of a convex portion present on the surface of the glass substrate with reference to a result of measurement obtained in the profile measuring step and executing local machining upon the convex portion under a machining condition depending upon the degree of convexity, and polishing, after the flatness control step, the surface of the glass substrate subjected to the local machining. The surface of the glass substrate subjected to the local machining is subjected to acid treatment after the flatness control step and before the polishing step.

This invention relates to a method of producing a glass substrate for a mask blank and a method of producing a mask blank and, in particular, to a method of producing a glass substrate for a mask blank for use with light in an ultrashort wavelength range, such as F2 excimer laser (fluorine: having a wavelength of 157 nm) and EUV light (extreme ultra violet: having a wavelength of 13 nm), as an exposure light source and a method of producing a mask blank of the type.
Following the improvement of a ULSI device having a higher density and a higher accuracy in recent years, a glass substrate for a mask blank is required to have a substrate surface of a finer structure. Such tendency towards the finer structure of the substrate surface becomes more and more accelerated year by year. In particular, as an exposure light source of a shorter wavelength is used, the demand for a profile accuracy (flatness) and a quality (defect size) of the substrate surface becomes strict. Thus, the glass substrate for a mask blank is required to have an extremely high flatness and to be free from a microscopic defect.
For example, in case where F2 excimer laser is used as the exposure light source, the glass substrate is required to have a flatness of 0.25 μm or less and a defect size of 0.07 μm or less. In case where EUV light is used as the exposure light source, the glass substrate is required to have a flatness of 0.05 μm or less and a defect size of 0.05 μm or less.
Upon production of a glass substrate for a mask blank, proposal has already been made of a precision polishing technique intended to reduce a surface roughness (for example, see Japanese Patent Application Publication (JP-A) No. 64-40267 (Reference 1)).
The precision polishing technique described in Reference 1 comprises the steps of polishing the substrate surface by the use of an abrasive primarily comprising cerium oxide and then finish-polishing the substrate surface by the use of colloidal silica. In case where the glass substrate is polished by the above-mentioned technique, use is typically made of a double-sided polishing apparatus of a batch type capable of receiving a plurality of glass substrates and simultaneously polishing opposite surfaces of the glass substrates.
In the precision polishing technique mentioned above, it is theoretically possible to achieve a desired flatness by reducing an average grain size of abrasive grains. Actually, however, under the influence of a mechanical accuracy of various components of the polishing apparatus, including a carrier for holding the glass substrate, a surface table for clamping the glass substrate, and a planetary gear mechanism for moving the carrier, and so on, the flatness of the glass substrate stably obtained is limited to about 0.5 μm.
In view of the above, proposal has recently been made of a leveling method for leveling or flattening the glass substrate by local machining using plasma etching or a gas cluster ion beam (for example, see Japanese Patent Application Publication (JP-A) No. 2002-316835 (Reference 2) and Japanese Patent Application Publication (JP-A) No. H08-293483 (Reference 3)).
The leveling method disclosed in References 2 and 3 comprises the steps of measuring a surface profile (convexity and concavity, peak and valley) of the glass substrate and executing local machining upon a convex portion under a machining condition (such as the amount of plasma etching or the amount of the gas cluster ion beam) depending upon the degree of convexity of the convex portion so as to flatten the surface of the glass substrate.
In case where the flatness of the surface of the glass substrate is adjusted by the local machining using the plasma etching or the gas cluster ion beam, a roughened surface or a machining-affected layer (a damaged layer) is formed on the glass substrate after the local machining. Therefore, it is necessary to perform polishing for a short time after the local machining in order to repair the roughened surface or to remove the machining-affected layer.
However, if polishing is performed in the state where machining scraps of the glass substrate or a reaction product produced by local machining are left on the surface of the glass substrate, microscopic defects having a depth on the order of several nanometers to several tens nanometers are caused on the surface of the glass substrate. As a result, it is impossible to obtain the glass substrate having a surface roughness Ra of 0.2 nm or less. The surface roughness Ra is representative of a center-line-mean roughness which is defined in Japanese Industrial Standard JIS B0601 and is also disclosed in U.S. Pat. No. 6,544,893 B2.

Method of producing a glass substrate for a mask blank and method of producing a mask blank


The cement admixture and the cement admixture composite of the present invention can improve the water-reducing ability of cement compositions and the like and enhance the strength and durability of hardening products produced therefrom and further can adjust the viscosity of such compositions so as to facilitate the works at the sites of handling the same. The above-mentioned cement admixture is a cement admixture comprising a polycarboxylic acid polymer containing a specific site, and the above-mentioned cement admixture composite comprises two or more species of cement admixtures, wherein at least one of them is said cement admixture.

Cement admixtures comprising a polycarboxylic acid polymer have been widely used for cement compositions such as cement paste, mortar, and concrete. They are now essential in constructing civil engineering and building structures and the like from a cement composition. Such cement admixtures are used as a water reducing agent and the like. They increase the fluidity of cement compositions to thereby reduce the water requirement of the cement compositions and therefore are effective in improving the strength, durability, and the like, of hardening products. As such water reducing agents, polycarboxylic acid water reducing agents comprising polycarboxylic acid polymers as main component, which are superior in water-reducing performance to naphthalene and other conventional water reducing agents, have already led to good results in many cases as air-entraining and high-range water-reducing admixture.
However, cement admixtures are required to be able not only to show water-reducing performance in such cement compositions but also to improve cement compositions in viscosity to thereby facilitate the works at the sites of handling them. Thus, they are required at the sites of civil engineering and building structure construction not only to be able to show water-reducing performance but also to provide a viscosity in such the level that the works will be facilitated at the sites of handling them. If a cement admixture can exhibit such performance characteristics, it will improve the working efficiency in civil engineering and building structure construction.
With respect to such requirements, Japanese Kokai Publication Hei-09-248438 proposes a dispersant for decreasing the viscosity of hydraulic compositions such as cement. However, in construction sites, it is required to make cement compositions easier to be handled, and have improved basic performances. Thus, it has been asked for providing cement admixtures satisfying such requirements.

Cement admixture and cement admixture composite


A calibration device and method for lateral force calibration in small force measuring devices such as atomic force microscopes is disclosed. A platform has a substantially planar surface including a slot for accommodating at least part of the AFM cantilever tip, one or more supporting legs arranged to provide sprung resistance to the platform and a capacitive drive means for driving the platform laterally with respect to the AFM cantilever tip.

Measurements of small forces, in the nanonewton and piconewton range, have become important in recent years due to the widespread use of the Atomic Force Microscope (AFM) and associated instruments. There is a need to measure such small forces accurately, for example, protein-protein interactions or materials properties via the small force applied to an indenting tip.
The quantification of interaction forces is much more problematic. Force on the tip is inferred from the deflection of the cantilever, using an assumed value for the cantilever spring constant. The accuracy to which the spring constant is known is the limiting factor in the accuracy of a force measurement. Many methods have been proposed for calibrating the stiffness of an AFM probe, but none are traceable, and typical accuracy is only about 20-30%.
Reference artifacts for dimensional calibration of AFM have been available from many sources for ten years or more, but calibration of the force constant of AFM cantilevers is more troublesome. Uncalibrated cantilevers lead to very large errors in the measurement of nanonewton forces, such as in direct experiments to break individual covalent bonds by AFM, or the measurement of protein interaction forces. Commercial reference artifacts are available, but offer no traceability to the SI measurement system. This is important because there are two important methods of measuring nanoscale forces, AFM and optical tweezers. AFM is most conveniently calibrated using reference cantilevers, whereas optical tweezer forces are estimated based on the rate of change of photon momentum. Both methods are used, for example, in measuring bond-breaking forces. They must both have a common force scale, or burgeoning work in both areas will be difficult to build-upon. What is more, a traceable calibration method is now timely.
AFMs measure topography accurately, and are calibrated for this purpose quite easily using step-height standards. Some AFM instruments even incorporate laser interferometry to make traceable height measurements. However accuracy is rarely mentioned for AFM force measurements. There is an increasing need for the accurate measurement of small lateral forces by AFM, in the mechanical analysis of contamination on semiconductor surfaces, polymer blends, functional thin films, recording media and measuring adhesion of nanoparticulates at surfaces. The lateral force signal is useful for identifying surface composition where the materials are relatively flat but have significantly different friction characteristics. When combined with the use of chemically functionalised AFM tips, lateral force imaging can reveal contrast between different surface species where none can be seen in any other scanned probe mode. Many existing and future applications use the lateral force signal only to provide image contrast, but in many other applications the quantitative comparison of lateral force measurements is essential. This has been difficult so far, due to the wide range of torsional constants seen in even supposedly similar cantilevers. Cantilever coatings, to improve reflectivity, or chemically functionalise the tip, can have a significant effect on spring and torsional constants that are difficult to model. A calibration method is required.
A wide variety of methods have been used to calibrate normal spring constant, including thermal vibrations, reference cantilevers of measured dimensions, and radiation pressure. Commonly assigned co-pending patent application No. PCT/GB2004/002134, which is herein incorporated by reference discloses a MEMS device designed for the calibration of normal forces in AFMs, allowing piconewton and nanonewton force measurements to be made traceable to the SI system. However, calibration of lateral forces is more of a problem. Thermal vibrations can be useful, but there are fewer other options. Many of the methods that have been tried for the purpose of normal force calibration have extensions to allow the calibration of lateral forces, but some have no obvious method of being extended in this way, and are likely to be limited to the calibration of normal forces only. Those existing methods able to measure the torsional constant typically require accurate dimensional measurements (e.g. in an SEM) or high frequency power spectrum measurement that is beyond the bandwidth of the signal amplifiers supplied as part of the AFM electronics. In other words, these methods require additional facilities the AFM user may not have access to, and even if available, requires special training to achieve the accuracy needed.

The Secretary of State for Trade and Industry of Her Majesty's Britannic Government


Disclosed are substituted indolealkanoic acids useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their synthesis.

The use of aldose reductase inhibitors (ARIs) for the treatment of diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/NAD+ ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase.
The use of aldose reductase inhibitors for the treatment of diabetic complications has been extensively reviewed, see: (a) Textbook of Diabetes, 2nd ed.; Pickup, J. C. and Williams, G. (Eds.); Blackwell Science, Boston, Mass. 1997; (b) Larson, E. R.; Lipinski, C. A. and Sarges, R., Medicinal Research Reviews, 1988, 8 (2), 159-198; (c) Dvornik, D. Aldose Reductase Inhibition. Porte, D. (ed), Biomedical Information Corp., New York, N.Y. Mc Graw Hill 1987; (d) Petrash, J. M., Tarle, I., Wilson, D. K. Quiocho. F. A. Perspectives in Diabetes, Aldose Reductase Catalysis and Crystalography: Insights From Recent Advances in Enzyme Structure and Function, Diabetes, 1994, 43, 955; (e) Aotsuka, T.; Abe, N., Fukushima, K.; Ashizawa, N. and Yoshida, M., Bioorg. & Med. Chem. Letters, 1997, 7, 1677, (f) T., Nagaki, Y.; Ishii, A.; Konishi, Y.; Yago, H; Seishi, S.; Okukado, N.; Okamoto, K., J. Med. Chem., 1997, 40, 684; (g) Ashizawa, N.; Yoshida, M.; Sugiyama, Y.; Akaike, N.; Ohbayashi, S.; Aotsuka, T.; Abe, N.; Fukushima, K.; Matsuura, A, Jpn. J. Pharmacol. 1997, 73, 133; (h) Kador, P. F.; Sharpless, N. E., Molecular Pharmacology, 1983, 24, 521; (i) Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E., J. Med. Chem. 1985, 28 (7), 841; (j) Hotta, N., Biomed. & Pharmacother. 1995, 5, 232; (k) Mylar, B.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.; Dee, F. D.; Siegel, T. W.; Singleton, D. H., J. Med. Chem. 1991, 34, 108; (l) Dvornik, D. Croatica Chemica Acta 1996, 69 (2), 613.
Previously described aldose reductase inhibitors most closely related to the present invention include those sighted in: (a) U.S. Pat. No. 5,700,819: 2-Substituted benzothiazole derivatives useful in the treatment of diabetic complications, (b) U.S. Pat. No. 4,868,301: Processes and intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains, (c) U.S. Pat. No. 5,330,997: 1H-indazole-3-acetic acids as aldose reductase inhibitors, and (d) U.S. Pat. No. 5,236,945: 1H-indazole-3-acetic acids as aldose reductase inhibitors. Although many aldose reductase inhibitors have been extensively developed, none have demonstrated sufficient efficacy in human clinical trials without significant undesirable side effects. Thus no aldose reductase inhibitors are currently available as approved therapeutic agents in the United States; and consequently, there is still a significant need for new, efficacious and safe medications for the treatment of diabetic complications.

This patent is subject to a terminal disclaimer.

The Institute for Pharmaceutical Discovery, LLC


Each of one or more devices to be detachably attached to a mechanical substructure includes rails on opposed sides with insertion/extraction mechanisms. Each of a plurality of pairs of guides mounted on the substructure slidably receives and retains a respective set of rails upon attachment of the devices. The insertion/extraction mechanism includes one or more pivotable handles associated with each device for retaining the device with the substructure. A spring extending from a rail makes electrical contact with electrostatic discharge ground pads on the substructure to discharge existing static charge from the device prior to electrical engagement between an electrical connector on the device and an electrical connector on the substructure. An apertured plate of the substructure includes a plurality of apertures through which the devices are inserted/extracted. A face plate may be hingedly attached to and removable from the apertured plate to cover all of the apertures therein that accommodate insertion/extraction of the devices.

1. Field of the Invention
The present invention relates to mating assemblies and, more particularly, to a guide assembly for mechanically supporting and electrically connecting a rail mounted device.
2. Description of the Related Prior Art
Various mechanical substructures, such as printed wiring boards and other mechanical devices provide support for detachably attached devices of various sorts that are electrically connected to elements attendant the mechanical substructure. No industry standard presently exists for mounting such devices on the mechanical substructure. Accordingly, provisions must be made unique to each device to mount same. Furthermore, the electrical interconnections vary widely in type and usually require manual engagement. The potential for substantial damage due to static electricity to components mounted on the mechanical substructure or components of a device being mounted exists. To dissipate any electrostatic charges, known procedures must be employed but the carrying out of such procedures is sometimes omitted with attendant actual or potential damage to one or more components.

Apparatus for inserting, retaining and extracting a device from a compartment


A method and system for producing an image to be displayed are disclosed herein. The image includes a plurality of pixels. An example of the method includes dedicating a fixed amount of memory to store a data structure for a pixel of plurality of pixels. The method also includes building a visibility function and determining a partial color sum for each fragment of the plurality of fragments. A pixel color is determined using the visibility function and the partial color sums.

Correctly rendering transparent surfaces might require sorting many transparent fragments back-to-front or front-to-back for each pixel on the screen. This operation can be very intensive from a computational and memory bandwidth standpoint, and is generally slow and power inefficient. Known methods employ an a priori unbounded amount of memory, which is proportional to the amount of visible transparent fragments on the screen.
Some methods of approximation that do not require sorting transparent fragments are known. These methods are relatively faster and more efficient, but still require an unbounded amount of memory. Additionally, these methods may use two or more rendering passes in order to generate the desired image.
The same numbers are used throughout the disclosure and the figures to reference like components and features. Numbers in the 100 series refer to features originally found in FIG. 1; numbers in the 200 series refer to features originally found in FIG. 2; and so on.

Real-time order-independent transparent rendering


The present subject matter relates to methods and compositions for identifying soybean plants that having increased Phytophthora root and stem rot resistance. The methods use molecular markers to identify and to select plants with increased Phytophthora root and stem rot resistance or to identify and deselect plants with decreased Phytophthora root and stem rot resistance. Soybean plants generated by the methods disclosed are also a feature of the present subject matter.

Phytophthora root and stem rot (PRSR), caused by the soil borne pathogen Phytophthora sojae, has been reported in most soybean growing areas throughout the world, since it was first noted in Indiana in 1948 and again in Ohio in 1951 (Dorrance et al. 2007; Erwin and Ribeiro 1996; Kaufmann and Gerdemann 1958; Schmitthenner 1985). PRSR was ranked as the second most destructive soybean disease after soybean cyst nematode (SCN) that suppressed soybean yield in the United States from 1996 to 2009, which caused the annual yield losses of 44.7 million bu (Koenning and Wrather 2010; Wrather and Koenning 2009).
Deployment of race-specific resistant soybean cultivars has been the primary strategy for the management of PRSR as it is highly effective and economically and environmentally safe in reducing soybean yield losses from Phytophthora disease (Dorrance et al. 2007; Dorrance and Schmitthenner 2000; Schmitthenner 1999). To date, approximately 25 Rps genes/alleles have been identified, distributing at 19 loci across eight different chromosomes. Chromosome 3 (Chr. 3) (MLG N) has the most Rps genes/alleles mapped, including Rps1a, Rps1b, Rps1c, Rps1d, Rps1k, Rps7, Rps9, RpsUN1, RpsYu25, RpsYD29, and an unnamed Rps gene reported in a Japanese cultivar 'Waseshiroge' (Demirbas et al. 2001; Fan et al. 2009; Gao et al. 2005; Lin et al. 2013; Sugimoto et al. 2011; Sun et al. 2011; Weng et al. 2001; Wu et al. 2011a; Yao et al. 2010; Zhang et al. 2013). Two Rps genes, Rps2 and RpsUN2, have been mapped at the end of Chr. 16 (MLG J), which is a well-known resistance gene cluster region (Kanazin et al. 1996; Lin et al. 2013; Polzin et al. 1994). Interestingly, Rps3 (containing three alleles 3-a, 3-b, 3-c) and Rps 8 have been mapped to another resistance gene rich region on Chr. 13 (MLG F) (Demirbas et al. 2001; Gordon et al. 2006). RpsJS, a recently identified Rps gene, is linked with Rps4, Rps5, and Rps6 and all of which are located on the short arm of Chr. 18 (MLG G) (Demirbas et al. 2001; Sandhu et al. 2004; Sun et al. 2014). In addition, RpsYB30, Rps ZS18, RpsSu and Rps10 have been mapped to Chr. 19 (MLG L), Chr. 2 (MLG D1b), Chr. 10 (MLG O) and Chr. 17 (MLG D2), respectively (Wu et al. 2011b; Yao et al. 2010; Zhang et al. 2013; Zhu et al. 2007).
Many of these Rps genes have already been successfully deployed in soybean breeding programs to control PRSR. Nevertheless, these genes may only be effective for 8 to 15 years due to the rapid and continuous evolving of the pathogen under selection pressures (Schmitthenner 1985). In addition, pyramiding known Rps genes into a single cultivar may not be an effective long-term breeding strategy because a recombining pathogen population could create new combinations of virulence alleles as rapidly as breeders can stack resistance genes (McDonald and Linde 2002). Therefore, identifying novel Rps genes is still needed to effectively manage Phytophthora disease.
A novel Phytophthora resistance locus is identified in this disclosure. In addition, markers linked to the disclosed novel Phytophthora resistance locus are also identified. Markers that are linked to the novel Phytophthora resistance locus include SSR, InDel and SNP markers. The markers identified in this disclosure can be used for Phytophthora resistance genotyping to support a breeding program. Using the presently disclosed markers to perform Phytophthora resistance genotyping in support of a breeding program provides, among other benefits: cost and time savings; early selection of desired progeny; and more accurate and rapid commercialization of Phytophthora resistant soybean varieties. Candidate genes underlying the phenotype for the novel Phytophthora resistance locus disclosed herein are also described.

Genetic locus associated with phytophthora root and stem rot in soybean


Digital maps digitized by scanning paper maps are smoothed by identifying regions which should be of a uniform color, empirically selecting sets of colors which the pixels of a given region might have in the raw map, empirically determining the statistical probability of occurrence of pixels of each color of the selected set in the region, defining groups of connected pixels having colors within the selected set, and resetting the color of all the pixels in a group to a predetermined region color if, and only if, the pixels of the group satisfy the determined statistical probability of occurrence. The inventive method provides uniform coloring of the map where desired, without affecting the sharpness of small-print map annotations.

A number of systems have been developed in recent years, mostly for military and transportation industry purposes, which involve the electronic projection, on a screen located in a vehicle or aircraft, of a map showing relevant information regarding the area in which the vehicle or aircraft is traveling. Such maps are known as digital maps because they are composed, like a video image, of a large number of pixels whose color is digitally encoded.
Digital maps are conventionally produced by scanning printed paper maps to generate a digital electronic image of the paper map. The quality of the digitization is adversely affected by a variety of factors relating to the printing and scanning process. These factors are principally the following:
a) The paper map has defects introduced by the printing process (e.g. uneven inking or ink smears). PA1 b) Noise is introduced by the scanning process. In other words, the color that is sampled for a pixel will not be completely accurate. PA1 c) When the paper map is printed, some regions are represented by numerous small dots of similar or different colors. On physical paper maps, these regions appear to the eye as being of a single solid color, but they show up as noise when digitized. PA1 a) the map appears noisy on the screen, especially on a close-in zoom. For example, an ocean area, which one would expect to be solid blue, appears on the screen as several different shades of blue with white dots scattered in regular patterns. PA1 b) The compression efficiency is decreased. These maps take up considerable room on the computer's hard disk, so it is desirable to compress them as much as possible. The more uniformly colored the map is, the more it can be compressed.
The limited quality of the digitization causes two principal problems when the digitized data is imaged on a computer monitor:
Consequently, although the prior art digital maps have proven generally suitable for their intended purposes, they possess inherent deficiencies which detract from their overall effectiveness.
The prior art has attempted to solve this problem by traditional image smoothing methods using, for example, averaging or interpolating techniques which work well on "real" images such as scenes. These methods, however, can have undesirable side effects when used on "artificial" images such as maps, because they tend to blur fine-print annotations which are a vital component of maps.
It is thus desirable to provide a way to smooth out the noisy appearance of the imaged map, and to so modify it as to maximize its compressibility, yet without degrading the map annotations. Although this is a well recognized problem, the proposed solutions have, to date, been ineffective in providing a satisfactory remedy.

Heuristic smoothing filter for digital maps


The invention concerns a transparent and polarizing viewing element (2) divided into several zones (2a, 2b). At least one of the zones (2a) is associated with a light polarizing filter. The light passing through the optical surface is affected differently for two of said zones (2a, 2b) depending on the polarizing direction of said light. The polarizing filter is obliquely oriented relative to a horizontal direction (H) in the operational position of the element (2; 5), with an angle between the filter orientation and said horizontal direction of 90 degrees and of 0 degree.

U.S. Pat. No. 6,250,759 discloses spectacle lenses designed for recreational activities, such as golf, hunting or fishing. Such lenses are divided into several zones, the light transmission characteristics of which are adapted according to the objects or the scene observed when these activities are being practiced. In particular, separate zones of the lens may have different light-filtering characteristics depending on a polarization of said light.
The field of view of a vehicle driver, a motorcyclist or an aircraft pilot has particular characteristics. In particular, it comprises two separate portions. A first portion of the field of view, generally a lower portion of the field, is occupied by the instrument panel of the vehicle or aircraft. The instrument panel often incorporates one or more displays, for example of the liquid-crystal display type. Such displays produce light whose polarization characteristics depend on the technologies used and on the ergonomic choices made by the designers of driver or pilot compartments. In particular, it is possible to consider two display technology families, namely passive-matrix displays and active-matrix displays. In particular, the illumination state of a pixel of the screen corresponds:                in the case of STN (supertwisted nematic) passive-matrix displays, to the emission of polarized light oriented at an angle of 0°;        in the case of DSTN (double supertwistednematic) passive-matrix displays, to the emission of polarized light oriented at an angle of +90°; and        in the case of TFT (thin-film transistor) active-matrix displays, to the emission of polarized light oriented at an angle of +45°.
The abovementioned angles are given relative to a horizontal reference direction. When looking at the observer, the 0° reference direction is oriented to the right and the angles are counted positively in the counterclockwise sense.
The second portion of the field of view is occupied by the external scene, visible through the windshield or directly in the case of a motorcyclist. This second portion of the field in general constitutes an upper portion of the field of view of the driver or pilot. It is therefore located above that portion of the field of view occupied by the instrument panel. The light that comes from the external elements located in this second portion of the field of view is usually unpolarized, that is to say natural light. However, it may also be polarized following a reflection on a transparent surface.
The visibility of the instrument panel displays constitutes a major challenge in the design of driver or pilot compartments. This is because the contrast of the displays is attenuated by the light that enters the driver's compartment or into the cockpit, or which is present around a motorcycle driver, and which illuminates the observer and the instrument panel. It may then be difficult to distinguish between the lit and unlit states of the pixels of the display.
A dark rim is often placed above the displays of the instrument panel in order to reduce the amount of ambient light that illuminates these displays. However, such rims are not very effective, and they are unattractive and bulky. Furthermore, they may impede the accommodation of the driver's or pilot's eye when it moves from the instrument panel to the external visible scene, or conversely from the scene to the instrument panel.

Transparent and polarizing viewing element having a zone associated with an obliquely oriented polarizing filter

Essilor International (compagnie Generale D'optique)


The invention relates to a master cylinder, in particular for a controlled motor vehicle brake system, including a first and a second piston which is displaceable in a housing and has a captive spring, a first end of the spring bearing at least indirectly against the piston and a second end thereof against a sleeve which is displaceable with respect to the piston and the movement of which with respect to the piston is limited by a pin provided on the piston and by a stop washer, the stop washer being arranged on a free end of the pin. In order to avoid impact noise upon rapid release of the brake, the stop washer of the first piston has a device for the damped abutment of the sleeve.

A master cylinder of this type is known, for example, from DE 10 2004 057 137 A1, which is incorporated by reference. It is considered to be a disadvantage of the known master cylinder that upon rapid release of the brake the sleeve of the first piston abruptly strikes the stop washer, since the captive spring urges the first piston back to its starting position against the direction of actuation. In this case undesired impact noise is produced and is transmitted into a passenger compartment of the vehicle via a braking force booster fastened to the master cylinder.

Master cylinder in particular for a controlled motor vehicle brake system


A method for assembling an electrical connecting apparatus having a support member, a probe board, and spacers arranged between the support member and the probe board. A height of at least either each abutting part of the support member or each abutting part of the probe board facing the abutting part is measured, and a length of each of the plurality of spacers is measured. Based on measurement values obtained by these measurements, a spacer appropriate for maintaining tips of numerous probes provided on the probe board on the same plane is selected for each pair of the both abutting parts.

As one of the conventional electrical connecting apparatuses of this kind is proposed an electrical connecting apparatus comprising a probe board provided with a plurality of probes and enabling adjustment of the planarity of the probe board (refer to Patent Document 1). With this conventional electrical connecting apparatus, a thrusting force or a tensile force can act from a support member supporting the probe board toward a part of the probe board. Adjustment of this acting force can correct bent deformation of the probe board even if the probe board is bent to maintain the planarity of the probe board.
Accordingly, since the planarity of the probe board can be maintained by the aforementioned adjustment work after the probe board has been attached to the support member even if the probe board is bent and deformed at the time of manufacture of the probe board provided with the plurality of probes, the tips of the plurality of probes extending from the probe board can be held on the same plane. Thus, since the tips of all the probes can reliably contact electrical connecting terminals, corresponding to the respective probes, of an electrical circuit as a device under test, efficient electrical contact can be attained between them.
However, in the aforementioned prior art described in Patent Document 1, adjustment is needed every time of attachment of the probe board to the support member in accordance with bent deformation introduced in each probe board so that all the probe tips are located on the same plane. The adjustment work to make all the probe tips appropriately contact the aforementioned corresponding respective electrical connecting terminals of the device under test in a state where the probe board is attached to the support member is troublesome and requires skills. Especially, in a test of numerous integrated circuits formed on a semiconductor wafer, the number of probes of the probe assembly significantly increases, and thus the adjustment work to let such numerous probes appropriately contact the corresponding respective pads on the semiconductor wafer is not easy.
Under such circumstances, the present applicant proposed in a prior International Patent Application (PCT/JP2005/009812) an electrical connecting apparatus that requires no planarity adjustment work of the probe board after being attached to the support member regardless of the deformation of the probe board and enables reliable electrical connection between the probes and the corresponding electrical connecting terminals of the electrical circuit as a device under test.
In this electrical connecting apparatus, the probes are formed on the probe board that is bent and deformed in a free state under no load so that the tips are aligned on the same plane. Between the attachment surface of the support member and the probe board is arranged a spacer allowing an attachment bolt to pass therethrough, and the spacer acts to keep the aforementioned deformation of the probe board at the time of tightening of the attachment bolt. Accordingly, since the probe board is attached to the reference surface of the aforementioned support member in a state of keeping the aforementioned deformation, all the probe tips are located on the same plane.
Thus, after the probe board is attached to the support member, the tips of all the probes can be thrust to the respective electrical connecting terminals of the electrical circuit as a device under test approximately uniformly without the need for the conventional adjustment work for planarization of the probe board. As a result, the aforementioned conventional troublesome planarity adjustment work is not needed per replacement of the probe assembly, which enables an efficient electrical test.
However, the length dimension of the space of this kind includes a process tolerance, which is an allowable error at the time of manufacture of it. Also, the respective abutting parts of the support member and the probe board receiving the edge surfaces of the spacer also include respective process tolerances. Thus, even when the electrical connecting apparatus having the support member, spacer, and probe board manufactured within the respective process tolerances is assembled, variation exceeding a predetermined tolerance may occur in the height positions of the probe tips due to the synergistic effect of the process tolerances of the respective parts.
In order to restrict this variation, there is an idea of decreasing the respective process tolerances of the support member, the spacer whose one edge abuts on the attachment surface of the support member, and the probe board on which the other edge of the spacer abuts. However, heightening their process accuracies to decrease the process tolerances of the respective component parts raises their costs, as a result of which the price of the electrical connecting apparatus gets high.
[Patent Document 1] Japanese Patent Appln. Public Disclosure No. 2003-528459

Method for assembling electrical connecting apparatus


A magazine for a firearm having a magazine well has a body with the chamber for receiving ammunition. The body has an upper opening to the chamber, and has a contact portion with adjustable screws that contact a surface in the magazine well. Adjustment of the screws is used to establish a precise selected position of the magazine with respect to the receiver, permitting adjustment of the feed height, feed angle and ejector position. Four screws are provided, one at each corner of the upper surface of the magazine.

Firearm receivers that utilize a magazine designed for Ruger model 10/22 firearms all have dimensional differences in the area where the magazine mates with the receiver. Even firearms from the same manufacturer of the same model designation have differences in the receiver dimensions. As a result, existing available magazines have had to be manufactured with sufficiently loose fits to enable them to try to fit as many combinations of receivers as possible, with the accompanying result that they do not fit any one receiver very well, to the performance detriment of the firearm.
Function of a firearm is directly related to the fit of the magazine in the receiver, so loose fitting magazines may cause unreliable firearm functioning. On the other hand, the more exactly the magazine fits the firearm receiver, the more reliable the function of the firearm can be expected to be. This is in conflict with the need to manufacture loose fitting magazines to ensure insertability in receivers that are of varying tolerances from the manufacture's intended optimal design specification.
In addition, even if all receivers were manufactured to dimensional perfection manufacturing variations in magazines may generate unreliability. Further, different brands and lots of ammunition may require different dimensional relationships between a magazine and the receiver.
There is a need for a magazine that fits into a wide range or receiver tolerances, with reliable function in each.
The present invention overcomes the limitations of the prior art by providing a magazine for a firearm having a magazine well that has a body with the chamber for receiving ammunition. The body has an upper opening to the chamber, and has a contact portion with adjustable screws that contact a surface in the magazine well. Adjustment of the screws is used to establish a precise selected position of the magazine with respect to the receiver, permitting adjustment of the feed height, feed angle and ejector angle. Four screws are provided, one at each corner of the upper surface of the magazine.

Firearm magazine with position adjustment


A thin, lightweight electrical connector box utilizing fewer components due to a construction in which air, instead of insulator boards, is used as the insulating material between the ECU, other electrical components, and an internal circuit contained within the electrical connector box. Externally facing connector modules are sandwiched between a lower case and un upper case. Mounting posts are formed on each end of connector modules to fixedly secure two ends of an ECU baseboard through insertion into opposing holes formed therein. The ECU baseboard is supported by connector modules within the region between the lower case and the upper case.

1. Field of the Invention
The present invention relates to an electrical connector box including an improved structure for the internal support of an electronic control unit (ECU).
2. Description of Related Art
Japanese Kokai Patent 2002-84630 is an example of a prior art electrical connector box constructed to enclose an electronic control unit within a case. FIG. 7 illustrates electrical connector box 1 which is described by JP 2002-84630. As FIG. 7 illustrates, multiple bus bars 4 and insulator boards 5 are oriented in a stacked configuration within a case formed by upper case 2 and lower case 3, each bus bar 4 having been press blanked from a sheet of electrically conductive metal. Insulator board 6 is located between ECU 7 and bus bars 4.
Locating insulator board 6 between ECU 7 and bus bars 4 and other devices, however, increases the number of required components as well as the size and weight of electrical connector box 1.
In automotive applications where the electrical connector box is placed within the instrument panel opposing the front passenger seat facing the passenger's knees, it is preferable that space be provided between the instrument panel and the electrical connector box to provide a crush zone to lessen the force of impact should the passenger happen to strike the instrument panel as a result of sudden braking.


Apparatus for treating waste, particularly all types of medical waste, to facilitate its disposition includes a treatment vessel having an open top pivotal within a housing to a waste-loading position with its open top aligned with the housing inlet for receiving the waste, a waste-treating position for shredding the waste by a shredder unit disposed within the treatment vessel, and a waste-removing position with its open top aligned with the housing outlet for removing the shredded waste. The apparatus further include a compactor head for compacting the waste within the treatment vessel, a water feed line, and a disinfectant feed line, for feeding water and a disinfectant into the treatment vessel, for mixing with the waste while it is being compacted and shredded.

The present invention relates to apparatus for treating waste to facilitate its disposition. The invention is particularly useful for treating medical waste of all types, and is therefore described below with respect to this application.
Waste in general, and medical waste in particular, present a number of disposal problems. Medical waste, as generated in medical, veterinary, dental and laboratory facilities, includes a wide variety of forms, such as bandages, gloves, infusion bags, hypodermic needles, syringes, products of dialysis, human and animal waste. Such waste must be disposed in a safe, expeditious and hazard-free manner. In large medical facilities, the medical waste is generally collected at a central location and disposed by incineration, grinding, and/or heating. Such processes are not only costly, but may also be environment-unfriendly in the odors generated or in the degradation of the environment.
Because of the different types of medical waste to be disposed, a number of devices have been developed which include shredders for shredding the medical waste in order to reduce the overall volume and to facilitate sterilization. Examples of apparatus of this type are described in U.S. Pat. No. 5,673,861 by Charles Miller, and in U.S. Pat. No. 5,620,654 by Beni Mosenson, one of the inventors in the present application. While the invention described in the latter patent has been incorporated in commercial apparatus, such an apparatus is relatively large and costly, and therefore has been found to be more suitable for relatively large medical facilities, such as large-size and medium-size hospitals, than for relatively small facilities, such as medical, dental, veterinary and dialysis clinics.
An object of the present invention is to provide a relatively simple and compact apparatus for disposing of waste in general, and medical waste in particular, in a safe, expeditious and hazard-free manner. Another object of the invention is to provide such an apparatus particularly suitable for use by relatively small facilities such as medical, dental, dialysis and veterinary clinics.
According to one aspect of the present invention, there is provided apparatus for treating waste to facilitate its disposition, comprising: a housing having an inlet for introducing the waste to be treated; a treatment vessel within the housing and having an open top for receiving and removing the waste, the treatment vessel being pivotal to a waste-loading position with its open top aligned with the housing inlet for receiving waste introduced therethrough, and to a waste-treating position for treating the waste within the treatment vessel; and a shredder within the treatment vessel for shredding waste therein before being removed from the treatment vessel.
The term shredder, as used herein, is intended to include any device which shreds, grinds, or otherwise reduces the waste materials to small particles or pieces for disposal.
According to further features in the described preferred embodiments, the housing also has an outlet, separate from the inlet, for removing the waste after its treatment; and the treatment vessel is also pivotal to a waste-removing position with its open top aligned with the housing outlet for removing therethrough the waste after treatment in the treatment vessel.
According to further features in the described preferred embodiments, the shredder is driven by a drive within the housing and coupled to the shredder within the treatment vessel by a shaft passing through a side wall of the treatment vessel; the treatment vessel is pivotally mounted about the shaft.
According to further features in the described preferred embodiment, the apparatus further comprises: a compactor head aligned with the open end of the treatment vessel when the treatment vessel is in the waste-treating position so as to be reciprocatable within the treatment vessel to compact the waste therein; and a control system permitting operation of the compactor head only when the treatment vessel is in its waste-treating position. A water supply line feeds water into the treatment vessel to be mixed with the waste therein during the operation of the compactor head and shredder.
When the apparatus is to be used for disposing medical waste, the apparatus would further comprise a feed line for feeding a disinfectant into the treatment vessel to be mixed with the waste and the water during the operation of the compactor head. In one described preferred embodiment, the disinfectant is a liquid disinfectant fed into the treatment vessel via the compactor head so as to be mixed with the waste and the water within the treatment vessel during the operation of the compactor head. In another described preferred embodiment, the disinfectant is ozone which is fed directly into the treatment vessel during the operation of the compactor head.
According to further features in the described preferred embodiments, the housing outlet is occupied by a waste-removal drawer normally in an inner position aligned with the open end of the treatment vessel when the treatment vessel is in its waste-removing position to receive the waste therefrom, but is movable outwardly to enable removal of the waste from the drawer. Preferably, the waste-removal drawer has a bottom which is slanted downwardly from its outer side toward its inner side to permit liquid in the treated waste to separate from the solids and to drain to the inner side of the drawer. The drawer includes an outlet opening at its inner side to drain the liquid therefrom.
As will be described more particularly below, such apparatus provides a number of important advantages particularly making it suitable for use in small facilities for disposing medical waste. Since the complete treatment, from the introduction of the raw medical waste to its final disinfected and disposable form, is performed in a single treatment vessel, the handling of the medical waste is greatly simplified, and the chances of infecting handlers or equipment are greatly reduced. Since the treatment vessel in which the waste is treated is pivotally mounted to its various positions for loading, treating and removing the waste, the invention may be implemented in compact apparatus of relatively small size suitable for small offices and clinics. In addition, the provision of the compactor head, the water supply line, and the disinfectant feed line, enable the medical waste to be converted to a reduced-volume and disinfected form for disposable in a safe, expeditious and hazard-free manner.
Further features and advantages of the invention will be apparent from the description below.

Apparatus for treating waste, particularly medical waste, to facilitate its disposition


A checkout device which can be gripped for carrying, installation, and removal. The checkout device includes a generally L-shaped housing including a first housing portion suited to placement within a checkout counter, and a second housing portion mounted above the first housing portion and suited to extending above the checkout counter. The first and second housing portions include a barcode reader for sending scanning light beams from a first aperture in the first housing portion and a second aperture in the second housing portion to form a multi-line scan pattern. The second housing portion has a rear surface including a hand grip.

The present invention relates to a checkout device and more specifically to a checkout device with a hand grip.
Large barcode scanners, such as multi-aperture barcode reader, may be heavy and awkward to carry, install, or remove.
Therefore, it would be desirable to provide a checkout device with a hand grip.


A system and method for generation and display of a dynamic looming ball deviation symbology (DLBDS) to a pilot receives inputs from a plurality of sources and displays a single source 3D deviation indicator to limit a scan requirement of a pilot. The system generates and displays the DLBDS relative to an ownship flight path marker intuitively useful to indicate each of a lateral deviation, a vertical deviation, and a longitudinal deviation relative to a desired object or position relative to the desired object. The DLBDS is displayed relative to the ownship aircraft and indicates deviation to be corrected to position the aircraft at the desired position relative to the object.

Increasing situational awareness may be a continuous goal of aviation professionals. A lack of situational awareness may be a causal factor in many aircraft accidents.
One limitation in pilot situational awareness may include an overload of displayed information available to the pilot. Too much information may be as hazardous as not enough information. With multiple sources of guidance information, a pilot may become overloaded and a pilot scan may break down leading to deviation in one or more axes of desired trajectory.
Traditional flight directors may display deviation in only two axes: vertical and lateral. This limitation requires a pilot to continuously take eyes away from a primary flight display to reference longitudinal deviation. Whether the longitudinal deviation is range, time, or speed, the pilot must look elsewhere to reference the longitudinal deviation and increase possible deviations in vertical and lateral trajectories while looking elsewhere.
Therefore, a need remains for a system and related method which may overcome these limitations and provide a novel solution to pilot guidance offering an intuitive single source of pilot guidance displayed on a pilot display.

Looming ball pilot guidance and cuing symbology


An electronic keyboard instrument includes a keyboard attachment frame section having a keyboard section; a rear frame section joined to a rear portion of the lower surface of the keyboard attachment frame section and having pedals provided at its bottom portion; and an electronic circuit that generates heat when activated and includes a power transformer and an amplifier. The electronic circuit is vertically provided on the inner surface of a rear body section of the rear frame section. Hole portions and ventilation holes are provided at a bottom portion of the rear body section. Ventilation holes are provided at the keyboard attachment frame section.

1. Field of the Invention
The present invention relates to an electronic keyboard instrument having an electronic circuit that generates heat when activated.
2. Description of the Related Art
Conventionally, an electronic keyboard instrument having a keyboard is used for musical performance. The electronic keyboard instrument has an electronic circuit that includes a power unit, a transformer, and various circuit boards. Such an electronic circuit of the electronic keyboard instrument is generally provided under or behind a keyboard in an instrument body. Accordingly, a portion of the instrument body located under or behind the keyboard assumes a large size, resulting in an increase in the overall size of the electronic keyboard instrument.
For size reduction, a certain electronic keyboard instrument (as disclosed in, for example, Japanese Utility Model Application Laid-Open (kokai) No. 5-52893) is configured as follows: a power unit and a transformer are provided on a bottom plate in the interior of a rear frame section which supports a rear portion of an instrument body; and a panel on which a computer board, and a drive circuit board for driving keys and pedals are mounted is provided above the power unit and the transformer in the interior of the rear frame section.
However, in the course of musical performance by the above-mentioned electronic keyboard instrument in which the electronic circuit including the power unit is provided in the interior of the rear frame section, the power unit and the transformer generate heat, and the heat ascends in the interior of the rear frame section. Accordingly, in the electronic keyboard instrument, the heat ascending in the interior of the rear frame section heats the panel located above the power unit and the transformer. The drive circuit board mounted on the panel including components susceptible to heat. The above-mentioned electronic keyboard instrument involves a problem that heat deteriorates those components susceptible to heat or shortens their life.


A communication unit (12) of a service center (10) transmits and receives information such as analysis information to and from a plurality of automatically analyzing apparatuses (100). A database (16) stores the information such as the analysis information. An analysis information parsing unit (14) evaluates and parses results of analyses made by the automatically analyzing apparatuses using the analysis information stored in the database. The reagent parameter registration unit (18) registers information on reagents in the database (16). The communication unit (12), responsive to a request from an automatically analyzing apparatus, retrieves information on analysis parameters related to managed reagents from the database for transfer to the automatically analyzing apparatus. In this way, analysis parameters can be readily set for a testing item to be analyzed using a reagent.

An automatically analyzing apparatus relies on a chemical reaction of a sample and a reagent introduced into an reaction container to quantitatively measure contents of the sample. For using the automatically analyzing apparatus, analysis parameters must be set into the automatically analyzing apparatus as analysis conditions, requiring a large number of steps for this work. Here, the analysis parameters refer to parameters for each testing item in the automatically analyzing apparatus, and basically include information such as the amount of dispensed sample, reagents used for an analysis and amounts thereof, the wavelength of absorbance under measurement, the type of reaction process and a method of calculating a concentration, a standard sample and known concentration for use in a calibration, and the like. The information relates to reagents, and differs from one another depending on reagent makers dedicated to the manufacturing even for reagents used for analyzing the same testing item. In addition, even with reagents manufactured by the same reagent maker, contents of analysis parameters may result in different information for different manufacturing lots. Thus, analysis parameters to be set must be always the latest analysis parameters related to reagents set in the automatically analyzing apparatus.
As a first method of setting analysis parameters into an automatically analyzing apparatus, for example, as described in JP-A-11 211731, it is known that user sets parameters through a keyboard or the like as initial settings. Also, as a second method, for example, as described in JP-A-5-288756, it is known that reagent identification bar codes adhered on reagent containers are read by a bar code reader, and a variety of parameters are read from a computer based on identification codes inscribed in the bar codes to set the parameters into an automatically analyzing apparatus.

Method of management of analytical data and system for management of analytical data


A magenta ink for ink-jet recording contains a coloring agent, water and a water soluble organic solvent. Different types of dyes are employed as the coloring agent. In particular, a dye (1) represented by the general formula (1) is used together with at least one dye selected from the group consisting of a dye (2) represented by the general formula (2) in a free acid form, C. I. Acid Red 289 and C. I. Acid Red 52.

1. Field of the Invention
The present invention relates to a magenta ink for ink-jet recording.
2. Description of the Related Art
In an ink-jet recording method, a magenta ink is required in order to form a full-color image. Generally known examples of the magenta dye used in such a magenta ink include C. I. Acid Red 14, C. I. Direct Red 227 and the like. Here, C. I. Acid Red 14 is a monoazo xanthene-based dye that is capable of imparting relatively good ejection stability and color developing properties to an ink, and C. I. Direct Red 227 is a disazo-based dye that is capable of imparting relatively good ejection stability to an ink (U.S. Pat. No. 6,228,156).
In recent years, an ink for ink-jet recording is required to not only exhibit good ejection stability and color developing properties but also to have additional characteristics such as a high level of light fastness and resistance to active gas such as ozone. Therefore, the dyes such as C. I. Acid Red 14 and C. I. Acid Red 227 are also required to exhibit these characteristics.
However, the magenta dyes such as C. I. Acid Red 14 and C. I. Direct Red 227 described above do not have sufficient light fastness and ozone resistance. Therefore, in an ink-jet recorded image produced using an ink-jet recording magenta ink containing either of such dyes, the degree of deterioration of the image is not insignificant even under normal storage conditions.
As described above, among magenta dyes commonly employed in a magenta ink for ink-jet recording, magenta dyes such as C. I. Acid Red 14 have relatively good color developing properties, i.e., they provide vivid color and have a hue suitable for obtaining a wide range of colors by color mixing. However, these dyes tend to have a relatively low level of light fastness and ozone resistance.
Meanwhile, a magenta dye such as a 1-alkyl-3-alkyl or aryl-4-cyano-pyrazole-5-yl azo dye disclosed in U.K. patent No. 1,566,985 is known to have relatively good light fastness and active gas resistance. However, a heavy metal cyanide is used in the manufacture of the dye, thereby causing problems with waste treatment. In addition to this, such a magenta dye has a hue insufficient to obtain a wide range of colors by color mixing and also has insufficient vividness. Furthermore, such a magenta dye is likely to cause problems when it comes into contact with various members employed in an ink-jet recording apparatus. Therefore, a problem exists with ejection stability during long-term use in an ink-jet printer provided with an ink-jet recording magenta ink in which such a magenta dye, having relatively good light fastness and active gas resistance is employed.


The present invention relates to manufacturing processes for the preparation of a pharmaceutical dosage form comprising nifedipine and candesartan cilexetil and optionally at least one diuretic characterized in that nifedipine is released in the body in a controlled (modified) manner and the candesartan cilexetil is released rapidly (immediate release (IR)) and optionally the diuretic is released rapidly (immediate release (IR)) and the pharmaceutical dosage forms obtainable by these processes.

The present invention relates to manufacturing processes for the preparation of a pharmaceutical dosage form comprising nifedipine and candesartan cilexetil and optionally at least one diuretic characterized in that nifedipine is released in the body in a controlled (modified) manner and the candesartan cilexetil is released rapidly (immediate release (IR)) and optionally the diuretic is released rapidly (immediate release (IR)) and the pharmaceutical dosage forms obtainable by these processes.
The calcium antagonist nifedipine is, as established active ingredient, successfully used in hypertension therapy and known from e.g. GB 1173862.
The angiotensin II antagonist candesartan, its prodrug candesartan cilexetil and its medicinal use as antihypertensive drug is known from EP 0 459 136.
Diuretics are medicaments used for eliminating water from the human or animal body. In some instances, elimination of salts, too, is increased. This results in a reduction of plasma volume and peripheral resistance. Diuretics are primarily employed for lowering blood pressure. There are various types of diuretics. Carboanhydrase inhibitors (acetazolamide): blockade of proton secretion and sodium bicarbonate re-absorption, mainly at the proximal tubulus. Nowadays use limited almost exclusively to ophthalmology for the treatment of glaucomas. Loop diuretics (furosemide, torasemide, bumetanide, etacrynic acid, piretanide): reversible inhibition of an Na/2Cl/K carrier system at the thick ascending limb of the loop of Henle. Potassium-sparing diuretics (amiloride, triamterene): blockade of the Na channels at the late distal tubulus and at the collecting tube, inhibition of Na re-absorption, as a consequence reduced K secretion. Aldosterone antagonists (spironolactone, potassium canrenoate, eplerenone): competitive binding at the aldosterone receptor, as a consequence inhibition of Na re-absorption and K secretion, used for ascites associated with cirrhosis of the liver and as additional therapeutic for chronic heart failure. Thiazide diuretics and other sulphonamide diuretics (hydrochlorothiazide (=HCTZ), chlorothiazide, chlorthalidone, xipamide, indapamide, mefruside): reversible inhibition of the Na—Cl cotransport at the early distal tubulus (luminal), inhibition of carboanhydrase, reduction of GFR, hydrochlorothiazide frequently employed in combination with antihypertensive agents. The addition of a diuretic such as, for example, HCTZ in monotherapy enhances the hypotensive action of the combination.
Combinations of a diuretic and angiotensin II antagonists are known to the person skilled in the art, for example from EP 1 306 088 B (candesartan and furosemide), but also the following fixed-dose combinations for treating high blood pressure such as, for example, Hyzaar® (=losartan potassium plus HCTZ) from Merck, Co-Diovan® (=valsartan plus HCTZ) from Novartis or Boehringer's Micardis Plus® (=telmisartan plus HCTZ).
In view of the biological properties of nifedipine and/or nisoldipine and the angiotensin II antagonists, it is crucial for both active ingredients to be absorbed from the low sections of the bowel without significant loss of bioavailability. This is the case with only about 30-50% of all active ingredients, and therefore appropriate selection of the combination active ingredients is crucially important for developing an IR/slow-release combination product.
It is advantageous especially for the long-term therapy or prophylaxis and secondary prophylaxis of cardiovascular disorders to have the active ingredients available in a form which, through a modified release of active ingredients, leads to a reduction in the peak-trough ratio and makes administration once a day possible.
In the development of formulations, account must also be taken of the physicochemical and biological properties of the active ingredients, for example the relatively low water solubility of nifedipine (approx. 9 mg/l) and the plasma half-life of about 2 hours. Accordingly, special pharmaceutical formulations with which nifedipine undergoes a modified release, taking account of its physicochemical and biological properties, are necessary for the desired administration once a day.
In the sense of the present invention the term release in the body in a controlled (modified) manner with respect to nifedipine has the meaning that 85% nifedipine (based on the declared amount of nifedipine) is released from the dosage form over a period of at least 4 and at most 24 hours, and less than 20% of the nifedipine within 4 hours, and from 43 to 80%, more preferably from 45 to 75%, in particular preferably from 50 to 70% of the nifedipine within 12 hours in an in-vitro release test carried out according to the USP release method using apparatus 2 (paddle) at 100 revolutions per minute in 900 mL of phosphate buffer pH 6.8 with addition of 1% sodium lauryl sulphate as the release medium at 37° C.
In the sense of the present invention the term release in the body is rapid (immediate release (IR)) with respect to candesartan cilexetil and/or a diuretic has the meaning that that at least 70%, preferably at least 80% of the candesartan cilexetil (based on the declared amount of the candesartan cilexetil) is dissolved within a period of 60 minutes in an in-vitro dissolution test carried out according to the USP dissolution method using apparatus 2 (paddle) at 75 revolutions per minute in 900 mL phosphate buffer pH 6.5 with the addition of 0.7% Tween 20 as the dissolution medium at 37° C.
In the sense of the present invention the term release in the body is rapid (immediate release (IR)) with respect to a diuretic has the meaning that that at least 70%, preferably at least 80% of the HTCZ (based on the declared amount of the HTCZ) is dissolved within a period of 60 minutes in an in-vitro dissolution test carried out according to the USP dissolution method using apparatus 2 (paddle) at 75 revolutions per minute in 900 mL phosphate buffer pH 6.5 with the addition of 0.7% Tween 20 as the dissolution medium at 37° C.
Combinations of an angiotensin II antagonist and, firstly, calcium channel blockers or, secondly, diuretics are known from WO 92/10097. Explicitly described are the combinations of eprosartan and nifedipine and eprosartan and hydrochlorothiazide. Specifically disclosed are fast-release hard gelatine capsules and tablets.
Combinations of candesartan cilexetil and hydrochlorothiazide are disclosed in EP 0 753 301B.
Dosage forms releasing the active compounds nifedipine or nisoldipine in combination with an angiotensin II antagonist in modified/delayed form and their preparation are described, for example, in WO 2007/003330. In these formulations, both nifedipine and the angiotensin II antagonist are released in delayed form.
WO2008/044862 discloses pharmaceutical dosage forms comprising an active ingredient combination of at least one calcium channel blocker and at least one angiotensin II antagonist characterized in that the calcium channel blocker is released after a certain lag time immediately whereas the angiotensin II antagonist is released immediately (chronotherapy). Explicitly disclosed are the combinations of losartan and amlodipine.
WO2010/060564 discloses pharmaceutical dosage forms comprising an active ingredient combination of nifedipine or nisoldipine and at least one angiotensin II antagonist and/or at least one diuretic, characterized in that nifedipine or nisoldipine is released in the body in a controlled (modified) manner and the angiotensin II antagonist and/or the diuretic is released rapidly (immediate release (IR)), and also processes for their preparation, to their use as medicaments and to their use for the prophylaxis, secondary prophylaxis or treatment of disorders.
Particularly suitable dosage forms with modified/delayed release of the active ingredient nifedipine are based on osmotic release systems. Preferably, in these osmotic release systems, bi-layer tablets are surrounded by a semipermeable membrane which has at least one orifice. The water-permeable membrane is impermeable for components of the core, but allows water to enter the system from outside by osmosis. The water which has penetrated in then releases, by the resulting osmotic pressure, the active ingredient in dissolved or suspended form from the orifice(s) in the membrane. The overall active ingredient release and the release rate can be controlled substantially via the thickness and porosity of the semipermeable membrane, the composition of the core and the number and size of the orifice(s). Advantages, formulation aspects, use forms and information on production processes are described inter alia in the following publications: U.S. Pat. Nos. 4,327,725, 4,765,989, US 20030161882, EP 1 024 793.
Coated osmotic release systems are likewise known. Thus, EP 0 339 811 describes an osmotic release system consisting of a cellulose acetate coat which comprises nifedipine and swelling agent in the core and is surrounded by a mantle coating of HPMC (hydroxypropylmethylcellulose) having a layer thickness of 0.0025 cm. U.S. Pat. No. 4,948,592, WO 93/03711 and WO 93/00071 describe osmotic release systems comprising a proportion of active ingredient in the core with a delayed release profile and a proportion of the same active ingredient in the mantle coating which can be released directly. Here, the mantle coatings comprise in each case only a small part of the total amount of active ingredient required for pharmaceutical activity. In such case, the pharmacopoeial requirements for content uniformity of dosage forms apply to the total amount of the active ingredient, to the sum of active ingredient in the core and in the mantle coating. Thus, the overall content variability of the active ingredient is somewhere between the typically low variability of tablets prepared by compression and the typically high variability of products prepared by film coating.
When rapid release of a second active ingredient is required, it is necessary to incorporate the entire amount of the second active ingredient into the outer mantle layer of the dosage form. In such cases, i.e. mantle coatings that contain the total amount of an active ingredient (active coatings), the pharmacopoeial requirements for content uniformity of dosage forms solely apply to the amount of the active ingredient in the mantle coating.
It is well known to those skilled in the art that pharmaceutical film coating processes typically result in a higher variability with regard to the mass of the film coating as compared to for example tableting processes with regard to the mass of the tablet cores. This is mainly due to the fact that film coating is a batch process. In a tableting process each single tablet is produced under the same conditions and thus, the variability of the tablet mass is typically low, i.e. relative standard deviations of the tablet mass are typically below 3%, in most cases even below 1.5%. In a pharmaceutical film coating process a complete batch of tablets is coated during a limited time and the film coating mass applied to each single tablets depends on how often and for how long time periods that specific tablets is exposed to the spraying zone. For that reason, the variability of the film coating mass is typically high, i.e. relative standard deviations of the film coating mass are generally above 5% and typically above 7.5% and often even above 15%. As film coatings are often used for cosmetic reasons only (e.g. colour and smooth surface), the high variability is not regarded as critical to the quality. This is also not the case when film coatings are used to protect the tablet from environment effects; in such cases the only requirement is that all tablets are sufficiently protected. In the case of modified release coatings, the film coating mass needs to be controlled in such a way that the variability of the drug release profile is acceptable. This can generally be achieved although the typical high variability of the film coating mass, as the sensitivity of the release profile variability to the film coating variability is less than proportional.
Furthermore, it is well known to those skilled in the art that pharmaceutical film coating processes typically exhibit a certain loss of coating suspension during spraying, i.e. a small but variable and hardly predictable portion of the sprayed coating suspension is deposited on the surface of the coater drum or removed with the exhaust air instead of being deposited on the tablets. In the cases of cosmetic and protective film coatings such losses are typically compensated by predefined overages of e.g. 5-15%. Also in the case of modified release coatings, overages are well established to compensate losses during spraying as the sensitivity of the release profile to the overall film coating mass is less than proportional.
However, in the case of active coatings (and especially if the active ingredient is solely present in the active coating), the inherent variability of the coating process and the poor predictability of spraying losses during manufacturing is in conflict with the pharmacopoeial requirements for content uniformity. Moreover, the pharmacopoeial requirements have become even stricter recently.
Challenges in developing fixed dose combinations using active coating technology are discussed by Desai et al., Pharmaceutical Development Fundamentals: Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms, Pharmaceutical Development and Technology, 1-12 (2012). Chen et al., Modeling of pan coating process: Prediction of tablet content uniformity and determination of critical process parameters, Journal of Pharmaceutical Sciences 99, 3213-24 (2010) provide an overview on factors influencing the coating uniformity. Remarkably, according to these predictions acceptable coating uniformity is only achieved after undesirably long spraying times, such as e.g. up to 1200 min, i.e. 20 hours. Specific examples of active coating applications relating to selected active ingredients, specific coating polymers and specific tablet cores to be coated, are provided in US 2005/0214373 A1, US 2005/0266080 A1, and WO 2012/031124 A2. No general guidance how to optimize process conditions in order to improve active coating processes with regard to content uniformity and determination of coating endpoint are provided therein. Furthermore, coating efficiency is regarded a specific challenge in active coating processes; e.g. Wang et al., An evaluation of process parameters to improve coating efficiency of an active tablet film-coating process, International Journal of Pharmaceutics 427, 163-169 (2012) describe means to optimize coating efficiency.
In the European Pharmacopoeia the requirements for the content uniformity of tablets used to be described in the general chapter 2.9.6 Uniformity of content of single-dose preparations. The acceptance criterion was that out of 10 tablets, all individual assays should be in the range of 85% to 115% of the average assay, or—as stage 2 testing—out of 30 tablets, all individual assays should be in the range of 75% to 125% of the average assay, and not more than 1 tablet should be outside the range of 85% to 115% of the average assay.
However, a new and stricter requirement has been introduced into the European Pharmacopoeia in the Supplement 5.2 as a new general chapter 2.9.40 Uniformity of dosage units. Therein, an acceptance value (AV) is defined as follows:AV=|M−X|+ks wherein X is the mean of the individual contents, M is the reference value, k is the acceptability constant and s is the sample standard deviation. The reference value is depending on the experimental results for X:                if X is between 98.5% and 101.5%, then M=X;        if X is below that range, then M=98.5%;        if X is above that range, then M=101.5%.
For example, if X is 97.5%, the term |M−X| results in 1%. Similarly, if X is 102.5%, the term |M−X| also results in 1%. For that reason, it is preferred that X is as close to 100% as possible, and it is particularly preferred that X is within the range of 98.5% to 101.5%.
The pharmacopoeial requirement is that AV should not exceed 15%. The test is first performed for n=10 tablets and the AV value is calculated using an acceptability constant of k=2.4. If this test fails, further 20 tablets can be investigated and the AV value for all n=30 tablets is calculated using an acceptability constant of k=2.4. In other words, in order to meet the new strict pharmacopoeial requirements for content uniformity, the mean value of the individual contents should be as close to the range of 98.5%-101.5% as possible. Simultaneously it is also necessary to control the standard deviation of the individual content below 7.5%, preferably significantly below 7.5%.
In addition to the AV requirement it is also required that all individual assays should be in the range of 75% to 125%.
Thus, there is a need to provide manufacturing processes for the dosage form comprising nifedipine and candesartan cilexetil and optionally a diuretic like HTCZ for all scales of pharmaceutical manufacturing that reliably and reproducibly lead to products fulfilling the pharmacopoeial requirements regarding content uniformity of the active ingredient solely present in an active coating. In other words, there is a need to provide active coating processes for all scales of pharmaceutical manufacturing that reliably and reproducibly control the mean of individual contents close to 100% and the respective standard deviation as low as possible, with an inter-tablet variability of the candesartan cilexetil content of less than 5%, preferably less than 4.8%, more preferably less than 4.5%.
It is well known to those skilled in the art, that as a means to improve the uniformity of active ingredient distribution, the active ingredient can be employed in a small particle size. For example, the active ingredient can be used in micronized form. However, in some cases micronization can negatively influence the stability of active ingredients. Without wishing to be limited to any specific theory, this may be due to the increase of reactive surface and/or partial amorphization during micronization, even if such amorphization occurs in a very low and hardly detectable extent.
In US 2007/0082055, it is disclosed that particle size reduction of candesartan cilexetil has an adverse effect on its chemical stability, namely micronization gives rise to the levels of the desethyl compound. In US 2007/0082055, it is further disclosed that the stability of candesartan cilexetil can be improved by a process comprising slurrying a sample of candesartan cilexetil of fine particle size in a suitable solvent for a suitable amount of time and recovering stable candesartan cilexetil of fine particle size.
WO 2008/045006 disclose the stabilization of candesartan cilexetil via the use of antioxidants. WO 2005/070398, WO 2005/084648, WO 2005/079751, and US 2010/0041644 disclose the stabilization of candesartan cilexetil by the use of several compounds, including esters, fatty substances, co-solvents and water-soluble polymers. WO 2005/084648 also mentions the potential use of polyvinyl alcohol.
Thus, there is a need to provide manufacturing processes for the dosage form comprising nifedipine and candesartan cilexetil and optionally a diuretic like HTCZ for all scales of pharmaceutical manufacturing that reliably and reproducibly lead to chemically stable products fulfilling the pharmacopoeial requirements regarding content uniformity of the active ingredient solely present in an active coating.
Terahertz pulsed imaging (TPI) is a recent non-destructive measurement technique that can be used to determine the coating thickness on pharmaceutical tablets. As an imaging technique it can spatially resolve the distribution of the coating layer over the entire surface of a tablet. The technique works by using short pulses of terahertz radiation (FWHM<1 ps), that are focused onto the surface of a tablet. Polymers are semitransparent to terahertz radiation and hence a part of the pulse can penetrate into the coating while the other part of the pulse is reflected to the detector. At every subsequent interface where a change in refractive index occurs, further parts of the pulse are reflected back and can be detected as additional reflection pulses (FIG. 2). Using the time-delay between the reflection pulses, the coating thickness of the material can be calculated. Detailed information about the measurement are dislosed in Zeitler et al., Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting—a review. Journal of Pharmacy and Pharmacology 59, 209-223 (2007). Ho et al., Analysis of sustained-release tablet film coats using terahertz pulsed imaging, Journal of Controlled Release 119, 253-261 (2007) discloses a good agreement between coating thickness measurements obtained by TPI and microscopic reference data.
Ho et al., Monitoring the film coating unit operation and predicting drug dissolution using terahertz pulsed imaging, Journal of Pharmaceutical Sciences 98, 4866-4876 (2009) discloses the use of TPI technique to monitor the growth of the coating layer with process time during a coating run in off-line measurements.
May et al., Terahertz in-line sensor for direct coating thickness measurement of individual tablets during film coating in real-time, Journal of Pharmaceutical Sciences 100, 1535-1544 (2011) discloses the use of this technology to measure the coating thickness of individual tablets during a coating run (in-line). There are however no reports on the applicability of TPI measurements for thick coating layers (>200 μm) or active coating processes yet.
Both, NIR and Raman spectroscopy are known as a process analytical technology (PAT) tool for a variety of applications such as end point determination in blending, process control of granulation, drying and coating operations. De Beer et al., Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes, Int. J. Pharm. 417, 32-47 (2011) summarizes the state of the art in that respect.
NIR spectroscopy is being discussed as a powerful process analytical technology tool for more than a decade. Gendre et al., Development of a process analytical technology (PAT) for in-line monitoring of film thickness and mass of coating materials during a pan coating operation, Eur. J. Pharm. Sci. 43, 244-250 (2011) and Gendre et al., Real-time predictions of drug release and end point detection of a coating operation by in-line near infrared measurements, Int. J. Pharm. 421, 237-43 (2011) disclose the use of NIR spectroscopy to in-line monitor the film thickness and the corresponding effect on in vitro-release of modified release coatings. Active coatings are however not disclosed. Kim et al., Investigation of an active film coating to prepare new fixed-dose combination tablets for treatment of diabetes describe active film coatings containing glimepiride and the use of off-line NIR spectroscopy to monitor the coating process. Content uniformity data are however not reported while reported single values range from 93.1 to 108.1%. Accordingly, FIGS. 6 and 7 of Kim et al. also display significant variability.
The use of Raman spectroscopy as a potential process analytical technology tool has been proposed more recently. In comparison to NIR spectroscopy, Raman spectroscopy offers higher structural selectivity. Müller et al., Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging, Eur J Pharm Biopharm. 80, 690-697 (2012) disclose the use of Raman spectroscopy to in-line monitor the film thickness and the corresponding effect on in vitro-release of modified release coatings. Müller et al., Feasibility of Raman spectroscopy as PAT tool in active coating. Drug. Dev. Ind. Pharm. 36, 234-243 (2010) and Müller et al., Validation of Raman spectroscopic procedures in agreement with ICH guideline Q2 with considering the transfer to real time monitoring of an active coating process, J. Pharm. Biomed. Anal. 53, 884-894 (2010) disclose the use of Raman spectroscopy to determine the amount of coatings containing the active pharmaceutical ingredient diprophylline. The active coatings were applied to uniform cores in these studies. Active coatings on bilayer tablets are however not disclosed. Obviously, bilayer tablet cores provide an inhomogeneous background for any spectroscopic measurements.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step, especially onto bilayer tablet cores.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step, especially onto bilayer tablet cores comprising Nifedipine.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step for candesartan cilexetil, especially onto bilayer tablet cores comprising Nifedipine.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step for candesartan cilexetil, especially onto osmotic release bilayer tablet cores comprising Nifedipine.

Process for manufacturing a pharmaceutical dosage form comprising nifedipine and candesartan cilexetil